Sakamoto Toshiya, Kuboki Satoshi, Furukawa Katsunori, Takayashiki Tsukasa, Takano Shigetsugu, Yoshizumi Arihito, Ohtsuka Masayuki
Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
Liver Int. 2023 Jan;43(1):194-207. doi: 10.1111/liv.15346. Epub 2022 Jul 7.
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.
Regulations and functions of TRIM27 for activating STAT3 in HCC were assessed using 207 HCC samples or HCC cells.
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.
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.
TRIM27通过与USP7结合而稳定，并介导多种癌症的肿瘤进展；然而，TRIM27-USP7复合物在肝癌中对STAT3激活的作用尚不清楚。
使用207例肝癌样本或肝癌细胞评估TRIM27在肝癌中激活STAT3的调控及功能。
部分肝癌病例中TRIM27表达增加。高TRIM27表达是肝癌术后预后不良的独立预测因素。它与肝癌中EpCAM、波形蛋白、MMP-9的表达以及STAT3的激活相关。TRIM27表达与USP7表达相关，高TRIM27表达且高USP7表达的肝癌显示出增强的STAT3激活，导致预后更差。在高TRIM27表达的肝癌中，p-JAK1表达与STAT3激活相关。在体外，敲低USP7可降低TRIM27表达，提示USP7对TRIM27的稳定至关重要。敲低TRIM27或USP7可抑制STAT3激活，而TRIM27的过表达可加速STAT3激活；因此，STAT3激活需要形成TRIM27-USP7复合物，这通过增强上皮-间质转化和癌症干细胞样特性导致侵袭性肿瘤增殖和侵袭。体外证实JAK1与TRIM27-USP7复合物结合。USP7抑制剂删除TRIM27-USP7复合物可通过抑制STAT3激活显著抑制肿瘤细胞侵袭。
TRIM27通过与USP7结合而稳定，并通过STAT3激活与肝癌侵袭性肿瘤进展相关，导致术后预后不良。因此，TRIM27-USP7复合物是肝癌有用的预后预测指标和有前景的治疗靶点。
