Secretory Stanniocalcin 1 promotes metastasis of hepatocellular carcinoma through activation of JNK signaling pathway

• Published in: Cancer letters Vol. 403; pp. 330 - 338
• Main Authors: Chan, Kristy Kwan-Shuen, Leung, Carmen Oi-Ning, Wong, Carmen Chak-Lui, Ho, Daniel Wai-Hung, Chok, Kenneth Siu-Ho, Lai, Ching-Lung, Ng, Irene Oi-Lin, Lo, Regina Cheuk-Lam
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 10.09.2017; Elsevier Limited
• Subjects: Animals; Antineoplastic Agents - pharmacology; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomarkers, Tumor - secretion; Breast cancer; c-Jun protein; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - secondary; Carcinoma, Hepatocellular - secretion; Cell migration; Cell Movement - drug effects; Cloning; Disease-Free Survival; Gene expression; Gene Expression Regulation, Neoplastic; Glycoproteins - blood; Glycoproteins - genetics; Glycoproteins - metabolism; Glycoproteins - secretion; HCC; Hepatocellular carcinoma; Humans; Hypoxia; JNK; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; Kaplan-Meier Estimate; Liver cancer; Liver Neoplasms - enzymology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - secretion; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - secondary; Lung Neoplasms - secretion; Metastases; Metastasis; Mice, Inbred BALB C; Mice, Nude; Ovarian cancer; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proteins; RNA Interference; Rodents; Signal transduction; Signal Transduction - drug effects; Stanniocalcin; STC1; Time Factors; Transcription factors; Transfection; Tumor Burden; Tumor Hypoxia; Tumor Microenvironment; Up-Regulation; United States > US; STC1; HCC; JNK
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2017.06.034

The hypoxic microenvironment is well-characterized in hepatocellular carcinoma (HCC). Delineation of hypoxia-responsive events is an integral part to understand the pathogenesis of HCC. We studied the functional role and clinical relevance of Stanniocalcin 1 (STC1), a hypoxia-induced molecular target, in HCC. In our clinical cohort, STC1 transcript was up-regulated in HCC tumor tissues. Moreover, STC1 protein was detected in the sera of HCC patients. A higher serum STC1 level was correlated with larger tumor size and poorer 5-year disease-free survival. Functionally, recombinant STC1 protein (rhSTC1) promoted cell migration and cell invasion in vitro; and the effect was abolished by co-treatment of anti-STC1 neutralizing antibody. By in vivo mouse model, silencing of STC1 in HCC cells downregulated secretory STC1 level and suppressed lung metastasis. Furthermore, we found that rhSTC1 activated the JNK pathway, as evidenced by altered expression of the key molecular targets pJNK and p-c-Jun. The functional effects conferred by rhSTC1 were abrogated by co-treatment of JNK inhibitor. In summary, secretory STC1 enhances metastatic potential of HCC via JNK signaling. It potentially serves as a prognostic serum biomarker and a therapeutic target for HCC. •A higher serum STC1 level in HCC patients was correlated with poorer survival•Secretory STC1 enhances metastatic potential of HCC via JNK pathway•Secretory STC1 is a potential prognosticator and therapeutic target for HCC