WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma.
WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma.
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WWC2 是一个独立的预后因素，可通过 Hippo 信号传导阻止肝细胞癌的侵袭
DOI：
10.1111/jcmm.13281
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发表时间：
2017-12
影响因子：
5.3
通讯作者：
Cao Y
中科院分区：
文献类型：
--
作者：
Zhang Y;Yan S;Chen J;Gan C;Chen D;Li Y;Wen J;Kremerskothen J;Chen S;Zhang J;Cao Y
WWC家族蛋白通过抑制Yes相关蛋白（雅普）（Hippo途径的主要效应物）的转录活性，负调控HEK 293细胞增殖和器官生长。支架蛋白WWC 1（也称为KIBRA）的功能已在细胞和动物模型中进行了深入研究。然而，WWC 2在癌症中的表达和临床病理学意义的特点很差。本研究旨在阐明WWC 2在肝细胞癌（HCC）中的生物学功能和作用机制。回顾性分析显示，与配对的相邻非癌组织相比，WWC 2在95例临床HCC组织中显著下调。此外，WWC 2表达的缺失与晚期临床病理特征显著相关，包括静脉浸润、较大的肿瘤大小和晚期TNM分期。阳性WWC 2表达与显著更好的5年总生存率相关，并且WWC 2是HCC总生存率的独立预后因素。此外，我们证实WWC 2抑制肝癌细胞的体外侵袭能力。在同一组HCC组织中也观察到升高的雅普表达。Pearson相关系数分析显示，肝细胞癌中WWC 2表达与核雅普蛋白表达呈负相关。从机制上讲，我们证实了WWC 2的过表达通过激活大肿瘤抑制因子1和2激酶（LATS 1/2）抑制HCC细胞的侵袭和转移潜力，这反过来又磷酸化转录共激活因子雅普。总体而言，这项研究表明WWC 2通过负调节Hippo信号通路作为肿瘤抑制因子发挥作用，并可作为HCC的预后标志物。
WWC family proteins negatively regulate HEK293 cell proliferation and organ growth by suppressing the transcriptional activity of Yes‐associated protein (YAP), a major effector of the Hippo pathway. The function of the scaffolding protein WWC1 (also called KIBRA) has been intensively studied in cells and animal models. However, the expression and clinicopathologic significance of WWC2 in cancer are poorly characterized. This study aimed to clarify the biological function and mechanism of action of WWC2 in hepatocellular carcinoma (HCC). Retrospective analysis revealed WWC2 was significantly down‐regulated in 95 clinical HCC tissues compared to the paired adjacent non‐cancerous tissues. Moreover, loss of WWC2 expression was significantly associated with advanced clinicopathological features, including venous infiltration, larger tumour size and advanced TNM stage. Positive WWC2 expression was associated with significantly better 5‐year overall survival, and WWC2 was an independent prognostic factor for overall survival in HCC. Moreover, we confirmed WWC2 inhibits HCC cell invasive ability in vitro. Elevated YAP expression was also observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated WWC2 expression correlated inversely with nuclear YAP protein expression in HCC. Mechanistically, we confirmed overexpression of WWC2 suppresses the invasive and metastatic potential of HCC cells by activating large tumour suppressor 1 and 2 kinases (LATS1/2), which in turn phosphorylates the transcriptional co‐activator YAP. Overall, this study indicates WWC2 functions as a tumour suppressor by negatively regulating the Hippo signalling pathway and may serve as a prognostic marker in HCC.
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影响因子：
13.5
作者：
Apte, Udayan;Gkretsi, Vasiliki;Bowen, William C.;Mars, Wendy M.;Luo, Jian-Hua;Donthamsetty, Shashikiran;Orr, Ann;Monga, Satdarshan P. S.;Wu, Chuanyue;Michalopoulos, George K.
通讯作者：
Michalopoulos, George K.
影响因子：
4.5
作者：
Stein C;Bardet AF;Roma G;Bergling S;Clay I;Ruchti A;Agarinis C;Schmelzle T;Bouwmeester T;Schübeler D;Bauer A
通讯作者：
Bauer A
影响因子：
10.7
作者：
Wennmann, Dirk Oliver;Schmitz, Juergen;Kremerskothen, Joachim
通讯作者：
Kremerskothen, Joachim
影响因子：
3.4
作者：
Wang, S.;Li, H.;Chen, G.
通讯作者：
Chen, G.
影响因子：
4.8
作者：
Wilson, Kayla E.;Li, Ying-Wei;Zhang, Jianmin
通讯作者：
Zhang, Jianmin