Serum Nardilysin, a Surrogate Marker for Epithelial–Mesenchymal Transition, Predicts Prognosis of Intrahepatic Cholangiocarcinoma after Surgical Resection

Abstract

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 patients with ICC who underwent surgical resection in two independent cohorts to assess its prognostic impact. We also analyzed NRDC mRNA levels in cancerous tissue specimens from 43 patients with ICC. 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 ¼ 79) and validation (n ¼ 19) cohorts. A correlation was observed between serum protein levels and cancerous tissue mRNA levels of NRDC (Spearman r ¼ 0.413; P ¼ 0.006). The gene knockdown of NRDC in ICC cell lines attenuated cell proliferation, migration, and tumor growth in xenografts, and increased 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 patients with ICC. Conclusions: Serum NRDC, a possible surrogate marker reflecting the EMT state in primary tumors, predicts the outcome of ICC after surgical resection.

Prognostic and Predictive Molecular Markers in Cholangiocarcinoma

“…Indeed, SOX4 transcription factor, a member of the SOX (SRY-related HMG-box) family, has been shown to promote EMT in vitro, while SOX4 overexpression in tumor tissue indicated poor prognosis in patients with iCCA [ 86 ]. Moreover, elevated serum level of nardilysin (N-arginine dibasic convertase, NRDC), a soluble cytosolic protein, correlated with increased NRDC mRNA expression in tumor tissue and EMT-inducing transcription factors, and was associated with shorter OS and DFS in patients with iCCA [ 87 ].…”

Deficiency of Nardilysin in the Liver Reduces Serum Cholesterol Levels

“…Previous studies using NRDC whole body deficient mice revealed that NRDC deficiency could suppress the progression of liver diseases in mice. 21,26) In humans, high serum NRDC levels predict poor prognosis of hepatocellular carcinoma based upon viral hepatitis C, 26) as well as intrahepatic cholangiocarcinoma. 27) However, roles of hepatic NRDC in metabolic disorders have not yet been fully defined.…”

LncRNA RHPN1-AS1 promotes cholangiocarcinoma progression and predicts poor clinical outcome through miR-345-5p/YAP1 axis

“…Cholangiocarcinoma (CCA) is a devastating biliary malignancy with an abysmal overall 5-year survival rate at stages III and IV of less than 10%, [1]. CCA is one of the most di cult intra-abdominal cancers, occurring via the malignant transformation of the epithelium lining of the biliary tree, called cholangiocytes, that derive from the bile ductules [2,3]. Histologically, CCAs can be classi ed into intrahepatic cholangiocarcinoma (iCCA), distal cholangiocarcinoma (dCCA) and perihilar cholangiocarcinoma (pCCA) subtypes [4].…”