TRIM27-USP7 complex promotes tumour progression via STAT3 activation in human hepatocellular carcinoma
TRIM27-USP7 complex promotes tumour progression via STAT3 activation in human hepatocellular carcinoma
复制标题
DOI：
10.1111/liv.15346
复制
发表时间：
2022-07-07
影响因子：
6.7
通讯作者：
Ohtsuka, Masayuki
中科院分区：
文献类型：
--
作者：
Sakamoto, Toshiya;Kuboki, Satoshi;Ohtsuka, Masayuki
TRIM 27通过与USP 7结合而稳定，并介导几种癌症的肿瘤进展;然而，TRIM 27-USP 7复合物对HCC中STAT 3激活的作用尚不清楚。方法采用207例肝癌标本或肝癌细胞，检测TRIM 27对STAT 3的调控作用。结果TRIM 27在部分肝癌组织中表达增强。TRIM 27高表达是HCC术后不良预后的独立预测因子。肝癌组织中EpCAM、vimentin、MMP-9的表达及STAT 3的活化与肝癌组织中EpCAM、vimentin、MMP-9的表达密切相关。TRIM 27表达与USP 7表达相关，TRIM 27高表达与USP 7高表达的HCC显示增强的STAT 3活化，导致预后较差。在TRIM 27高表达的HCC中，p-JAK 1表达与STAT 3激活相关。在体外，USP 7敲低降低了TRIM 27表达，表明USP 7对于TRIM 27稳定是必需的。TRIM 27或USP 7的敲低抑制了STAT 3的活化，而TRIM 27的过表达加速了STAT 3的活化;因此，STAT 3的活化需要TRIM 27-USP 7复合物的形成，这通过增强EMT和CSC样性质导致了侵袭性肿瘤增殖和侵袭。在体外证实JAK 1与TRIM 27-USP 7复合物的结合。通过USP 7抑制剂删除TRIM 27-USP 7复合物通过抑制STAT 3活化显著抑制肿瘤细胞侵袭。结论TRIM 27通过与USP 7结合而稳定，并通过激活STAT 3与HCC的侵袭性肿瘤进展相关，导致术后预后不良。因此，TRIM 27-USP 7复合物是一个有用的预后预测因子和一个有希望的治疗靶点。
Background & Aims TRIM27 is stabilized by binding to USP7 and mediates tumour progression in several cancers; however, the roles of TRIM27-USP7 complex on STAT3 activation in HCC are unknown. Methods Regulations and functions of TRIM27 for activating STAT3 in HCC were assessed using 207 HCC samples or HCC cells. Results TRIM27 expression was increased in some cases of HCC. High TRIM27 expression was an independent predictor for poor prognosis in HCC after surgery. It was correlated with the expression of EpCAM, vimentin, MMP-9, and activation of STAT3 in HCC. TRIM27 expression was correlated with USP7 expression, and HCC with high TRIM27 expression together with high USP7 expression showed enhanced STAT3 activation, resulting in poorer prognosis. p-JAK1 expression was correlated with STAT3 activation in HCC with high TRIM27 expression. In vitro, USP7 knockdown decreased TRIM27 expression, suggesting that USP7 was essential for TRIM27 stabilization. Knocking down of TRIM27 or USP7 suppressed STAT3 activation and overexpression of TRIM27 accelerated STAT3 activation; therefore, the formation of TRIM27-USP7 complex was needed for STAT3 activation, which led to aggressive tumour proliferation and invasion by enhancing EMT and CSC-like property. Binding of JAK1 to TRIM27-USP7 complex was confirmed in vitro. Deletion of TRIM27-USP7 complex by USP7 inhibitor significantly inhibited tumour cell invasion by suppressing STAT3 activation. Conclusions TRIM27 is stabilized by binding to USP7 and is related to aggressive tumour progression in HCC via STAT3 activation, resulting in poor prognosis after operation. Therefore, TRIM27-USP7 complex is a useful prognostic predictor and a promising therapeutic target for HCC.