Bmi1 drives hepatocarcinogenesis by repressing the TGFβ2/SMAD signalling axis
Bmi1 drives hepatocarcinogenesis by repressing the TGFβ2/SMAD signalling axis
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Bmi1 通过抑制 TGFbeta2/SMAD 信号轴来驱动肝癌发生。
DOI：
10.1038/s41388-019-1043-8
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发表时间：
2020-01-01
期刊：
影响因子：
8
通讯作者：
Xu, Chuanrui
中科院分区：
文献类型：
--
作者：
Li, Bin;Chen, Yuyuan;Xu, Chuanrui
Bmi1 is overexpressed in one-third of hepatocellular carcinoma (HCC) patients and acts as an oncogene in hepatocarcinogenesis. However, the underlying mechanism is unclear. The role of TGF beta signalling in HCC is not well defined as well. Here, we report that TGF beta 2 is a target of Bmi1 in HCC and has a tumour-suppressing role. In Bmi1-knockout mouse livers and HCC cell lines, TGF beta 2/SMAD cascade proteins were upregulated. TGF beta 2 expression was inversely correlated with Bmi1 expression in human and mouse HCC tissues. In vitro, Bmi1 knockdown activated TGF beta 2/SMAD signalling and led to cell apoptosis via upregulation of p15 and p21. TGF beta 2 inhibition rescued the inhibitory effect of Bmi1 knockdown on HCC cell survival, proliferation, and cell-cycle progression. In vivo, restoration of TGF beta 2 expression blocked Bmi1/Ras-driven hepatocarcinogenesis in mice. Chromatin immunoprecipitation and luciferase reporter assays revealed that Bmi1 repressed TGF beta 2 expression by binding to its promoter as a co-factor of polycomb repressor complex 1. Our findings elucidate the molecular mechanism underlying hepatic Bmi1-driven carcinogenesis and highlight the importance of TGF beta 2 as a tumour suppressor in HCC development.
