BIRC6 promotes hepatocellular carcinogenesis: Interaction of BIRC6 with p53 facilitating p53 degradation
BIRC6 promotes hepatocellular carcinogenesis: Interaction of BIRC6 with p53 facilitating p53 degradation
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BIRC6 促进肝细胞癌变：BIRC6 与 p53 相互作用促进 p53 降解。
DOI：
10.1002/ijc.29194
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发表时间：
2015-03-15
影响因子：
6.4
通讯作者：
Dong, Ling
中科院分区：
文献类型：
--
作者：
Tang, Wenqing;Xue, Ruyi;Dong, Ling
编码凋亡抑制蛋白（IAP）的基因在人类癌症中经常过表达。然而，BIRC 6，IAP的成员，在肝细胞癌（HCC）中的表达模式和临床意义仍不清楚。在这里，我们研究了BIRC 6在肝细胞癌发生中的作用。我们使用免疫印迹和免疫化学分析来确定BIRC 6在7个肝癌细胞系和160个HCC标本中的水平。我们评估了BIRC 6表达的诊断价值及其与临床参数的相关性。使用慢病毒介导的沉默方法敲低BIRC 6，并在体外和体内研究了BIRC 6沉默在三种肝癌细胞系中的生物学后果。我们发现BIRC 6过表达与血清ALT水平和HCC血管浸润显著相关。肿瘤组织中BIRC 6阳性表达的患者生存率低，复发率高。BIRC 6敲低显著抑制细胞增殖，导致G1/S停滞，并使肝癌细胞对索拉非尼诱导的肝癌细胞凋亡敏感，这被靶向p53的RNA干扰部分逆转。机制研究表明，BIRC 6与p53相互作用并促进其降解。体内研究表明，BIRC 6敲低抑制异种移植肿瘤生长，并增加肿瘤细胞对索拉非尼的敏感性。总之，这些发现表明，HCC标本中的BIRC 6过表达表明预后不良，并且其与p53的相互作用促进p53的降解，导致致癌和抗凋亡状态。
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.