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 demonstate 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. What's new? Inhibition of apoptosis proteins (IAPs) are involved in carcinogenesis, but for some, such as BIRC6, an IAP that facilitates proteasomal degradation of pro-apoptotic proteins, the mechanisms by which they facilitate tumor development remain unclear. This report sheds new light on the effect of BIRC6 on hepatocellular carcinoma (HCC) development. BIRC6 was found to influence carcinogenesis via modulation of the cell cycle, cell proliferation, and apoptosisactivities that were dependent on its interaction with p53. In addition, BIRC6 expression levels were correlated with HCC prognosis. The findings suggest that BIRC6 is a promising prognostic marker and therapeutic target in HCC.
[1]Fudan Univ, Inst Liver Dis, Zhongshan Hosp, Dept Gastroenterol & Hepatol, Shanghai 200032, Shanghai, Peoples R China.
[2]Fudan Univ, Coll Basic Med Sci, Key Lab Mol Virol, Shanghai 200032, Shanghai, Peoples R China.
[3]Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Glycoconjugate Res,Minist Publ Hlth, Shanghai 200032, Shanghai, Peoples R China.
[4]Fudan Univ, Zhongshan Hosp, Dept Hepat Surg, Liver Canc Inst, Shanghai 200032, Shanghai, Peoples R China.
(8.0+极速模式)