Serum nardilysin, a surrogate marker for epithelial-mesenchymal transition, predicts prognosis of intrahepatic cholangiocarcinoma after surgical resection

Purpose: Few studies have investigated prognostic biomarkers in patients with intrahepatic cholangiocarcinoma (ICC). Nardilysin (NRDC), a metalloendopeptidase of the M16 family, has been suggested to play important roles in inflammation and several cancer types. We herein examined the clinical significance and biological function of NRDC in ICC. Experimental Design: We measured serum NRDC levels in 98 ICC patients who underwent surgical resectionin two independent cohorts to assess its prognostic impact. We also analyzed NRDC mRNA levels in cancerous tissue specimens from 43 ICC patients. We investigated the roles of NRDC in cell proliferation, migration, gemcitabine sensitivity, and gene expression in ICC cell lines using gene silencing. Results: High serum NRDC levels were associated with shorter overall survival and disease-free survival in the primary (n=79) and validation (n=19) cohorts. A correlation was observed between serum protein levels and cancerous tissue mRNA levels of NRDC (Spearman's =0.413, p=0.006). The gene knockdown of NRDC in ICC cell lines attenuated cell proliferation, migration, and tumor growthin xenografts, andincreased sensitivity to gemcitabine. The gene knockdown of NRDC was also accompanied by significant changes in the expression of several epithelial-mesenchymal transition (EMT)-related genes. Strong correlations were observed between the mRNA levels of NRDC and EMT-inducing transcription factors, ZEB1 and SNAI1,in surgical specimens from ICC patients. Conclusions:Serum NRDC, a possible surrogate marker reflecting the EMT state in primary tumors, predicts the outcome of ICC after surgical resection.

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