title: The collagen triple helix repeat containing 1 facilitates hepatitis B virus-associated hepatocellular carcinoma progression by regulating multiple cellular factors and signal cascades.
abstract: Hepatitis B virus (HBV) infection is one of the major causes of acute and chronic liver diseases, fulminant hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). HCC accounts for more than 85% of primary liver cancers and is the seventh most common cancer and the third leading cause of cancer-related deaths. However, the mechanism by which HBV induces HCC is largely unknown. Collagen triple helixes repeat containing 1 (CTHRC1) is a secreted protein and has characteristics of a circulating hormone with potentially broad implications for cell metabolism and physiology. CTHRC1 is associated with human cancers, but its effect on HCC is unknown. Here, we revealed that CTHRC1 expression is highly correlated with HCC progression in HBV-infected patients, and demonstrated that HBV stimulates CTHRC1 expression by activating nuclear factor-kappa B (NF-κB) and cAMP response element binding protein (CREB), through extracellular signal-regulated kinase/c-Jun N-terminal kinase (ERK/c-JNK) pathway. In addition, CTHRC1 activates hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) through regulating phosphoinosmde-3-kinase/protein kinase B/mammalian target of rapamycin (PI-3K/AKT/mTOR) pathway. More interestingly, CTHRC1 enhances colony formation, migration, and invasion of hepatoma cells by regulating p53 and stimulating matrix metalloproteinase-9 (MMP-9) expression. In addition, knock-down of CTHRC1 results in the repression of HBV-associated carcinogenesis in nude mice. Thus, we revealed a novel mechanism by which HBV facilitates HCC development through activating the oncoprotein CTHRC1, which in turn enhances HBV-related HCC progression by stimulates colony formation, migration, and invasion of hepatoma cells through regulating multiple cellular factors and signal cascades.
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Chengliang
authors.initials: C
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: He
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Yingle
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Kailang
authors.initials: K
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wu
mesh_terms: D000328:Adult; D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D016022:Case-Control Studies; D002460:Cell Line; D045744:Cell Line, Tumor; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D055815:Young Adult
chemical_list: D001685:Biological Factors; C502426:CTHRC1 protein, human; D016326:Extracellular Matrix Proteins; D015513:Oncogene Proteins
keywords: collagen triple helix repeat containing-1; colony formation, migration and invasion in hepatoma cells; hepatitis B virus; hepatocellular carcinoma; matrix metalloproteinase 9