Immunohistochemical Profile of Tumor Suppressor Proteins RASSF1A and LATS1/2 in Relation to p73 and YAP Expression, of Human Inflammatory Bowel Disease and Normal Intestine

Abstract

The intestinal neoplastic transformation is a possible risk of chronic inflammatory bowel disease (IBD). Previous evidence in mice IBD provides a role for the RAS-association domain family tumor suppressor protein 1 A (RASSF1A), in the repairing process following mucosa epithelium damage, through cooperation with the HIPPO-signaling molecules p73, and YAP. HIPPO pathway which has been implicated in stem cell activity includes as key components for signal transduction the large tumor suppressor homology Ser/Thr kinases LATS1/2. The aim of this study was to assess immunohistochemically, using specific antibodies, the RASSF1A and LATS1/2 expression patterns in a cohort of patients with IBD including 52 ulcerative colitis (UC), 24 Crohn's disease (CD) and 24 IBD unclassified (IBD-U), compared with normal intestine from non-IBD patients (control group). The relationship between subtypes of IBD and RASSF1A and LATS1/2 expression, both individually and related to p73 and YAP/pYAP(Ser127) proteins was also investigated. Quantitative analyses of the immunohistochemical findings in mucosa cells revealed a significantly decreased expression in UC and IBD-U for RASSF1A expression and a significantly elevated expression in UC, IBD-U, and CD for LATS1/2 expression compared with normal mucosa (P < 0.05). However, ROC curve analysis showed that only LATS1/2 could differentiate IBD from control group. RASSF1A expression was significantly correlated with LATS1/2 in UC with dysplasia (P < 0.0001), and p73 in UC (P < 0.001), and IBD-U (P < 0.02). The expression of all proteins did not differ significantly between subtypes of IBD (P ≥ 0.05). RASSF1A-LATS1/2 co-expression was mainly observed in IBD samples. These findings suggest that tumor suppression proteins RASSF1A and LATS1/2 may be involved in the pathogenesis of human IBD and imply a potential cooperation of RASSF1A, and HIPPO signaling pathways in human bowel inflammation.

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