Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1324-1332. eCollection 2020.
Potential clinical value of interleukin-31 and interleukin-33 with their receptors expression as diagnostic and predictive factors in endometrial cancer: a case-control study
Xi Zeng 1 2, Jing Li 3, Le-Ni Kang 2 4, Ming-Rong Xi 1 2, Guang-Dong Liao 1 2
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PMID: 32661468 PMCID: PMC7344009
Free PMC article
Abstract
Aims: To evaluate the potential role of interleukin-31 and interleukin-33 in diagnosis and prognosis from endometrial cancer. Methods: Tissue samples and clinical data were collected from 260 patients with endometrial cancer and 150 control patients with benign uterine diseases. Immunohistochemistry and ELISA testing quantified the expressions of interleukin-31 and interleukin-33 and their receptors. After surgery, all patients were followed up for an average of 56.3 months. Surgical effects were evaluated based on the patients' symptoms and signs. A two-sided P value <0.05 was considered significant. Results: IL-31, IL-33 and their receptors were significantly accumulated with the progression of endometrial cancer, in comparison to the controls. Moreover, the expressions were correlated with clinical characteristics, including tumor stage, differentiation, and associated with patients' disease-free survival. Conclusions: Limited data was available between the expressions of IL-31 and IL-33 and the receptors in patients with endometrial cancer. Our study findings suggested that the expressions of IL-31 and IL-33 might become possible biomarkers for the diagnosis and prediction in endometrial cancer.

Keywords: IL-31/IL-31R; IL-33/ST2; biomarkers; endometrial cancer.

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2
Int J Clin Exp Pathol
. 2020 May 1;13(5):1053-1059. eCollection 2020.
Borderline ovarian tumor in the pediatric and adolescent population: a clinopathologic analysis of fourteen cases
Mengwei Xu 1, Bowei Wang 2, Yonghua Shi 1
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PMID: 32509078 PMCID: PMC7270684
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Abstract
Borderline ovarian tumors (BOTs) are rare among children and adolescents. This study was to probe into the clinicopathologic characteristics and prognosis in children and adolescents with BOT. A retrospective investigation was performed on 14 adolescents younger than age 21 years diagnosed with BOT. Clinical presentation, preoperative characteristics, surgery, tumor stage, histology, and recurrence were collected. The results showed that median age at diagnosis was 17.5 years, mostly after menarche. Abdominal mass/pain were the most common presenting symptoms. Median tumor size was 14 cm. Cancer antigen-125 (CA-125) in the blood serum was elevated by 41.67% (5/12), and CA-199 was elevated by 16.67% (2/12). All patients had fertility-preserving surgery: 66.67% (8/12) via laparoscopy (LSC) and cystectomy, 33.33% (4/12) via laparotomy and unilateral salpingo-oophorectomy (USO), and 1 case recurred, and underwent panhysterectomy and bilateral salpingo-oophorectomy. 4 out of 14 tumors (28.57%) had serous and 10 of 14 (71.43%) had mucinous histology. Five tumors showed histological microinvasion. Median follow-up time was 52 months. 10 of 14 cases were alive at last follow-up without disease, and 4 of 14 cases were at lost visit. Thus BOTs in children and adolescents are very rare tumors which have excellent prognosis even in advanced stages, when managed with fertility-preserving procedures. Close follow-up is important because of the high recurrence rates many years after diagnosis.

Keywords: Borderline ovarian tumor; adolescent; pediatric.

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3
Int J Clin Exp Pathol
. 2020 May 1;13(5):1024-1029. eCollection 2020.
Expression of nm23-H1, p53, and integrin β1 in endometriosis and their clinical significance
Renjie Duan 1, Yue Wang 1, Aiqin Lin 1, Likai Lian 1, Huiru Cao 1, Wenjie Gu 1, Tiechen Li 1, Qing Sun 2
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PMID: 32509074 PMCID: PMC7270686
Free PMC article
Abstract
To investigate the expression and clinical significance of nucleoside diphosphate kinase A (nm23-H1), p53, and integrin β1 in endometriosis, normal and ectopic endometrial tissues were collected and the levels of nm23-H1, p53, and integrin β1 proteins were detected by western blotting. We also measured the mRNA expression of nm23-H1, p53, and integrin β1 in endometrial epithelial cells by droplet digital PCR, based on endometrial tissues using laser capture microdissection. Moreover, primary stromal cells from normal and ectopic endometrial tissues were also cultured and treated with different concentrations of estrogen. We assessed the mRNA levels of nm23-H1, p53, and integrin β1 by quantitative PCR. Compared with normal endometrial tissue, the levels of nm23-H1 and p53 proteins were significantly downregulated in ectopic endometrial tissues, while integrin β1 protein was upregulated. The same expression trend in the mRNA levels of nm23-H1, p53, and integrin β1 was also observed in both endometrial epithelial cells and stromal cells. In addition, with increasing estrogen concentration, nm23-H1 and p53 mRNA levels gradually decreased, while integrin β1 mRNA expression increased. Nm23-H1 and p53 may inhibit the progression of endometriosis, while integrin β1 has a promoting effect, and estrogen is involved in this process.

Keywords: Nm23-H1; endometriosis; estrogen; integrin β1; p53.

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4
Int J Clin Exp Pathol
. 2020 May 1;13(5):1146-1158. eCollection 2020.
FOXO1 and hsa-microRNA-204-5p affect the biologic behavior of MDA-MB-231 breast cancer cells
Chang-Yu Liang 1, Zhi-Guang Huang 1, Zhong-Qing Tang 2, Xiao-Ling Xiao 1, Jing-Jing Zeng 1, Zhen-Bo Feng 1
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PMID: 32509089 PMCID: PMC7270695
Free PMC article
Abstract
RNA molecules and targeting microRNA (miRNA) have been reported as novel focuses in recent research on breast cancer. This study aimed to probe the expression of FOXO1 in the MDA-MB-231 cell line and to explore the target effects of FOXO1 with hsa-microRNA-204-5p (miR-204) on the biologic behavior of MDA-MB-231 cells. The expression of FOXO1 mRNA and protein in MDA-MB-231 cells were derived and verified from the public databases, literature, and experimental assays, then the downregulation of FOXO1 was confirmed in the MDA-MB-231 cell line. The target binding of FOXO1 and miR-204 was predicted by miRWalk and confirmed by luciferase reporter assays. MiR-204 targeted the 3' untranslated region of FOXO1 and reduced FOXO1 expression in miR-204-transfected cells, resulting in cell growth amplification but inhibition of cell migration and apoptosis, which were assessed using the MTT method, wound healing assays, and flow cytometry, respectively. The protein levels of serine-threonine kinase (AKT), c-jun N-terminal kinase (JNK), extracellular regulatory protein kinase (ERK), and the phosphorylated protein kinases (P-AKT, P-JNK, and P-ERK) were measured by western blot. It was found that AKT, JNK, and ERK remained constant, but P-AKT, P-JNK, and P-ERK were upregulated after miR-204 transfection. In summary, the expression of FOXO1 was downregulated in MDA-MB-231 cells; and the target binding of miR-204 and FOXO1 affected phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signal pathways, leading to different alterations of cellular activity in MDA-MB-231 cells.

Keywords: FOXO1; MDA-MB-231; biological behavior; miR-204.

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5
Int J Clin Exp Pathol
. 2020 May 1;13(5):989-994. eCollection 2020.
The role and mechanism of gastrodin in the medial prefrontal cortex autophagy of PTSD rats
Xiuwen Lei 1 2, Yefeng Yuan 1, Qin Zou 1
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PMID: 32509070 PMCID: PMC7270697
Free PMC article
Abstract
Background: This study provided a reliable experimental basis for exploring the pathogenesis of PTSD-induced memory impairment, fear abnormalities, and affective disorders, aiming to facilitate new thinking for the prevention, treatment, and drug development of clinical PTSD.

Material and methods: A rat model of PTSD was established by continuous single stress stimulation method. The Morris water maze was used to detect the learning and spatial memory exploration abilities of rats. The autonomic motion behavior, fear, and anxiety of rats in each group was detected by the elevated plus maze test and the open field test. The immunofluorescence method was employed to observe and detect the changes of autophagy in mPFC neurons of PTSD rats. Western blotting was used to detect the expressions of autophagy-related genes Beclin-1 and LC3, autophagy substrate p62 protein, and apoptosis-related factors Bcl-2 and Bax.

Result: Gastrodin could improve the learning and spatial memory abilities of PTSD-SPS rats, the reduction of active movement and inquiry behavior, and the autophagy of mPFC neurons, and also increase the expressions of Beclin-1, LC3-I, LC3-II, and Bax proteins, as well as decrease the expressions of Bcl-2 and p62.

Conclusions: Gastrodin is effective in the treatment of PTSD-induced memory impairment, fear abnormalities, and affective disorders. The mechanism is related to autophagy in mPFC neurons.

Keywords: Gastrodin; PTSD; autophagy; medial prefrontal cortex.

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6
Int J Clin Exp Pathol
. 2020 May 1;13(5):1008-1016. eCollection 2020.
Association of CD44 and CD24 phenotype with lymph node metastasis and survival in triple-negative breast cancer
Weiyan Zou 1, Yan Yang 2, Rongsheng Zheng 2, Zishu Wang 2, Huihui Zeng 2, Zhelong Chen 3, Fen Yang 4, Junbin Wang 2
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PMID: 32509072 PMCID: PMC7270704
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Abstract
Background: CD44+CD24-/low phenotypes are associated with poor outcome of triple-negative breast cancer (TNBC); however, the role of the CD44+CD24-/low phenotype in lymph node metastasis and survival has not been fully understood in TNBC.

Methods: A total of 51 TNBC patients were included. CD44 and CD24 expression was determined using immunohistochemistry by which CD44 and CD24 were double-immunostained. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method.

Results: The proportion of the CD44+CD24-/low phenotype was 33.3% in TNBC specimens without lymph node metastases and 69.0% in those with lymph node metastases. In addition, the CD44+CD24-/low phenotype correlated significantly with tumor size, histologic classification, TNM stage, and lymph node metastasis (P < 0.05). The CD44+CD24-/low phenotype was detected in 69.0% of TNBC patients with lymph node metastases, and 51.7% of TNBC patients without lymph node metastases. In TNBC patients without lymph node metastases, the median DFS and OS were 18.2 and 28 months in cases with a CD44+CD24-/low phenotype and 26.5 and 42.5 months in those without a CD44+CD24-/low phenotype (P < 0.05), and in TNBC patients with lymph node metastases, the median DFS and OS were 17.2 and 25.7 months in cases with a CD44+CD24-/low phenotype and 24.5 and 39.3 months in those without a CD44+CD24-/low phenotype, respectively (P < 0.05).

Conclusions: CD44 and CD24 are independent prognostic markers for patients with TNBC. The CD44+CD24-/low phenotype correlates with more aggressive clinicopathologic features and is strongly associated with poor prognosis in patients with TNBC.

Keywords: CD24; CD44; Triple-negative breast cancer; cancer stem cells; lymph node metastasis; survival.

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7
Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1287-1299. eCollection 2020.
The impact of exogenous testosterone supplementation on spermatogenesis in a rat model of oligoasthenospermia
Qi An 1 2, Kaishu Zhang 3, Longlong Fu 2, Ying Guo 2, Changyong Zhang 4, Zhengyan Ge 5, Jing Ma 6, Yiqun Gu 1 2, Liandong Zuo 7
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PMID: 32661465 PMCID: PMC7344011
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Abstract
Oligoasthenospermia is one of the main causes of infertility in reproductive-age men. This study aimed to explore the feasibility of exogenous testosterone supplemental therapy (TST) for adult male rats with oligoasthenospermia model. The rats (n=40) were randomized equally into 4 groups: control group, model group, low-dose and high-dose groups (n=10, respectively). After establishment of an oligoasthenospermia model that was treated with glucosides of tripterygium wilfordii (GTWs), the low-dose and high-dose groups were treated with 2 testosterone undecanoate (TU) injections at doses of 7.5 mg and 15 mg for 8-week period (4-week intervals). Body weights, serum reproductive hormone levels, sperm measurements in the epididymis, and testis histology were monitored. The TU injections increased serum testosterone levels steadily. The epididymis sperm concentration and motility increased slowly in high dose group at 4-weeks whereas sperm measurements increased significantly in the TST groups at 8 weeks. In addition, exogenous TST increased the intra-testicular testosterone concentration somewhat and alleviated the testicular oxidative stress markers of Malondialdehyde (MDA) and level of GSH-PX (Glutathione Peroxidase) after 8 weeks treatment. The improvement of sperm and testicular function acted mainly by curbing mitochondrial apoptosis in the testis by modulation of Bcl-2, Bax, Caspase-3, and Caspase-9 expression. However, the results of immunohistochemistry and western blotting in the low-dose group were still lower than control values. TST at an appropriate dose within a period of 8 weeks was effective to stimulate spermatogenesis and alleviate inflammation, oxidative stress, and apoptosis through suppression of testis damage in this rat model of oligoasthenospermia.

Keywords: Oligoasthenospermia; glucosides of tripterygium wilfordii (GTWs); sperm; testosterone undecanoate (TU).

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8
Int J Clin Exp Pathol
. 2020 May 1;13(5):1176-1184. eCollection 2020.
Aberrant expression of WWOX and its association with cancer stem cell biomarker expression
Yunzhi Zhai 1, Yajuan Han 1, Zhengquan Han 1
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PMID: 32509092 PMCID: PMC7270669
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Abstract
Background: Nanog and CD133 are biomarkers of cancer stem cells (CSCs) that regulate cancer progression. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor protein that can inhibit tumor cell proliferation. The purpose of this study was to investigate the expression and clinical significance of Nanog, CD133, and WWOX in infiltrating breast cancer (IBC).

Methods: Expressions of Nanog, CD133, and WWOX in 204 IBC specimens and their corresponding control specimens were detected by immunohistochemistry. Patients' clinicopathologic and follow-up data were also collected.

Results: The rates of positive expression of Nanog and CD133 were significantly higher in IBC specimens than in control specimens, and their expression was positively associated with tumor size, grade, and tumor stages, lymph node metastasis (LNM), and tumor-node-metastasis (TNM) stage. The rate of positive expression of WWOX was significantly lower in IBC specimens than in control specimens, and its expression was inversely associated with tumor size, grade, and tumor stages, LNM, and TNM stage. Patients whose specimens expressed Nanog, CD133, or HER2 had a reduced overall survival (OS) when compared with patients not expressing these proteins. However, patients whose specimens expressed WWOX, ER, or PR had an increased OS when compared with patients who did not show expression. Multivariate analysis demonstrated that expression of Nanog, CD133, WWOX, ER, and HER2, and the TNM stage were independent prognostic factors for IBC patients.

Conclusions: Therefore, Nanog, CD133, and WWOX should be considered as promising prognostic factors and therapeutic targets in IBC.

Keywords: CD133; Infiltrating breast cancer; Nanog; WWOX; cancer stem cells; prognosis.

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9
Int J Clin Exp Pathol
. 2020 May 1;13(5):827-836. eCollection 2020.
Combination of astragaloside IV and ACEi ameliorates renal injuries in db/db mice
Hongyue Zhan 1 2, Pengxun Han 1, Menghua Wang 1, Yao Wang 1, Wenci Weng 1, Xuewen Yu 3, Changjian Yuan 1, Yuyan Li 1, Mumin Shao 3, Huili Sun 1
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PMID: 32509053 PMCID: PMC7270657
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Abstract
Evidences demonstrated that the effect on anti-proteinuria and renal protection of Chinese herbs combination with ACEi or ARB seemed to be better than ACEi or ARB alone. Astragaloside IV could decrease the urinary albumin excretion rate and could protect against renal injuries linking to its anti-oxidation ability. We aimed to investigate the effect of astragaloside IV combined with ACEi on diabetic nephropathy and to explore whether its underlying mechanism is dependent on anti-oxidation. 8-week-old male experiment mice were randomly assigned to five groups: lean wild type (wt) group, db/db group, db/db + astragaloside IV group, db/db + enalapril group, db/db + combination therapy with astragaloside IV and enalapril group. During the experiment, 24 hours urinary albumin, fasting glucose, body weight, and metabolic parameters were monitored in regular intervals. At the end of the study, tail blood pressure, serum H2O2, lipid, and liver function were measured and kidney histological injuries were evaluated. Results of the study indicated that combination therapy with astragaloside IV and ACEi further reduced 24 hours urinary albumin excretion rate, blood pressure, and body weight. Combination therapy reduced the foot process width, glomerular base membrane thickness, glomerular tuft cell proliferation, tubular cell atrophy, tubular base membrane thickness, and improved tubular cell proliferation. It modulated the body H2O2 metabolism and up-regulated the expression of the catalase in renal cortex. Astragaloside IV combined with ACEi exerted renal protective effects in db/db mice more significantly than their individual used. The mechanism possibly involved their synergistic effects on anti-oxidation.

Keywords: Diabetic nephropathy (DN); angiotensin-II converting enzyme inhibitor (ACEi); astragaloside IV (AS-IV); combination therapy; reactive oxygen species (ROS).

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10
Int J Clin Exp Pathol
. 2020 May 1;13(5):1197-1205. eCollection 2020.
Expression and clinical significance of Gal-3 and NFκB pathway-related factors in epithelial ovarian carcinoma
Hiu-Mei Luk 1, Dong-Yan Wang 2, Ling-Ling Xie 2, Xun-Yun Liu 2, Guo-Cai Xu 2, Huai-Wu Lu 2
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PMID: 32509095 PMCID: PMC7270682
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Abstract
Objective: To explore the expression and clinical significance of Gal-3 and NFκB pathway related factors in epithelial ovarian carcinoma cells.

Methods: 99 histologic specimens of epithelial ovarian cancer and 20 normal ovarian histologic specimens were collected, and the expressions of Gal-3, IκB and p65 were detected by immunohistochemistry. Their relationship with clinical characteristics was analyzed.

Results: The expression of Gal-3 and p65 was negatively correlated with the overall survival rate (P<0.05), while the expression of IκB was positively correlated with the overall survival rate (P<0.05). Expression of Gal-3, p65 and IκB were found associated with EOC platinum resistance (P<0.05), and expression of Gal-3 and p65 correlated with pathologic grading (P<0.05). IκB and Gal-3 were associated with the recurrence of EOC (P<0.05). IκB may be related to clinical stage (P<0.05). Multivariate analysis results showed that abnormal expression of Gal-3 may be an independent prognostic risk factors for the drug resistance to platinum-based chemotherapy (95% CI=5.336~34.112, P<0.05). The expression of Gal-3, p65, and IκB can be clinical immunohistochemical indicators that determine the prognosis of EOC, but the amount of Gal-3 expression was related to the epithelial ovarian cancer's pathologic type and overall survival, which suggested that Gal-3 can be used as a prognostic factor in epithelial ovarian cancer.

Conclusion: Targeted therapy of Gal-3 may become an effective potential new method against epithelial ovarian cancer.

Keywords: Galectin-3; IκB; clinical prognosis; epithelial ovarian cancer; p65.

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11
Int J Clin Exp Pathol
. 2020 May 1;13(5):923-933. eCollection 2020.
Oncogenic and prognostic role of CKAP2L in hepatocellular carcinoma
Penghui Wang 1 2, Xiaodong He 1
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PMID: 32509063 PMCID: PMC7270663
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Abstract
Cytoskeleton-associated protein 2-like (CKAP2L) exerts crucial function in the cell-cycle progression and mitotic spindle formation of neural stem/progenitor cells. However, in hepatocellular carcinoma (HCC), the expression pattern, clinical significance and biologic role of CKAP2L remain unexplored. We analysed The Cancer Genome Atlas (TCGA) database and found that CKAP2L was dramatically upregulated in HCC tissues at the mRNA level compared to adjacent tissues, which was validated in 48 paired HCC and para-tumor tissues using quantitative real-time PCR (qRT-PCR). Immunohistochemical analysis of tissue microarray revealed that CKAP2L was also significantly overexpressed at the protein level. Further clinical and survival analysis of the TCGA cohort revealed that increased CKAP2L expression was strongly associated with reduced overall survival. We further validated that higher CKAP2L protein expression was associated with worse prognosis in the Peking Union Medical College Hospital (PUMCH) cohort. Univariate and multivariate Cox regression analyses in the TCGA and PUMCH cohort suggested that CKAP2L overexpression was an independent risk factor for poor prognosis in HCC patients. Then, we validated that CKAP2L silencing inhibited HCC cell proliferation, migration, and invasion abilities. Knockdown of CKAP2L in Huh7 cells suppressed the growth of xenograft tumors in vivo. Furthermore, qRT-PCR and western blotting results demonstrated that the expression of Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β isoforms reduced obviously in Huh7 cells after depleting CKAP2L. This study demonstrated for the first time that high CKAP2L expression in HCC tissues is significantly correlated with poor prognosis in HCC patients and greatly facilitate the malignancy of HCC, thus providing a new prognostic biomarker and potential therapeutic target.

Keywords: CKAP2L; hepatocellular carcinoma; prognosis; therapeutic target.

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12
Int J Clin Exp Pathol
. 2020 May 1;13(5):1159-1168. eCollection 2020.
Diagnostic performances of the KWAK-TIRADS classification, elasticity score, and Bethesda System for Reporting Thyroid Cytopathology of TI-RADS category 4 thyroid nodules
Supeng Huang 1, Ning Meng 1, Mengting Pan 2, Bo Yu 2, Juan Liu 3, Kailin Deng 3, Mingrong Hu 1, Hongwei Zhou 1, Chao Qin 1
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PMID: 32509090 PMCID: PMC7270670
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Abstract
Objective: To explore the value of the KWAK Thyroid Imaging Reporting and Data System (KWAK-TIRADS), elasticity score (ES), and Bethesda System for Reporting Thyroid Cytopathology (BSRTC) in the diagnosis of suspicious thyroid nodules.

Materials and methods: The study included 392 cases of TI-RADS category 4 thyroid nodules that underwent thyroidectomy between January 2017 and October 2019. All patients underwent ultrasonography, ultrasound elastography, and fine-needle aspiration cytology (FNAC) before surgery. The nodules were classified into different categories based on the KWAK-TIRADS, ES, and BSRTC. Patients were divided into two groups based on postoperative pathological characteristics. The sensitivity (Se), specificity (Sp), and area under the receiver operating characteristic (ROC) curve were calculated. Student's t-test and Pearson chi-square test were used to compare diagnostic performance.

Results: There were 159 patients in the benign group and 233 in the malignant group. The percentage of malignant nodules in KWAK-TIRADS categories 4a, 4b, and 4c were 44.3%, 64.8%, and 92.9%, respectively. The percentages of malignant nodules in ES 2, 3, 4, and 5 were 0%, 37.1%, 93.8%, and 100%, respectively. The percentage of malignant nodules in BSRTC levels I, II, III, IV, V and VI were 57.1%, 2.8%, 9.9%, 76.6%, 99.1%, and 100%, respectively. Among those methods, the BSRTC had better diagnostic efficiency than the KWAK-TIRADS and ES (Sp 81.1%, Se 93.6%, and AUC 0.918, P<0.01). Among the combined methods, KWAK-TIRADS+ES+BSRTC was more effective than KWAK-TIRADS+ES, KWAK-TIRADS+BSRTC, and ES+BSRTC (Sp 93.7%, Se 91.4%, and AUC 0.967, P<0.01).

Conclusion: The combination of KWAK-TIRADS, ES, and BSRTC can improve the accuracy of identifying category 4 thyroid nodules.

Keywords: Bethesda System for Reporting Thyroid Cytopathology; KWAK-TIRADS; diagnosis; thyroid nodule; ultrasonic elastography.

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13
Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1313-1323. eCollection 2020.
Identifying specific miRNAs and associated mRNAs in CD44 and CD90 cancer stem cell subtypes in gastric cancer cell line SNU-5
Hui-Qi Liu 1, Xiong Shu 2, Qiang Ma 1, Rong Wang 1, Ming-Yu Huang 1, Xiang Gao 1, Yong-Nian Liu 1
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PMID: 32661467 PMCID: PMC7344010
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Abstract
Cancer stem cells (CSCs) are capable of generating multiple types of cells and play a vital role in promoting gastric cancer (GC) progression. Our previous research indicated that gastric CSCs with surface markers of CD44+ were more invasive compared to CD44- CD90+ CSCs (CD90+ CSCs), whereas CD90+ CSCs exhibited higher levels of proliferation than CD44+ CSCs. However, the mechanism and characteristics of marker-positive gastric CSCs are poorly understood. In this study, we profiled expression of miRNAs and mRNAs in CD44+ CSCs, CD90+ CSCs, and CD44- CD90- cell subtype (control) from SNU-5 cells by microarray analysis. Our results suggested some specially expressed miRNA-mRNA pairs in CD44+ and CD90+ CSCs. We performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to analyze the correlation and function of those pairs. We also validated the pairs that may play roles in metastasis by qRT-PCR. In CD44+ CSCs, we observed hsa-miR-15b-5p was up-regulated and its target genes AMOT, USP31, KALRN, EPB41L4B, ATP2B2, and EMC4 were down-regulated, which may relate to invasion and migration. In CD90+ CSCs, we observed hsa-miR-3631-3p is up-regulated, while its target genes QKI, TRIM67 and HMGA2 are down-regulated, which is associated with proliferation. We also found that hsa-miR-1910-5p is up-regulated while its target gene QKI and HMGA2 are down-regulated in CD90+ CSCs. The screened miRNA-mRNA pairs give us new insight into the mechanism of different phenotypes and biomarkers capable of identifying and isolating metastatic and tumorigenic CSCs. Those miRNA-mRNA pairs may also act as treatment for GC.

Keywords: CD44; CD90; Gastric cancer (GC); cancer stem cells (CSCs); miRNAs.

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14
Int J Clin Exp Pathol
. 2020 May 1;13(5):1017-1023. eCollection 2020.
Expression of circRNA circ_0026344 in gastric cancer and its clinical significance
Xinrong Zhang 1, Lei Zhang 2, Lihong Cui 1, Ming Chen 1, Dongying Liu 3, Jingjing Tian 1
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PMID: 32509073 PMCID: PMC7270661
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Abstract
Emerging evidence indicates that circular RNAs (circRNAs) are a novel class of biomarkers and therapeutic targets in malignancies. Circ_0026344 has been reported to be downregulated in colorectal cancer, and associated with prognosis. However, little is currently known regarding its expression and clinical significance in gastric cancer. In this study, we evaluated the expression level of circ_0026344 in two previous circRNAs chips (GSE78092 and GSE89143) for gastric cancer. 93 pairs of gastric cancer and adjacent non-tumour tissues were collected, and qRT-PCR was applied to determine circ_0026344 expression. The level of circ_0026344 in gastric cancer cells (MKN45 and AGS) and a normal gastric epithelial cell line (GES-1) was also analyzed. Chi-square test was used to identify the association between circ_0026344 level and clinicopathologic factors. Kaplan-Meier method with log-rank test was applied to compare survival curves. Cox regression analyses were used to assess the prognostic value of circ_0026344. In GSE24549 and GSE24550 datasets, downregulation of circ_0026344 was observed. In 93 cases of gastric cancer, circ_0026344 in cancer tissues was significantly decreased compared to adjacent non-cancerous tissues, and its level was markedly associated with tumour size, lymph node metastasis, TNM stage, and invasive depth. Furthermore, patients with lower expression of circ_0026344 showed significantly worse overall survival than those with higher expression. Additional, circ_0026344 expression was an independent predictor for overall survival. Summarily, our study highlights that downregulation of circ_0026344 is associated with tumour malignant behavior and it is a potential biomarker for gastric cancer prognosis.

Keywords: biomarker; circRNAs; circ_0026344; gastric cancer; prognosis.

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15
Int J Clin Exp Pathol
. 2020 May 1;13(5):1169-1175. eCollection 2020.
Correlation of MMP-9 gene polymorphisms with aneurysmal subarachnoid hemorrhage and its prognosis
Keqi Hu 1, Daquan Zhou 1, Xiangsheng Ao 1, Handong Liu 1, Feng Chen 1, Hongbin Wen 2
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PMID: 32509091 PMCID: PMC7270665
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Abstract
Background: Aneurysmal subarachnoid hemorrhage (aSAH)-associated gene polymorphism is of great significance for the accurate diagnosis and individualized treatment of aSAH. This study aims to investigate the expression of matrix metalloproteinase-9 (MMP-9) gene in the peripheral blood of patients with aneurysmal subarachnoid hemorrhage (aSAH) and explore the correlations of MMP-9 polymorphisms with the onset and prognosis of the disease. Methods: A total of 80 aSAH patients (aSAH group) and 24 healthy (control group) people receiving physical examination were enrolled in the study. Western blotting was applied to detect the expression of MMP-9 gene in the peripheral blood in aSAH patients and healthy people. The genotyping of single nucleotide polymorphisms (rs42512, rs56212 and rs61221) in the promoter region of MMP-9 gene was analyzed by means of conformation-difference gel electrophoresis. Chi-square test was applied to examine the applicability of the distribution frequency of MMP-9 genotypes with genetic equilibrium law. The correlations of MMP-9 alleles and gene polymorphisms with the onset and prognosis of aSAH were determined. Results: The expression of MMP-9 protein in aSAH group was significantly higher than that in control group (P<0.05). The Hardy-Weinberg equilibrium analysis showed that MMP-9 gene polymorphisms were in agreement with the genetic equilibrium law. According to the results of genetic association analysis, only the polymorphism rs42512 and its alleles were significantly correlated with the onset and prognosis of aSAH (P<0.05). However, polymorphisms rs56212 and rs61221 and their alleles had no association with the onset and prognosis of aSAH (P>0.05). Conclusion: The polymorphism rs42512 in the promoter region of MMP-9 gene is related to the onset of aSAH, which provides further evidence for the diagnosis of aSAH.

Keywords: MMP-9; aneurysmal subarachnoid hemorrhage; correlation; gene polymorphism.

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16
Int J Clin Exp Pathol
. 2020 May 1;13(5):901-911. eCollection 2020.
miR-16-5p and miR-145-5p trigger apoptosis in human gingival epithelial cells by down-regulating BACH2
Xiaoming Liu 1, Kai Su 2, Shijun Kuang 2, Min Fu 1, Zhiguang Zhang 2
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PMID: 32509061 PMCID: PMC7270702
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Abstract
Background: Periodontitis is the second most common dental disease worldwide. TNF-α is up-regulated in periodontal disease and induces inflammation and cell apoptosis in gingival epithelial cells (GECs). miRNAs/mRNA axis play an important role in cell progression and inflammation. However, studies on the pathogenesis of periodontitisare still scarce, especially in the regulation mechanism of miRNAs.

Methods: The expression and protein level of miR-16-5p, miR-145-5p, BACH2, and caspase 3 were determined by quantitative real time PCR and western blot, respectively. Cell viability was measured by MTT assay. Cell apoptosis was detected by flow cytometry. Dual-luciferase assay was applied to verify miR-16-5p and miR-145-5p target to the 3'UTR of BACH2.

Results: TNF-α induced miR-16-5p, miR-145-5p and caspase 3 expression, inhibited cell viability, promoted cell apoptosis in GECs. However, down-regulated miR-16-5p and miR-145-5p can restore the effects of TNF-α on GECs. In addition, dual-luciferase assay determined that BACH2 was a common target of miR-16-5p and miR-145-5p. Knockdown of BACH2 induced GECs apoptosis. Of note, cell apoptosis induced by miR-16-5p mimic, miR-145-5p mimic, and TNF-α was significantly reversed by up-regulating BACH2.

Conclusion: miR-16-5p and miR-145-5p mediate apoptosis induced by TNF-α in human gingival epithelial cells by targeting BACH2.

Keywords: BACH2; GECs; apoptosis; miR-145-5p; miR-16-5p.

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17
Int J Clin Exp Pathol
. 2020 May 1;13(5):972-978. eCollection 2020.
Nicotinamide nucleotide transhydrogenase acts as a new prognosis biomarker in hepatocellular carcinoma
Zhijiao Duan 1, Yang Song 1, Xuejing Zou 1, Shanshan Liu 1, Wanli Zhang 1, Li Liu 1
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PMID: 32509068 PMCID: PMC7270652
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Lipid metabolism is essential for cancer development. Nicotinamide nucleotide transhydrogenase (NNT) is abnormally expressed in multiple cancers; however, its role in HCC is unclear. We assessed the NNT expression level in The Cancer Genome Atlas (TCGA) cohort and Gene Expression Omnibus (GEO) datasets and found that the expression level of NNT was lower in HCC patients than non-cancer control subjects in the public databases. Survival analysis was conducted according to high and low NNT expression. Low NNT expression was significantly associated with a poor prognosis. For confirmation, the gene and protein expression of NNT in cancer and adjacent non-cancer tissues from HCC patients at our institute cohort indicated the lower expression level of NNT in cancer compared to adjacent non-cancer tissues using quantitative polymerase chain reaction and western blot, respectively. Bioinformatics was used to analyze the underlying mechanisms and establish the protein-protein interaction network of NNT. It showed that NNT is associated with functions of bile acid and fatty acid metabolism and their related genes. To conclude, our results supported that NNT expression is downregulated in HCC, and can serve as a novel prognostic biomarker.

Keywords: Hepatocellular carcinoma; lipid metabolism; nicotinamide nucleotide transhydrogenase; prognosis.

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18
Int J Clin Exp Pathol
. 2020 May 1;13(5):889-895. eCollection 2020.
miR-149 regulates the proliferation and apoptosis of human colonic carcinoma cells by targeting FZD5
Xiaozhu Liu 1, Yinfeng Li 1, Cuicui Chen 2, Laiqing Li 2
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PMID: 32509059 PMCID: PMC7270703
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Abstract
Objective: To explore the effects of miR-149 on the cell proliferation and apoptosis of colorectal cancer (CRC) and its potential molecular mechanism.

Methods: miR-149 expression patterns were detected in human CRC cell lines by quantitative real-time RT-PCR (Q-PCR). Online prediction software and luciferase reporter assay were performed to screen the functional targets of miR-149. CRC cells were transfected with miR-149 mimics or siRNAs of FZD5 and then divided into NC group (negative control), miR-149 mimics group (cells transfected with miR-149 mimics) and miR-149 mimics + SiFZD5 group (cells transfected by miR-149 mimics and SiFZD5). Moreover, the effects of miR-149 on the proliferation and apoptosis of CRC cells were also analyzed by MTT and flow cytometry assay. In addition, the expression of Wnt/β-catenin signal pathways related factors were shown by western blot analysis.

Results: Q-PCR results demonstrated that the expression of miR-149 was significantly lower in SW480 than that in the FHC cell line. Frizzled class receptor 5 (FZD5) was identified as a functional target of miR-149 through a series of experiments including Q-PCR, western blot analysis, and luciferase assay. Cellular functional experiments demonstrated that the cell viability and proliferation were greatly inhibited after miR-149 overexpression in SW480 cells. Furthermore, the proportion of apoptotic cells increased significantly after introducing miR-149 into SW480 cells. Furthermore, Wnt/β-catenin signal pathway was activated because of the lower expression of β-catenin and cyclinD1 in miR-149 mimics group. However, reducing FZD5 expression restored the expression of β-catenin and cyclin D.

Conclusions: Our data suggested that miR-149 may function as a tumor suppressor in CRC cells lines by targeting FZD5. miR-149/FZD5 may become a new therapeutic target for CRC.

Keywords: Frizzled class receptor 5 (FZD5); Wnt/β-catenin signal pathway; colorectal cancer (CRC); miR-149.

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19
Int J Clin Exp Pathol
. 2020 May 1;13(5):1253-1261. eCollection 2020.
Pathologic characteristics of spinal tuberculosis: analysis of 181 cases
Yongai Li 1, Yingqi Wang 1, Huiqiang Ding 2, Ning Zhang 3, Ailing Ma 3, Jiandang Shi 2, Ningkui Niu 2
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PMID: 32509101 PMCID: PMC7270693
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Abstract
Objective: This study aimed to provide a basis for the diagnosis of spinal TB by analyzing its pathologic characteristics.

Methods: The data of 181 patients with spinal TB who underwent surgery from January 2013 to January 2019 at the General Hospital of Ningxia Medical University were retrospectively analyzed. The participants comprised 80 men and 101 women with an average age of 45.1 ± 16.5 (range: 14-78) years. Based on the assessment of tissue samples, five patients had cervical TB, 49 had thoracic TB, 86 had lumbar TB, 22 had thoracolumbar TB, and 19 had lumbosacral TB. Tuberculous granulation tissue, sclerotic bone, sequestrum, and intervertebral disc tissue were collected for hematoxylin and eosin staining. The proportion of patients with atypical and typical pathologic characteristics was identified and compared for statistical analysis.

Results: The typical pathologic characteristics included tubercles, granulomas, caseous necrosis, multinuclear giant cells, infiltration of acute inflammatory cells, sequestration, and fibroblastic proliferation. A total of 119 patients had caseous necrosis, 95 had multinuclear giant cells, 68 had granulomatous inflammation, and 21 had tubercles. Moreover, 46 (25.4%) patients had at least three pathologic characteristics and only 12 (6.6%) exhibited all the pathologic characteristics. Of the 35 (19.3%) patients with atypical pathologic characteristics, 17 had lymphocyte infiltration, 10 had fibroblastic proliferation, 2 had hyaline changes, 1 had local hemorrhage, 1 chronic inflammatory change, 2 had sequestration, 1 had dilated and congested vessels, and 1 had acute suppurative inflammation.

Conclusions: The most common pathologic characteristics were caseous necrosis, multinuclear giant cells, granulomatous inflammation, and tubercles. Moreover, multiple pathologic characteristics were observed in patients with spinal TB and one type of these characteristics was dominant. However, atypical pathologic characteristics were also noted. Thus, both pathologic examination and clinical analysis must be performed to improve the diagnostic rate of spinal TB.

Keywords: Spinal tuberculosis; pathology; tissue sample.

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20
Int J Clin Exp Pathol
. 2020 May 1;13(5):1094-1107. eCollection 2020.
Clinical and biologic roles of PDGFRA in papillary thyroid cancer: a study based on immunohistochemical and in vitro analyses
Lin Shi 1, Hao Chen 1, Yong-Ying Qin 1, Ting-Qing Gan 2, Kang-Lai Wei 1
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PMID: 32509085 PMCID: PMC7270701
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Abstract
Background: Platelet-derived growth factor receptor alpha (PDGFRA) plays essential roles in several malignant tumors. Nevertheless, its clinical function in papillary thyroid cancer (PTC) is still unclear. This study aimed to examine the clinicopathologic implication and potential molecular underpinning of PDGFRA in PTC.

Material and methods: Relative PDGFRA expression levels in eight cases of normal thyroid tissue, 15 cases of benign thyroid disease, and 90 cases of PTC were examined by immunohistochemistry (IHC). The prognostic value of PDGFRA was assessed by data mining of The Cancer Genome Atlas dataset. LV-PDGFRA overexpression and negative control CON220 lentivirus vectors were constructed and transfected into a PTC cell line. The capacity for cell proliferation, status of the cell cycle, efficiency of colony-forming, and migration ability of the PTC cells after PDGFRA were detected by multiple assays including methyl thiazolyl tetrazolium, flow cytometry, colony formation, transwell assay, and wound healing. Furthermore, bioinformatics analyses were conducted to determine the potential biologic mechanisms of PDGFRA.

Results: Results of IHC showed that PDGFRA expression was significantly upregulated in PTC samples and was associated with an advanced pathologic stage. Furthermore, patients with PDGFRA overexpression showed poor survival. Ectopically overexpressed PDGFRA accelerated the migration and invasion of PTC cells. Results of the bioinformatics analyses suggested that PDGFRA was involved in several cell proliferation-related pathways.

Conclusion: Collectively, our results indicate that PDGFRA overexpression is associated with the poor survival of patients with PTC and that PDGFRA is a potent oncogene in PTC because it significantly increases PTC cell migration and invasion. Thus, PDGFRA may be a promising novel biomarker and therapeutic target for treating PTC.

Keywords: Platelet-derived growth factor receptor alpha; migration; papillary thyroid cancer.

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21
Int J Clin Exp Pathol
. 2020 May 1;13(5):854-868. eCollection 2020.
INHBA knockdown inhibits proliferation and invasion of nasopharyngeal carcinoma SUNE1 cells in vitro
Sida Peng 1 2, Jiani Wang 3, Pan Hu 3, Wenhui Zhang 4, Huan Li 3, Lihua Xu 1 5 2
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PMID: 32509056 PMCID: PMC7270653
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Abstract
Up-regulated expression of INHBA has been reported in multiple malignant tumors. However, in nasopharyngeal carcinoma (NPC), the expression pattern and clinical significance of INHBA are still unclear. This study aimed to detect the expression of INHBA and its prognostic significance in NPC, then explore the tumor-associated functions of INHBA gene and the potential mechanism. The INHBA expression of mRNA levels in tumor tissues and noncancerous nasopharyngeal tissues was investigated by RT-qPCR. The protein expression in cells were detected by western blot. Cell proliferation was detected by CCK assay and cell invasion ability was evaluated by Transwell assay. The expression of INHBA in paraffin-embedded NPC tissues was detected by immunohistochemistry (IHC). Statistical analyses were further applied to assess the clinical significance of INHBA expression. The result reveals INHBA mRNA level is elevated in NPC tissues compared to those in noncancerous nasopharyngeal epithelial tissues. In paraffin-embedded NPC tissues, immunoreactivity of INHBA was primarily detected in 53.70% (58/108) of these patients. The overexpression was notably associated with the clinical stage (UICC) (P=0.048), N classification (P=0.042), carotid sheath involvement (P=0.016), and decreased disease-free survival (DFS) (P=0.004) and overall survival (OS) (P=0.010). Multivariate analysis revealed that INHBA expression was an independent prognostic factor for DFS (P=0.028). CCK assay showed SUNE1 cells' proliferation was decreased in INHBA knockdown group than control. Transwell assay showed the invasion of SUNE1 cells was decreased in INHBA knockdown group by comparison with control. Further study showed knockdown of INHBA expression in SUNE1 cells could block the TGF-β signaling pathway. In conclusion, INHBA is up-regulated in NPC, and is significantly correlated with clinical stage (UICC), N stage, carotid sheath involvement, and survival. Knockdown INHBA in SUNE1 cells could inhibit the cells' proliferation and invasion. The underlying mechanism may be blockade of the TGF-β signaling pathway.

Keywords: INHBA; NPC; invasion; prognosis; proliferation.

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22
Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1372-1380. eCollection 2020.
Upregulation of FHIT gene expression in endometrial carcinoma by RNA activation
Qing Zhu 1 2, Xia Wu 3, Yuanli Huang 3, Mingyang Tang 4, Ligao Wu 1 2
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PMID: 32661472 PMCID: PMC7344018
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Abstract
Endometrial carcinoma is the most common malignant tumors of the reproductive system, and fragile histidine triad (FHIT) plays an important role in multiple tumors. The purpose of this study was to investigate the expression of FHIT gene in endometrial carcinoma, and its effect on proliferation, invasion, and metastasis after upregulation. In vitro, the endometrial carcinoma cell lines were cultured. The FHIT-saRNA expression vector was constructed. The endometrial carcinoma cell line that upregulated the expression of FHIT was established, and whether the saRNA had a direct targeting regulation on the FHIT was verified. A difference of expression of FHIT in normal endometrial and endometrial carcinoma was detected. We detected the proliferation of endometrial carcinoma cell lines before and after activating FHIT. The endometrial carcinoma cell lines were compared with the corresponding transiently transfected cell lines in their capabilities of cell migration and invasion. The results showed that the expression of FHIT in endometrial carcinoma was significantly decreased or even deficient compared with normal endometrium. Upregulating the expression of FHIT is related to inhibiting the proliferation, invasion and metastasis of endometrial carcinoma. The possible mechanism is related to the regulation of cell cycle regulation, and plays a role in inhibiting tumor proliferation. The research on molecular mechanism in the development and progression of endometrial carcinoma has important theoretical significance for improving the diagnosis, treatment and prognosis of clinical tumors.

Keywords: Endometrial carcinoma; FHIT; RNA activation; invasion and metastasis; proliferation.

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23
Int J Clin Exp Pathol
. 2020 May 1;13(5):995-1007. eCollection 2020.
Clinical significance of PI3K/Akt/mTOR signaling in gastric carcinoma
Eun-Jung Jung 1, Ja Hee Suh 1, Woo Ho Kim 2, Hee Sung Kim 3
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PMID: 32509071 PMCID: PMC7270689
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Abstract
The mTOR signaling pathway has been linked to various cancers, but the contribution of alterations in this pathway to clinicopathological characteristics have not been established in gastric cancer. To investigate PIK3CA mutations and the expression of proteins in the PI3K/Akt/mTOR signaling pathway in sporadic gastric cancer. We analyzed PIK3CA mutation and microsatellite instability as well as immunohistochemical expressions of p-Akt, PTEN, p-mTOR, p-4EBP1, p-S6, p-p70S6, and eIF4E in 368 FFPE (formalin-fixed paraffin embedded) tissue from patients with sporadic gastric cancer. Associations between expression and clinicopathologic parameters and patient survival were evaluated. We found PIK3CA mutations in 4 of 173 cases (2.3%). In immunohistochemical analyses, we detected positive p-Akt expression in 22.0% of cases (81/368), negative PTEN expression in 21.5% of cases (79/368), positive p-mTOR expression in 68.6% of cases (243/354), positive p-4EBP1 expression in 58.2% of cases (202/347), positive p-S6 expression in 42.7% of cases (148/347), positive p-p70S6 expression in 51.1% of cases (179/350), and positive eIF4E expression in 78.3% of cases (275/351). In a clinicopathologic analysis, intestinal type was significantly associated with positive p-4EBP1 expression (P < 0.001). In a Kaplan-Meier survival analysis, PTEN loss (P = 0.002) and pS6 positivity (P = 0.043) are significantly associated with reduced overall survival (OS). PTEN loss (P = 0.001), pS6 positivity (P = 0.009), and eIF4E positivity (P = 0.003) are significantly associated with reduced disease free survival (DFS) (disease free survival). In Cox regression multivariate analysis, PTEN loss was an independent factor of reduced time. Alterations of mTOR pathway protein expression are associated with reduced survival in gastric cancer. Significance was noted in the association of pS6 positivity and eIF4E positivity e with reduced survival in univariate analysis and the association of PTEN loss and reduced DFS in univariate analysis as well as multivariate analysis for DFS.

Keywords: PI3K; immunohistochemistry; mTOR; mutation; survival; therapeutic target.

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24
Int J Clin Exp Pathol
. 2020 May 1;13(5):869-879. eCollection 2020.
The overexpression of lncRNA MEG3 inhibits cell viability and invasion and promotes apoptosis in ovarian cancer by sponging miR-205-5p
Pingping Tao 1, Binlie Yang 1, Huiya Zhang 2, Liyan Sun 1, Yungen Wang 2, Weiping Zheng 2
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PMID: 32509057 PMCID: PMC7270692
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Abstract
Purpose: Ovarian cancer is a common and fatal cancer in women. The long non-coding RNA (lncRNA) MEG3 was reported to affect the cellular processes of ovarian cancer, but the mechanisms remain unclear. Here, we aimed to explore the potential regulatory mechanism of MEG3 in ovarian cancer.

Materials and methods: A reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was conducted to analyze the expression levels of MEG3 and miR-205-5p in tissues and cell lines. An MTT assay was utilized to determine the cell viability of ovarian cancer SKOV-3 and OVCAR-8 cells. A flow cytometry analysis was employed to disclose the ovarian cancer cell apoptosis. The migration and invasion of SKOV-3 and OVCAR-8 cells were examined using a Transwell assay. A bioinformatics analysis indicated miR-205-5p as a direct target of MEG3, and a luciferase reporter assay was conducted to validate the interaction between MEG3 and miR-205-5p.

Results: MEG3 was significantly down-regulated, while miR-205-5p was up-regulated in ovarian cancer tissues and cell lines. The overexpression of MEG3 and the knockdown of miR-205-5p inhibited cell viability, migration and invasion but promoted the apoptosis rate in ovarian cancer cells. MiR-205-5p was identified as a downstream gene of MEG3 and is negatively regulated by MEG3. The introduction of miR-205-5p reversed the up-regulation of MEG3-mediated suppression effects on cell viability, migration and invasion and increased cell apoptosis in ovarian cancer cells.

Conclusion: The overexpression of lncRNA MEG3 inhibits cell proliferation and cell invasion and promotes apoptosis in ovarian cancer by sponging miR-205-5p.

Keywords: MEG3; apoptosis; cell viability; miR-205-5p; migration and invasion; ovarian cancer.

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25
Int J Clin Exp Pathol
. 2020 May 1;13(5):964-971. eCollection 2020.
Sepsis causes heart injury through endoplasmic reticulum stress-mediated apoptosis signaling pathway
Lei Li 1, Xin Peng 1, Lichun Guo 1, Yuhan Zhao 1, Qinghong Cheng 1 2
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PMID: 32509067 PMCID: PMC7270664
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Endoplasmic reticulum stress (ERS), arising from the loss of dynamic balance in endoplasmic reticulum function under stress and inflammation, has been implicated in the progression of sepsis. Multiple organ failure caused by sepsis still has a high mortality rate, of which the heart is one of the more damaged organs. In this research, a rat model of sepsis was set up by cecal ligation and puncture (CLP); serum myocardial enzyme levels were measured using an automated biochemical analyzer, inflammatory cytokine levels were measured by ELISA kit, and cardiac histology and cardiomyocyte apoptosis were measured by hematoxylin and eosin (H&E) staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to assess the extent of myocardial damage. Western blot was used to detect expression of related proteins. The results showed that serum myocardial enzymes and pro-inflammatory factors were elevated in septic rats, and the increase was most significant in the CLP 24 h group. At the same time, the myocardium of septic rats had a histopathologic abnormality. After CLP, levels of endoplasmic reticulum stress related protein were upregulated. After 12 and 24 hours, the density of apoptotic cells in the myocardium of CLP-treated rats increased significantly, and the expression of apoptosis-related proteins changed significantly. This suggests that the unfolded protein response occurs during sepsis and causes damage to the heart muscle. Endoplasmic reticulum stress-mediated apoptotic signaling pathway is one of the causes of cardiac injury caused by sepsis, and may be a key to clinical prevention of cardiac dysfunction caused by sepsis.

Keywords: Sepsis; endoplasmic reticulum stress; myocardial injury.

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26
Int J Clin Exp Pathol
. 2020 May 1;13(5):934-943. eCollection 2020.
Myocyte-specific enhancer factor 2D promotes tumorigenesis and progression in tongue squamous cell carcinoma
Yang Liu 1, Wenjun Yu 1, Yan Zhu 1, Zhenni Sun 1, Xingang Huang 2, Jianhua Zhou 3, Ruyong Yao 4, Qian Zhang 4, Jianzhong Qiu 3, Lu Yue 1
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PMID: 32509064 PMCID: PMC7270656
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Abstract
Tongue squamous cell carcinoma (TSCC) ranks as one of the most common cancers worldwide and has a poor prognosis. Myocyte-specific enhancer factor 2 (MEF2D) has recently been considered as a novel factor involved in cancer development. In the present study, the function and underlying mechanism of MEF2D in TSCC were investigated. The levels of MEF2D mRNA and protein were determined in human TSCC samples by RT-qPCR and western blot, respectively. The interaction between MEF2D expression and clinicopathologic features was evaluated by IHC and analysis of clinical information. MEF2D-mediated effects on proliferation, migration, and invasion were explored in TSCC cells after transfection with MEF2D-siRNA. The results showed higher expression of MEF2D at both the mRNA and protein levels in TSCC carcinoma tissues than in paracarcinoma tissues. Furthermore, high expression of MEF2D was positively correlated with tumor differentiation and lymphatic metastasis. MEF2D knocked down TSCCA cells also had reduced proliferative, migratory, and invasive abilities compared to those of control cells. Together, these data confirmed that knockdown of MEF2D might suppress the growth and metastasis of TSCC, which further indicated that MEF2D might serve as a therapeutic target for TSCC treatment.

Keywords: Tongue squamous cell carcinoma (TSCC); myocyte-specific enhancer factor 2 (MEF2D); proliferation; tumorigenesis.

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27
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1073-1080. eCollection 2020.
A case of small hepatocellular carcinoma with malignant ductular reaction
Tomohiro Iwasaki 1, Aki Kubota 1, Makoto Suzuki 1, Tadashi Terada 1
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PMID: 32509081 PMCID: PMC7270666
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Abstract
Herein reported is the unique case of a small hepatocellular carcinoma (HCC) with several foci of a minor (10% in area) component of "malignant ductular reactions". The patient was 51-year-old man who was a drinker. HBV/HCV were negative. The tumor was small (12×10×11 mm), solid, expansile and reddish-brown, and contained fibrous septa. The background was cirrhotic without alcoholic features. Histologically, the tumor was well differentiated HCC, and, besides the HCC, it contained several small foci consisting of the following four biliary epithelial elements: clusters of small cells (CSC), ductules (D), ductular hepatocytes (DH), and bile ducts (BD). The proportion of area was as follows: HCC 90%, CSC 3%, D 3%, DH 2%, and BD 2%. These non-HCC elements were intimately admixed and formed several foci that were characteristically located in the fibrous septa (FS), except for CSC which were situated among HCC cells close to FS. There were gradual merges between HCC and CSC, CSC and D, D and DH, and D and BD, respectively. Cells of CSC and D resembled rat oval cells. Cells of these four elements had atypical features regarded as malignant. Immunohistochemically (IHC), HCC were positive for arginase, HepPar1, and less frequently CK7. CSC were positive for CK7. D were positive for arginase, HepPar1, CK7, CK19, EMA, and EpCAM. DH were positive for arginase, HepPar1, and CK7. BD were positive for CK7, CK19, EMA, EpCAM and mucin. Although such tumors as this have been termed stem cell-related cancers, our case lacked definite evidence for stem cell origin in histology as well as in the IHC that showed negativity for KIT, CD34, and OCT3/4. The above findings suggest that CSC, D, DH and BD are analogous to the ductular reaction seen in hepatic inflammation. Therefore, we termed the phenomenon "malignant ductular reaction". It is suggested in the present tumor that at first only HCC developed, and then HCC cells in the interface with FS transformed to CSC, like a fetal ductal plate. Then, the CSC gave rise to D, which in turn led to DH and BD in FS, all findings of which are most likely sequential considering embryonic biliary development. The idea that the present tumor was at first D carcinoma and then D developed on one hand into CSC and HCC, and on the other into DH and BD seems possible, but its probability appears low because the vast majority of the present tumor had the phenotype of HCC.

Keywords: HCC; case report; ductular reaction; liver stem cells.

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28
Int J Clin Exp Pathol
. 2020 May 1;13(5):1108-1120. eCollection 2020.
Stable silencing of ROR1 regulates cell cycle, apoptosis, and autophagy in a lung adenocarcinoma cell line
Qi Zhou 1, Shiyi Zhou 1, Huili Wang 1, Yanping Li 1, Xiaoqian Xiao 1, Jiahui Yang 1
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PMID: 32509086 PMCID: PMC7270672
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Abstract
Lung cancer has the highest mortality and recurrence rate among cancers in the world. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been widely recognized for its role in promoting the growth and metastasis of lung cancer, but its comprehensive role and molecular mechanisms in regulating cell cycle, apoptosis, and autophagy remain unclear. In this study, a series of ROR1-stably silenced monoclonal clones from lung adenocarcinoma cell lines PC9, PC9erlo, and NCI-H1975 were successfully selected and confirmed by qRT-PCR, western blot, and flow cytometry, and used as cell models in the following assays. Our study clearly shows that blocking ROR1 significantly downregulates cell cycle-inducing molecules such as CDK4 and Cyclin E1, and anti-apoptotic molecules such as Bcl-XL and Bcl-2, while it markedly upregulates pro-apoptotic molecules such as Bak, Caspase-3, and Caspase-7, which extends our previous observation on the molecular mechanism of ROR1-mediated tumor growth in lung adenocarcinoma. Our data also show that silencing ROR1 promotes autophagy since the key molecules involved in autophagy including ATG7, ATG12, BNIP3L, LC3A, LC3B, and NBS1 were up-regulated. We further screened key phosphokinase signaling pathways downstream of ROR1 in lung adenocarcinoma by a human phospho-kinase array. Our data indicate that blocking ROR1 could deactivate Akt, then activate GSK-3α/β by de-phosphorylation, and finally deactivate mTOR. In this way blocking ROR1 could effectively regulate the cell cycle, apoptosis, and autophagy in lung cancer.

Keywords: ROR1; apoptosis; autophagy; cell cycle; lung adenocarcinoma.

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29
Int J Clin Exp Pathol
. 2020 May 1;13(5):837-845. eCollection 2020.
Reliability of acellular decalcified and decalcified teeth as bone graft material: an experimental and pathological study in rats
Ke Guo 1, Wenchao Wang 1, Zonglin Liu 1, Weifeng Xu 1, Shanyong Zhang 1, Chi Yang 1
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PMID: 32509054 PMCID: PMC7270698
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Abstract
Objective: The present study aimed to investigate the reliability of acellular decalcified teeth in the development of bone scaffolds and in bone regeneration in rats.

Methods: (1) Forty-eight human teeth were divided into two groups in vitro: twenty-four were decalcified, while the remaining twenty-four were decalcified and decellularized, following which a conventional scanning-electron microscope analysis was performed. (2) In another experiment, six male SD rats aged 10-12 weeks were selected, then decalcified and acellular decalcified teeth were embedded subcutaneously in the abdomen of the rats. After 4 weeks, the rats were sacrificed for H-E staining and immunohistochemical staining to observe the inflammatory reaction around the two materials. (3) In the ectopic osteogenesis experiment, bone defects were simulated in bilateral craniotectal areas of 12 male SD rats (age 10-12 weeks), following which acellular decalcified teeth were implanted in the right bone defect. The non-implanted left side was used as blank control. At week 4 and week 8, 6 rats were randomly selected for execution, complete specimens were obtained, and micro-CT scan was performed to compare the bone mass from gross morphology. H-E staining was performed at 4 and 8 weeks to observe the surrounding inflammatory response and immunohistochemistry was performed at 8 weeks to observe the degree of new bone formation. SPSS 23.0 software package was used for statistical processing.

Results: (1) Under scanning electron microscope, cells in the teeth subjected to acellular decalcification completely disappeared, leaving only inorganic scaffolds. (2) After 4 weeks, the amount of inflammatory reaction in the tissues surrounding acellular decalcified teeth was significantly lower than that in the tissues surrounding decalcified teeth. (3) After four and eight weeks, the amount of bone formation in the bone defects was significantly higher in rats implanted with acellular decalcified teeth than in those in the blank control group (P<0.05). After four and eight weeks, hematoxylin-eosin staining revealed that the degree of inflammatory response was similar around acellular decalcified teeth and blank controls. Immunohistochemistry indicated that the osteocalcin levels were significantly higher around acellular decalcified teeth than that around blank controls.

Conclusion: Acellular decalcified teeth show significantly decreased inflammatory reaction, better biocompatibility, better osteogenic potential, and better plasticity than decalcified teeth alone.

Keywords: Cranial defects; acellular bone matrix; decalcified bone matrix; extracted human teeth; rat.

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30
Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1349-1360. eCollection 2020.
Hyperplasia suppressor gene inhibits the proliferation and metastasis of glioma cells by targeting rho family proteins
Juncheng Wang 1, Bin Zhang 2 3, Haibo Liu 2, Qiao Wu 4, Peng Gao 1 2, Yourui Zou 2, Yanping Lan 1, Qinghua Zhang 5
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PMID: 32661470 PMCID: PMC7344015
Free PMC article
Abstract
Aim: To investigate the effect of the hyperplasia suppressor gene (HSG) on human glioma cell invasion and its possible mechanism.

Methods: Human glioma U251 cells were infected with recombinant viral vectors carrying the HSG gene sequence (HSG overexpression group) and HSG interference sequence (HSG suppression group). The negative control group with no-load virus transcription and a blank control group with only PBS treatment were set up. CCK-8 assay, cell scratch healing test, transwell migration, and invasion test were used to detect the effect of HSG expression on proliferation, migration and invasion of U251 glioma cells. Cell immunofluorescence and cell adhesion test were used to analyze the effect of HSG expression on cytoskeleton formation and adhesion ability of U251 cells. Gene chip technology was employed to preliminarily explore the effect of HSG expression change on the inherent gene expression in U251 cells. The expression of Rho family key molecule mRNA and protein was detected by light quantitative PCR and western blot.

Results: After 24 h of transcription with the recombinant virus vector, the cells showed a green color under an inverted fluorescence microscope. HSG expression increased in the HSG overexpression group (P < 0.01), and decreased in the HSG inhibition group (P < 0.01). Compared with the two control groups, the proliferation, scratch healing rate, migrating cell number, invasive cell number and adhesion cell number in the HSG overexpression group were markedly lower. After HSG overexpression, the morphology of U251 cells changed; filamentous pseudopods shortened and partially flaked. However, after HSG inhibition, the pseudopods grew toward both ends and were arranged axially. The overexpression of HSG inhibited the expression of rho family proteins (RhoA, Rock1, Rock2, Rac1, and Cdc42).

Conclusion: The overexpression of HSG inhibits the progression of glioma U251 cells by regulating the expression of rho family proteins.

Keywords: HSG; Rho protein; glioma; invasion; proliferation.

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31
Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1408-1414. eCollection 2020.
Detection of proteins associated with the pyroptosis signaling pathway in breast cancer tissues and their significance
Xia Wu 1, Xu Mao 1, Yuanli Huang 1, Qing Zhu 1, Jingwen Guan 2, Ligao Wu 1
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PMID: 32661477 PMCID: PMC7344002
Free PMC article
Abstract
Objective: To study the expression of pyroptosis signaling pathway related proteins in breast cancer tissues and paracancer tissues, analyze their relationship with breast cancer clinicopathologic features, and explore their relationship to prognosis.

Methods: Immunohistochemistry ElivisionTM plus was used to detect the expression of caspase-1, IL-1β and Gasdermin-D (GSDMD) in 108 cases of breast cancer and 23 cases of benign lesions adjacent to breast cancer.

Results: Using 108 cases of breast cancer and 23 cases of para-cancerous benign tissues, the pyroptosis signaling pathway effector proteins caspase-1, IL-1β, and GSDMD were positively correlated with each other. The higher the expression level, the lower the histophologic grade of breast cancer, the smaller the tumor size, the lower the clinical stage, the lower the possibility of lymph node metastasis, the lower the risk of death, and the better the prognosis.

Conclusions: Pyroptosis signaling pathway effectors caspase-1, IL-1β and GSDMD expression may play an important role in the invasion, metastasis, and prognosis of breast cancer.

Keywords: GSDMD; IL-1β; Pyroptosis; breast cancer; caspase-1.

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32
Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1381-1389. eCollection 2020.
Role of HOXB7 in promoting gastric cancer progression and oxaliplatin (L-OHP) resistance
Chunyan Yuan 1, Yun Xie 1, Xia Sheng 1, Xiaoli Xie 1, Jun Liu 1, Sien Zeng 2, Xuming Wang 2
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PMID: 32661473 PMCID: PMC7344019
Free PMC article
Abstract
Background and aim: Our study aimed to investigate the ways by which HOXB7 affects gastric cancer progression and oxaliplatin (L-OHP) resistance.

Methods: First, the expression of HOXB7 in paired cancer and paracancerous tissues of L-OHP-sensitive and L-OHP-resistant gastric cancer patients was qualitatively and quantitatively analyzed by immunohistochemistry. Then, the expression of HOXB7 in these tissues was further quantitatively analyzed at protein and transcriptional levels. The expression of HOXB7 in the SGC-7901 L-OHP-resistant gastric cancer cell line was further verified by immunofluorescence, western blot, and RT-qPCR. In addition, by transfecting the SGC-7901 cell line, control (sh-con) and HOXB-7-silenced (sh-HOXB7) gastric cancer cell lines were created. Subsequently, the migratory and invasive abilities of these cells were determined by the transwell assay. The proliferation rate of both control and HOXB-7-silenced cells induced by varying concentrations of L-OHP was detected by the CCK-8 assay, while the degree of apoptosis in the same cells induced by 60 µM L-OHP was detected by flow cytometry.

Results and conclusion: Results suggested that HOXB7 was overexpressed in both the tissues of L-OHP-resistant gastric cancer patients and the SGC-7901 gastric cancer cell line. Moreover, HOXB7 promoted the migratory and invasive abilities of gastric cancer cells. By silencing HOXB7 protein expression, the proliferation rate of L-OHP-resistant gastric cancer cells decreased considerably, while their degree of apoptosis increased significantly. These results showed that HOXB7 promoted gastric cancer progression and L-OHP resistance.

Keywords: Chemotherapy; HOXB7; L-OHP; drug resistance; gastric cancer; homeobox B7; oxaliplatin.

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33
Int J Clin Exp Pathol
. 2020 May 1;13(5):846-853. eCollection 2020.
Effects of Jinlongshe granules on gastric precancerous lesions in rats and its mechanism
Xiaowei Wang 1, Jingyu Xu 1, Xuan Zhang 1, Chenxi Zhang 2, Wenyi Zheng 2, Jianpeng Jiao 1, Xuan Liu 1, Xiaoqiang Yue 1
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PMID: 32509055 PMCID: PMC7270685
Free PMC article
Abstract
Objective: To investigate the anti-gastric precancerous lesions effect and mechanism of Traditional Chinese Medicine Jinlongshe (JLS) granules in ethanol extractive of A. manshuriensis (EEA)-induced gastric precancerous lesions rats.

Methods: A rat model with the part typical proliferation of the gastric epithelium mucosa was established by EEA. These rats received different doses of JLS granules treatment for four weeks. Bodyweight, histological and ultrastructural changes of gastric precancerous lesions were evaluated. The expression of Apelin and CD34 mRNA and proteins of the gastric tissue were analyzed by quantitative Realtime PCR, western blot and immunohistochemical staining.

Results: We found that the treatment of JLS granules prevented the bodyweight loss and improved behavioral abnormalities of rats that received EEA. The histological and ultrastructural analysis also showed that JLS granules ameliorated EEA induced gastric precancerous lesions in a dose-dependent manner. The expression levels of two critical proteins involved in the angiogenesis of gastric carcinoma, Apelin, and CD34, were significantly reduced by the treatment of JLS granules.

Conclusion: Our results indicated that JLS could inhibit the expression of the Apelin and CD34 genes in rat gastric mucosa, which reversed gastric precancerous lesions.

Keywords: Apelin; CD34; Gastric precancerous lesions; Jinlongshe; Traditional Chinese Medicine.

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34
Int J Clin Exp Pathol
. 2020 May 1;13(5):954-963. eCollection 2020.
Murine embryonic mesenchymal stem cells attenuated xerostomia in Sjögren-like mice via improving salivary gland epithelial cell structure and secretory function
Bangdong Gong 1, Ling Zheng 2, Wanxue Huang 1, Jincheng Pu 1, Shengnan Pan 1, Yuanyuan Liang 1, Zhenzhen Wu 1, Jianping Tang 1
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PMID: 32509066 PMCID: PMC7270676
Free PMC article
Abstract
Background: Xerostomia is the main manifestation from patients with Sjögren syndrome (SS). However, traditional immunosuppressive agents are nearly invalid due to complicated etiopathogenesis in salivary glands, including aberrant immune dysregulation, epithelial structure destruction, and diminished secretory function.

Objective: To investigate the therapeutic effect of murine embryonic mesenchymal stem cells (ME-MSCs) on salivary glandular epithelium structure and secretory function in Sjögren-like mice.

Methods: Salivary flow rate (SFR), blood glucose, and body weight was weekly monitored among treatment group, disease group, and health control group. ME-MSCs were used to treat NOD mice via tail vein injection. HE staining and transmission electron microscope was used to evaluate the structure of salivary gland epithelial cells (SGEC). TUNEL fluorescence staining and PCNA immumohistochemical staining was used to evaluate the SGEC apoptosis and proliferation. The SGEC secretory function was tested by PAS staining and amylase immumohistochemical staining.

Results: ME-MSC treatment could elevate SFR, restore the acini and micromorphologies, promote the SGEC proliferation, and suppress the SGEC apoptosis in NOD mice, but not restore to that in health control group. The SGEC structure was more intact in treatment group. Mucopolysaccharide and amylase of salivary acinar cells in treatment group was better than that in disease group, although transmission electron microscopy showed secretory granules were lower than those in healthy control.

Conclusion: ME-MSCs demonstrated its potential as a candidate treatment for xerostomia due to some effects on salivary flow rate in NOD mice by restoring the SGEC impairment and secretory function.

Keywords: Mesenchymal stem cells; Sjögren syndrome; salivary gland epithelium cells; xerostomia.

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35
Int J Clin Exp Pathol
. 2020 May 1;13(5):1035-1044. eCollection 2020.
Semi-comprehensive analysis of gene amplification in thymic malignant tumors using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization
Seiichi Kakegawa 1, Isao Matsumoto 1, Masaya Tamura 1, Munehisa Takata 1, Shuhei Yoshida 1, Daisuke Saito 1, Yusuke Tanaka 1, Hirofumi Takemura 1, Akishi Ooi 2
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PMID: 32509076 PMCID: PMC7270679
Free PMC article
Abstract
Research on the amplification of oncogenes in thymic malignant tumor is limited. In this study, we aimed to determine the gene amplification status of receptor tyrosine kinases and other cell regulator genes in thymic malignant tumors, with a view toward the future introduction of molecular targeted therapy. In addition, we examined the usefulness of multiplex, ligation-dependent probe amplification (MLPA) in the semi-comprehensive detection of these gene amplifications. The participants of this study were nine patients with thymic carcinoma and one patient with atypical carcinoid who underwent resection at our department from 1999 to 2016. Twenty-four oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, BRAF, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR) were analyzed for amplification by MLPA. In cases where amplification by MLPA was suspected, confirmation was performed by fluorescence in situ hybridization (FISH). Immunostaining for detected oncoproteins and p53 were performed in cases with confirmed oncogene amplification. MYC (2/10, 20%) and MDM2 (1/10, 10%) amplifications were detected using MLPA and FISH. Immunostaining in both cases was positive. The MDM2-amplified tumor relapsed and spread rapidly after operation despite the use of post-operative chemo-radiotherapy. MYC amplification may be involved in the carcinogenesis of thymic malignant tumors. In addition, MDM2 amplification may be a concern in the increased malignancy.

Keywords: MDM2; MYC; Thymic carcinoma; fluorescence in situ hybridization; gene amplification; multiplex ligation-dependent probe amplification.

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36
Int J Clin Exp Pathol
. 2020 May 1;13(5):880-888. eCollection 2020.
Infiltration of CD8 + FOXP3 + T cells, CD8 + T cells, and FOXP3 + T cells in non-small cell lung cancer microenvironment
Jianqing Hao 1, Helin Wang 1 2, Lai Song 3, Shuping Li 4, Nanying Che 5, Shucai Zhang 1, Hongtao Zhang 4, Jinghui Wang 1
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PMID: 32509058 PMCID: PMC7270696
Free PMC article
Abstract
Background: Studies about CD8+ FOXP3+ T cells as a subtype of regulatory T cells (Treg cells) in non-small cell lung cancer (NSCLC) are few. Associations among the clinicopathologic factors of NSCLC and tumor-infiltrating lymphocytes (TILs) such as CD8+ FOXP3+ T cells, CD8+ T cells, FOXP3+ T cells and tumor PD-L1 expression are unclear.

Methods: We retrospectively enrolled 192 patients who underwent resections for NSCLC. We used tissue microarrays (TMA) with multiplex immunofluorescence and immunohistochemistry staining to evaluate the expression of CD8, FOXP3, cytokeratin, DAPI and PD-L1. We then used Wilcoxon test, Kaplan-Meier method, and Cox hazard proportion model to analyze their relationships with clinicopathologic factors and prognosis.

Results: Density of tumor CD8+ FOXP3+ T cells was significant by univariate analysis, and positively associated with tumor CD8+ T cells and FOXP3+ T cells. Density of tumor CD8+ T cells was higher in lung adenocarcinoma (LUAD) than squamous cell carcinoma (LUSC), and was an independent prognostic factor for NSCLC. The density of tumor FOXP3+ T cells decreased with tumor size. Tumor PD-L1 expression was higher in LUSC than LUAD. Cox hazard proportion model analysis correlated being younger than 65 years, early TNM stage, early T stage, high tumor CD8+ T cell density, and adjuvant chemotherapy with longer overall survival.

Conclusion: Infiltration of CD8+ FOXP3+ T cells, CD8+ T cells, and FOXP3+ T cells is important in non-small cell lung cancer microenvironment, and needs to be investigated more.

Keywords: CD8+ FOXP3+ T cells; Lung cancer; PD-L1; multiplex immunofluorescence staining.

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37
Int J Clin Exp Pathol
. 2020 May 1;13(5):1185-1189. eCollection 2020.
Preliminary investigation of demographic signatures of intestinal parasitic infection in rural residents of Guangxi Zhuang Autonomous Region in China
Chen Huang 1 2, Rong Li 3, Jian Chen 3, Tippawan Liabsuetrakul 1, Wuxiang Shi 2
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PMID: 32509093 PMCID: PMC7270683
Free PMC article
Abstract
Background: Our present study was designed to initially unveil the epidemiological characteristics and underlying etiology of intestinal parasitic infection (IPI) in rural residents of Guangxi province in China through conducting a community-based cross-sectional survey.

Material and methods: By use of an epidemiological questionnaire survey and morphologic examination, a total 700 residents from dissimilar regions around rural areas in Guangxi province were recruited for fecal samples to explore ethnic differences in IPI. The fecal specimen was collected and used for microscopic inspection of visible signs of parasitic eggs. In addition, parasitic egg samples were screened and identified to characterize the parasite-bearing IPI cases.

Results: The statistical epidemiologic data exhibited that the early pathologic signs of ethnicity-sorted IPI-based rural residents occurred in a two-week period, such as headache and itchy skin. Following further one-year tracing, some potential pathological symptoms of rural locales with IPI were screened and identified, including diarrhea and anemia. Insufficient education seemed to be an underlying cause of IPI in rural residents. In addition, further morphologic signs of parasitic eggs and protozoa in IPI-based residents with pathologic symptoms were validated.

Conclusions: Overall, these preliminary epidemiologic findings demonstrate that detectable pathologic signs of IPI-based rural residents in Guangxi province were associated with poor education, thus local government needs a strategy for reducing IPI and improving quality of life in locals.

Keywords: Epidemiology; etiology; intestinal parasitic infection; symptom.

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38
Int J Clin Exp Pathol
. 2020 May 1;13(5):1190-1196. eCollection 2020.
Chance to rein in a cancer--Spontaneous regression of lung carcinoma (1988-2018): a 30-year perspective
Jingyao Zhang 1, Haijuan Wang 1, Chunxiao Li 1, Haili Qian 1
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PMID: 32509094 PMCID: PMC7270659
Free PMC article
Abstract
Background: Spontaneous regression of tumor is an extremely rare phenomenon in the oncology field and even rarer for lung cancer. However, the underlying mechanism is poorly understood. Summarizing the available clinical information and the supposed mechanism shed new light on lung cancer therapy strategies in the new era of immunotherapy.

Summary: We conducted a PubMed search using the retrieval tactics ("Lung Neoplasms" [Mesh]) AND "Neoplasm Regression, Spontaneous" [Mesh] for reports from 1988 to January 2018, and all references in the relevant literature were subsequently investigated for relevance. Using the criteria of Everson and Cole, 14 cases were finally defined as spontaneous regression and were reviewed in the research. Key messages: The information regarding patient characteristics, treatments, and follow-up has been summarized. In this review, we found that spontaneous lung cancer regression cases fall into two categories including: (1) neurologic disorders in 6 cases, half of whom suffered with paraneoplastic neurological syndromes (PNS) and (2) immunological reactions in 7 cases. Getting data on more spontaneous regression cases and more detailed information will definitely help us understand the mechanism for the body's surveillance system-cancer balance, creating a big chance to increase cancer immunotherapy.

Keywords: Spontaneous regression; immunological reaction; lung carcinoma; paraneoplastic neurological syndrome.

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39
Int J Clin Exp Pathol
. 2020 May 1;13(5):1066-1072. eCollection 2020.
Differences in pathologic characteristics between ductal carcinoma in situ (DCIS), DCIS with microinvasion and DCIS with invasive ductal carcinoma
Bing-Tian Liu 1, Jia-Ning Ding 2, Jian-Li Wang 3, Zhi-Shuang Li 4, Yin-Lu Ding 1, Rong Ma 5
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PMID: 32509080 PMCID: PMC7270677
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Abstract
In order to further our understanding of pathologic features in various ductal carcinoma in situ (DCIS) related breast ductal cancers, including DCIS, DCIS with microinvasion (DCIS-Mi) and DCIS with invasive ductal carcinoma (DCIS-IDC), a retrospective study including 453 cases of DCIS, 88 cases of DCIS-Mi, and 269 cases of DCIS-IDC was conducted. Statistical analysis showed significant pathological differences were found in DCIS, DCIS-Mi, and DCIS-IDC. Compared with DCIS, DCIS-IDC was significantly more associated with high nuclear grade, large tumor size, high Ki67 index, and lymph node metastasis (all P<0.05). Higher expression of steroid receptors was shown in DCIS-IDC than in DCIS (all P<0.05), but the status of HER2 between the two groups was similar (P=0.269). Compared with DCIS, DCIS-Mi was significantly more associated with high nuclear grade, large tumor size, comedonecrosis, absence of steroid receptors, HER2 overexpression, and high Ki67 index (all P<0.05). These features remain consistently even when compared with DCIS-IDC. According to the immunohistochemistry surrogate classification, the dominant types of DCIS and DCIS-IDC were luminal types (luminal A and luminal B, respectively), while the dominant type of DCIS-Mi was HER2 overexpression. These findings suggest that DCIS-Mi represents a distinct entity, and DCIS with features including high nuclear grade, large tumor size, comedonecrosis, steroid receptors negativity, HER2 positivity, and high Ki67 expression was more likely to have microinvasion than DCIS without these features.

Keywords: DCIS; ER; HER2; IDC; PR; microinvasion.

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40
Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1403-1407. eCollection 2020.
Clinicopathologic features of succinate dehydrogenase deficiencient renal cell carcinoma
Qing Zhu 1 2, Xia Wu 3, Yuanli Huang 3, Mingyang Tang 4, Ligao Wu 1 2
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PMID: 32661476 PMCID: PMC7343999
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Abstract
According to the WHO new renal tumor classification (2016), the clinical and pathologic characteristics, immunophenotype and molecular genetic characteristics of 2 cases of succinate dehydrogenase (SDH)-deficient renal cell carcinoma were retrospectively analyzed, and the relevant literature was reviewed. In 2 cases, there was 1 male and 1 female, the average age was 52.5 years old. The renal tumor average length was 4.2 cm. Tumor cut surface was solid, grayish yellow and soft. The tumor boundary was clear, and the cells were arranged in solid, nested, or small tubular growth. The cytoplasm was vacuolated or contained eosinophilic or light-stained flocculent substance, with a regular nucleus and no obvious nucleoli, showing low-grade nuclei. No atypical mitotic figures or necrosis were found. SDH-deficient renal cell carcinoma has a characteristic morphologic manifestation, and lack of SDHB expression in the immunophenotype. During the clinical diagnosis and treatment, the patient's condition and family genetic history should be asked for in detail, and genetic detection should be performed to confirm the diagnosis if necessary.

Keywords: Renal tumor; genetic detection; immunohistochemistry; succinate dehydrogenase.

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41
Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1333-1348. eCollection 2020.
Cigarette smoke supports stemness and epithelial-mesenchymal transition in bladder cancer stem cells through SHH signaling
Xianchao Sun 1 2, Jin Song 1, Enlai Li 1, Hao Geng 1, Yuan Li 3, Dexin Yu 1, Caiyun Zhong 3
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PMID: 32661469 PMCID: PMC7344017
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Abstract
Cancer stem cells (CSCs) are essential in every step of tumorigenesis and progression. As an important process in cancer development, epithelial-mesenchymal transition (EMT) has been reported to promote stem-like cells. Bladder cancer is one of the most common cancers in the urinary tract, and cigarette smoke (CS) is a preventable risk factor. In the present study, we tested the hypothesis that CS could promote stemness and EMT in bladder cancer. Bladder cancer UM-UC-3 and EJ cell lines were maintained in serum-free medium to grow as tumor spheres, characteristic of CSCs. Results demonstrated that CS enhanced tumor sphere formation capacity, upregulated expression of CSC markers, increased the proportion of the CD44+ cell population, and promoted EMT. Mechanistically, the Sonic Hedgehog (SHH) pathway regulated CS-triggered EMT and stemness. More importantly, among bladder cancer patients, smokers harbored higher levels of CSC markers and proteins for SHH signaling than non-smokers. Collectively, findings in this study highlight the critical role of CS in the stemness and EMT of bladder cancer. Smoking cessation and intervening in the SHH pathway may both be strategies to prevent bladder cancer.

Keywords: Bladder cancer; cancer stem cells; cigarette smoke; epithelial-mesenchymal transition; sonic hedgehog pathway.

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42
Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1451-1456. eCollection 2020.
Changes in inflammatory factors in SV40MES13 mesangial cells after silencing ApoM gene
Jiongjiong Liu 1, Yang Zhang 2, Xiao Zhang 3, Shuchang Zhang 2, Yunfei Hu 2, Lizhuo Wang 2, Jialin Gao 2, Yao Zhang 2
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PMID: 32661483 PMCID: PMC7344000
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Abstract
Objective: Inflammation is an important process in the occurrence and development of nephropathy, and ApoM is closely related to inflammation. This article aims to investigate the inflammatory changes of SV40 MES13 cells after ApoM gene silencing by western blot and to explore the relationship between ApoM and inflammation.

Methods: Control group glomerular mesangial cells (SV40 MES13), and the same cells after adding a small interfering RNA silencing ApoM gene for 24 h were observed under a microscope and photographed. After extracting the protein western blot was used to explore the associated inflammation of IL-6, P-Jak2, Erk, TNF-α, P-JNK, IKKβ, P-p38, IκBα, P-IKKα/β, NF-κB and P-NF-κB expression.

Results: Western blot showed that ApoM gene was successfully silenced in SV40 MES13 cells after adding small interfering RNA. The decrease of inflammatory factors IL-6 and P-Jak2 in Jak/Stat pathway was statistically significant. Inflammatory cytokines TNF-α and P-JNK in the NF-κB pathway decreased statistically significantly, while the inflammatory factor IKKβ increased statistically significantly.

Conclusion: Inflammation was suppressed in SV40 cells with ApoM gene silencing.

Keywords: Apolipoprotein; inflammation; kidney disease.

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43
Int J Clin Exp Pathol
. 2020 May 1;13(5):979-988. eCollection 2020.
Overexpression of EP300-interacting inhibitor of differentiation 3 predicts poor prognosis in patients with glioblastoma multiforme
Peng-Yu Diao 1, Shao-Xun Li 2, Jin Peng 1, Ji-Hu Yang 1, Yu-Chen Pan 1, Xiang-Ping Xu 1, Han Tang 1, Jin-Xian Hu 1, Hua-Fu Zhao 1, Guo-Dong Huang 1
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PMID: 32509069 PMCID: PMC7270700
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Abstract
EP300-interacting inhibitor of differentiation 3 (EID3) is a member of the IED family and has been associated with tumorigenesis and tumor development in different cancer types. However, the role of EID3 in glioblastoma multiforme (GBM) prognosis is not clear. Whole transcriptome sequencing data of 249 and 149 GBM patients were collected from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) database respectively. The correlation between EID3 expression and overall survival (OS)/clinical pathologic features of GBM patients was investigated. Based on the Wilcoxon rank-sum test, EID3 expression in GBM tissues was significantly lower than in normal brain tissues (P < 0.001), and significantly higher than in LGG (low-grade glioma) (P < 0.001).There was a significant correlation between high EID3 expression with poor OS in CGGA (P = 0.049) and TCGA data (P = 0.024). Gene set enrichment analysis (GSEA) data analysis revealed a significant difference (FDR < 0.25, NOM p-value < 0.05) in the enrichment of MSigDB Collection (h.all.v6.2.symbols.gmt). A total of eight enriched pathways were identified in the high EID3 expression group, including Myc Targets V1, Kras signaling DN, and DNA repair pathways. Multivariate Cox regression analysis indicated that high expression of EID3 correlated with poor OS (P = 0.032, HR = 1.41, CI: 1.03-1.90). We conclude that EID3 could serve as an independent factor for predicting the prognosis of patients with GBM. Moreover, it is associated with GBM development through the regulation of the Myc Targets, Kras signaling DN, and DNA repair pathways.

Keywords: EID3; glioblastoma; overall survival; prognosis.

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44
Int J Clin Exp Pathol
. 2020 May 1;13(5):1262-1269. eCollection 2020.
Risk factors and prognosis in patients with adenocarcinoma of esophagogastric junction with lymph node metastasis of Siewert II/III
Zhi Zheng 1 2, Yuxi Shang 3, Rui Xu 4, Haiqiao Zhang 1 2, Jie Yin 1 2, Jun Zhang 1 2, Zhongtao Zhang 1 2
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PMID: 32509102 PMCID: PMC7270673
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Abstract
Adenocarcinoma of the esophagogastric junction (AEG) has a high incidence, while the extent of lymph node dissection and prognosis are still controversial. This study aimed to explore the risk factors of lymph node metastasis and prognosis in Siewert II/III AEG patients. Between July 2013 and May 2017, a total of 65 patients who underwent surgical operation in Beijing Friendship Hospital were retrospectively reviewed. The patients were followed up until September 2017. Data were analyzed using logistic regression. Survival analyses were performed using Kaplan-Meier. Multivariate analysis revealed that histologic classification (OR=3.437, 95% CI: 1.046~11.294, P=0.042) and intravascular cancer embolus (OR=6.614, 95% CI: 1.942~22.524, P=0.003) were correlated with lymph node metastasis. The lymph nodes No. 1, 2, 3, 7, 11 and 110 indicated higher metastatic rate. The 3-year overall survival analysis revealed that lymph node metastasis (P=0.167) and tumor stage (P=0.429) exhibited no significant differences. Findings suggest that histologic type and vascular neoplasia are independent risk factors for lymph node metastasis. For Siewert II/III AEG patients, it is reasonable to perform radical gastrectomy combined with D2 lymph node dissection. For No. 110 lymph nodes should be dissected routinely. However, the long-term prognosis remains to be further studied.

Keywords: Adenocarcinoma of esophagogastric junction; Siewert II/III; logistic regression analysis; lymphatic metastasis; survival analysis.

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45
Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1390-1396. eCollection 2020.
miR-499a promotes PANC-1 cell proliferation by down-regulating PDCD4 expression in pancreatic ductal adenocarcinoma
Jianheng Bao 1, Zhonglian Li 1
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PMID: 32661474 PMCID: PMC7344005
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive digestive system tumors, but study of the molecular mechanism of occurrence and development of PDAC is considerably limited. In order to better understand the potential pathogenesis, the differentially expressed miRNAs were screened in PDAC and adjacent tissues using miRNAs microarrays. We found that miR-499a was significantly up-regulated in PDAC tissues compared with adjacent tissues, and protein-protein interaction (PPI) and gene ontology (GO) analyses indicated programmed cell death protein 4 (PDCD4) is a key target gene of miR-499a, which is involved in the regulation of transcription, cellular biosynthetic process, RNA metabolic process, and other multiple biologic processes. Moreover, PDCD4 mRNA and protein expression were obviously down-regulated in PDAC tissues compared with adjacent tissues. In vitro, up-regulating of miR-499a could decrease PDCD4 expression and promote cell proliferation in PANC-1 cells transfected with miR-499a mimics. Similarly, promoting proliferation was also observed in PANC-1 cells transfected with PDCD4 siRNA. In conclusion, we first found miR-499a was significantly up-regulated in PDAC tissues, and we promoted PANC-1 cell proliferation by down-regulating PDCD4 expression.

Keywords: PANC-1; PDCD4 expression; cell proliferation; miR-499a; pancreatic ductal adenocarcinoma.

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46
Int J Clin Exp Pathol
. 2020 May 1;13(5):1060-1065. eCollection 2020.
β-coronavirus infectious diseases: recommended strategies for the prevention and control of transmission
Guozhong He 1, Zhong Sun 2, Yao Zhao 1, Shuwei Zhang 1, Hongyu Chen 1, Zizhao Zhao 1, Guang Yang 1, Quan Zhou 1
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PMID: 32509079 PMCID: PMC7270699
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Abstract
In recent years, the incidence and mortality of infectious diseases in China are increasing. Infectious diseases, especially new infectious diseases, seriously threaten people's lives. Recent works found that most of the emerging infectious diseases come from wild life. At the same time, the impact of human activities on the environment has further deteriorated the living environment of wildlife. However, with the conducted in-depth research on virus, human beings increase the risk of getting infected. Taking Beta Coronavirus as the example, we analyzed the transmission risks of coronavirus in the prevention and control of the outbreaks of emerging infectious diseases, and recommend the prevention and control strategies before, during and after the viral outbreak. Additional works are urgently needed to better define the biological and epidemiological characteristics of these viruses.

Keywords: environment; infectious diseases; preventive measures; wildlife; β-Coronavirus.

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47
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1212-1215. eCollection 2020.
Simultaneous multiple primary cancers with concomitant inflammatory myofibroblastic tumor: a case report
Xingyu Lv 1 2, Jianming Ye 3, Guangyi Jiang 1 2, Yifan Wang 1 2, Jisheng Lv 4, Yong Wang 1
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PMID: 32509097 PMCID: PMC7270680
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Abstract
Multiple primary cancers are of rare occurrence. Most multiple primary cancers are metachronous multiple primary cancers, while simultaneous multiple primary cancers are rare. Inflammatory myofibroblastic tumors are rare. Inflammatory myofibroblastic tumor occurs most frequently in children and young adults. Herein, we report a rare case of simultaneous multiple primary cancers and inflammatory myofibroblastic tumor. A 44-year-old woman was admitted for a breast mass evaluation. The patient was positive for antinuclear, anti-mitochondrial, and anti-RO52 antibodies. Breast magnetic resonance imaging revealed a right breast mass. After neoadjuvant chemotherapy, modified radical mastectomy was performed. Postoperative histopathology revealed an invasive ductal carcinoma. Two months later, computed tomography revealed a nodule in the right upper lobe and ground-glass opacity in the lower lobe of the lungs. Lobectomy and lobe biopsy were performed. Postoperative histopathology revealed that the mass in the right upper lobe was an inflammatory myofibroblastic tumor and the right lower lobe lesion was an invasive adenocarcinoma. Immunohistochemistry of the inflammatory myofibroblastic tumor revealed negativity for anaplastic lymphoma kinase. At the 4-month follow-up, the patient showed good recovery. The etiology of multiple primary cancers and inflammatory myofibroblastic tumors is still unknown; in this case, we believe that autoimmune factors are the main cause of multiple primary cancers with concomitant inflammatory myofibroblastic tumor. Tissue biopsy is needed to ensure correct diagnosis of multiple primary cancers and inflammatory myofibroblastic tumor. Surgery-based comprehensive therapy is recommended. The prognosis is favorable and regular follow-up is necessary.

Keywords: Inflammatory myofibroblastic tumor; multiple primary cancers; primary breast cancer; primary lung cancer.

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48
Case Reports Int J Clin Exp Pathol
. 2020 Jun 1;13(6):1444-1450. eCollection 2020.
Non-HPV-related verrucous carcinoma of the endometrium: report of one case and review of literature
Di Sun 1, Haiyang Jiang 1, Ping Yang 1, Ying Liu 1
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PMID: 32661482 PMCID: PMC7344013
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The clinicopathologic diagnosis and treatment of a case of endometrial verrucous carcinoma were analyzed, combined with the relevant literature for review and discussion. The patient was a 67-year-old postmenopausal woman who had recurrent vaginal bleeding with increased secretion. The gross morphology and histopathology of the uterine cavity tumor had typical characteristic changes of verrucous carcinoma. There was obvious inflammation in the tumor background and squamous differentiation in the residual endometrial gland basal reserve cells. Tumor cell immunohistochemistry showed wild-type P53, P16 negative expression and HPV molecular test was negative. The expression of p63 was positive in squamous differentiated reserve cells, and Ki67 showed high proliferative activity. Verrucous carcinoma of endometrium is a rare tumor with low malignancy, that belongs to a special subtype of squamous cell carcinoma. It is easily missed or misdiagnosed and has a long diagnosis cycle. The diagnosis should be combined with clinical data, imaging and pathology. The pathogenesis of the disease is not clear. Surgical treatment is the first treatment, and the clinical prognosis is good.

Keywords: Endometrium; non-HPV-related; reserve cells; verrucous carcinoma.

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49
Int J Clin Exp Pathol
. 2020 May 1;13(5):1243-1252. eCollection 2020.
Long noncoding RNA MALAT1 promotes high glucose-induced inflammation and apoptosis of vascular endothelial cells by regulating miR-361-3p/SOCS3 axis
Kai Huang 1, Xuxia Yu 1, Yushan Yu 1, Lu Zhang 1, Yin Cen 1, Jinguo Chu 1
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PMID: 32509100 PMCID: PMC7270668
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Abstract
Vascular complications are the important pathophysiologic manifestations of patients with diabetes mellitus (DM) and many long non-coding RNAs (LncRNAs) are involved in this process. In this study, we aimed to investigate the relationships among LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), microRNA-361-3p (miR-361-3p), and suppressor of cytokine signaling 3 (SOCS3) in high glucose (HG)-induced human umbilical vein endothelial cell (HUVEC) injury and its underlying mechanism. We found that HG treatment significantly promotes MALAT1 and SOCS3 expressions, but inhibits miR-361-3p expression in HUVECs. Furthermore, through bioinformatics analysis and dual luciferase assay, we found that MALAT1 directly sponges miR-361-3p to counteract its suppression on SOCS3 expression. Moreover, knockdown of MALAT1 evidently inhibits HG-induced inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 expressions in HUVECs (and HUVEC apoptosis) by regulating the miR-361-3p/SOCS3 axis. In conclusion, our results indicate that knockdown of MALAT1 inhibits HG-induced vascular endothelial injury through regulating miR-361-3p/SOCS3 axis, suggesting that inhibition of MALAT1 as a potential target for endothelial injury therapy for DM.

Keywords: Diabetes mellitus; high glucose; metastasis-associated lung adenocarcinoma transcript 1; microRNA-361-3p; suppressor of cytokine signaling 3.

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50
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1086-1089. eCollection 2020.
Pseudovascular adenoid squamous cell carcinoma of the tongue: a case report and literature review
Xiaodong Han 1, Xiaozhen Lin 1, Xiaojun Shao 1
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PMID: 32509083 PMCID: PMC7270655
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Abstract
Pseudovascular adenoid squamous cell carcinoma (PASCC) is an uncommon histologic variant of squamous cell carcinoma, characterized by acantholysis in the cancer nests resulting in a pseudovascular appearance, and a subtype of acantholytic squamous cell carcinoma. It is relatively common in sun-exposed skin, but is extremely rare in oral cavity. A 56-year-old woman was referred to our department presented with a fast-growing mass in the front of the tongue for more than two months. Physical examination revealed a exophytic lesion with a pedicle in the anterior tongue. An incisional biopsy was performed. On microscopic examination, the tumor was composed of vessel-like anastomosing channels and dilated vessel-like spaces, similar to hemangioma, and the anastomosing channels contained free tumor cells. The nests of tumor cells with significant acantholysis were observed in some regions. Immunohistochemical examination revealed cells positive for pan-CK, CK5/6, p63, and negative for CD31 and CD34. The pathological diagnosis was confirmed as pseudovascular adenoid squamous cell carcinoma. The extended resection of the tumor and neck dissection was performed. There was no tumor recurrence or distant metastasis after 15 months of follow-up.

Keywords: Pseudovascular adenoid squamous cell carcinoma; acantholytic squamous cell carcinoma; immunohistochemistry; oral cavity.

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