The Rho GTPase Rnd1 inhibits epithelial\u2013mesenchymal transition in hepatocellular carcinoma and is a favorable anti-metastasis target

Cheng-Dong Qin,Hui-Chuan Sun,Zheng-Gang Ren,Ning Zhang,De-Ning Ma,Qing-An Jia,Zhao-You Tang,Cheng-Hao Wang,Xiao-Dong Zhu,Shi-Zhe Zhang,Zong-Tao Chai

doi:10.1038/s41419-018-0517-x

Abstract

Rnd1, a member of Rho GTPases, was found to be downregulated in human malignancies and downregulation of Rnd1 promotes tumor invasion via various mechanisms. However, the role of Rnd1 in hepatocellular carcinoma (HCC) progression remains unclear. In this study, our results demonstrated that Rnd1 was downregulated in HCC cells and in human HCC tissues. Low expression of Rnd1 was associated with aggressive clinic-pathologic characteristics, such as vascular invasion, and poor prognosis in patients who underwent curative surgery for HCC. Overexpression of Rnd1-suppressed cell growth, migration, invasion, and EMT processes in vitro and in vivo. Furthermore, Rnd1 blocked HCC progression by restricting EMT process through inhibition of the Raf/MEK/ERK cascade, and this was correlated with a reduction in RhoA activity. Combination of Rnd1 overexpression with sorafenib, a Raf signaling pathway inhibitor, showed a more potent inhibition on HCC metastasis. Moreover, epigenetic inhibitors (5-Aza and SAHA) increased the expression of Rnd1, and potentiated sorafenib-induced toxicity in HCC cells. In a conclusion, Rnd1-suppressed EMT-mediated metastasis of HCC by reducing the activity of the RhoA/Raf/MEK/ERK signaling pathway, functioning as a favorable anti-metastasis target for HCC patients. Rnd1 overexpression in combination with sorafenib may result in enhanced anti-metastasis efficacy in HCC.

Highlights

Rnd[1], a member of Rho GTPases, was found to be downregulated in human malignancies and downregulation of Rnd[1] promotes tumor invasion via various mechanisms
Multivariate analysis identified Rnd[1] expression as an independent risk factor for overall survival (OS) and disease-free survival (DFS) (Table 1). These results suggested that low Rnd[1] expression was associated with invasive characteristics and poor prognosis in hepatocellular carcinoma (HCC) patients
As Rnd[1] expression is associated with microvascular invasion in human HCC, we focused on the effects of Rnd[1] on migration and invasion of HCC cells

Summary

Introduction

Rnd[1], a member of Rho GTPases, was found to be downregulated in human malignancies and downregulation of Rnd[1] promotes tumor invasion via various mechanisms. Our results demonstrated that Rnd[1] was downregulated in HCC cells and in human HCC tissues. Rnd[1] blocked HCC progression by restricting EMT process through inhibition of the Raf/MEK/ERK cascade, and this was correlated with a reduction in RhoA activity. Combination of Rnd[1] overexpression with sorafenib, a Raf signaling pathway inhibitor, showed a more potent inhibition on HCC metastasis. Rnd1-suppressed EMTmediated metastasis of HCC by reducing the activity of the RhoA/Raf/MEK/ERK signaling pathway, functioning as a favorable anti-metastasis target for HCC patients. Decades of research have brought insight into step in invasion-metastasis cascades[5]. During this process, tumor cells reversibly transform from an epithelial phe-. Qin et al Cell Death and Disease (2018)9:486 had revealed that EMT played a key role in chemoresistance of HCC and could be modulated by microRNAs, genes, and drugs[7,8]

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