WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma.

Yijun Zhang,Jiewei Chen,Jiahuai Wen,Caixia Gan,Jiangbo Zhang,Shilu Chen,Yan Li,Shumei Yan,Dong Chen,Yun Cao,Joachim Kremerskothen

doi:10.1111/jcmm.13281

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common cancer and third leading cause of cancer-related deaths worldwide [1], and its incidence is increasing
In view of the ability of WWC2 to regulate the transcriptional activity of Yes-associated protein (YAP) by activating large tumour suppressor 1 and kinases (LATS1/2) in HEK293 cells, we suggested that WWC2 may inhibit cell invasion in HCC by negatively regulating Hippo signalling
Retrospective clinical association analysis using the Pearson chi-squared test revealed decreased WWC2 expression in HCC was positively associated with tumour size (P = 0.030), venous infiltration (P = 0.006) and advanced tumour stage (TNM stage III + IV; P = 0.001; Table 1)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer and third leading cause of cancer-related deaths worldwide [1], and its incidence is increasing. Surgical reaction and liver transplantation are currently the best curative options for HCC. Recurrence or metastasis is relatively common after resection [2]. Multiple signalling pathways contribute to the development of HCC. The Hippo pathway has been found to be involved in cell size regulation, cell proliferation, cell death and tumorigenesis of HCC [3,4,5,6]. The Hippo pathway contains a number of tumour suppressors and oncogenes.

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