title: BIRC6 promotes hepatocellular carcinogenesis: interaction of BIRC6 with p53 facilitating p53 degradation.
abstract: The genes that encode inhibitor of apoptosis proteins (IAPs) are frequently overexpressed in human cancers. However, the expression pattern and clinical significance of BIRC6, a member of IAPs, in hepatocellular carcinoma (HCC) remains unclear. Here we investigated the role of BIRC6 in hepatocellular carcinogenesis. We used immunoblot and immunochemical analyses to determine the levels of BIRC6 in 7 hepatoma cell lines and 160 HCC specimens. We evaluated the proognostic value of BIRC6 expression and its association with clinical parameters. A lentivirus-mediated silencing method was used to knockdown BIRC6, and the biological consequences of BIRC6 silencing in three hepatoma cell lines were investigated in vitro and in vivo. We found that BIRC6 overexpression was significantly correlated with serum ALT level and HCC vascular invasion. Patients with positive BIRC6 expression in tumor tissue had a poor survival and a high rate of recurrence. BIRC6 knockdown remarkably suppressed cell proliferation, caused G1/S arrest and sensitized hepatoma cells to sorafenib-induced apoptosis in hepatoma cells, which was partly reversed by RNA interference targeting p53. The mechanistic study revealed that BIRC6 interacted with p53 and facilitated its degradation. The in vivo study showed that BIRC6 knockdown inhibited xenograft tumor growth and increased the sensitivity of tumor cells to sorafenib in nude mice. Taken together, these findings demonstrate that BIRC6 overexpression in HCC specimens is indicative of poor prognosis and that its interaction with p53 facilitates the degradation of p53, leading to carcinogenesis and an anti-apoptotic status.
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai, Institute of Liver Disease, Fudan University, Shanghai, China.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Tang
authors.forename: Ruyi
authors.initials: R
authors.lastname: Xue
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Weng
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Ying
authors.initials: Y
authors.lastname: Fang
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Lingling
authors.initials: L
authors.lastname: Ji
authors.forename: Tingting
authors.initials: T
authors.lastname: Hu
authors.forename: Taotao
authors.initials: T
authors.lastname: Liu
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Huang
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.forename: Xizhong
authors.initials: X
authors.lastname: Shen
authors.forename: Si
authors.initials: S
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Dong
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011379:Prognosis; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C401541:BIRC6 protein, human; D051034:Inhibitor of Apoptosis Proteins; D010671:Phenylurea Compounds; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D000077157:Sorafenib
keywords: G1/S arrest; apoptosis; growth inhibition; tumorigenesis; ubiquitination