The NCX1/TRPC6 Complex Mediates TGFβ-Driven Migration and Invasion of Human Hepatocellular Carcinoma Cells

Jingyu Xu,Yuan Yang,Xuemei Liu,Hai Jin,Xubiao Nie,Rui Xie,Jilong Liu,Guorong Wen,Biguang Tuo,Jiaxing An

doi:10.1158/0008-5472.can-17-2061

Abstract

TGFβ plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC), yet the cellular and molecular mechanisms underlying this role are not completely understood. In this study, we investigated the roles of Na+/Ca2+ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFβ in human HCC. In HepG2 and Huh7 cells, TGFβ-stimulated intracellular Ca2+ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex-mediated Ca2+ signaling regulated the effect of TGFβ on the migration, invasion, and intrahepatic metastasis of human HCC cells in nude mice. TGFβ upregulated TRPC6 and NCX1 expression, and there was a positive feedback between TRPC6/NCX1 signaling and Smad signaling. Expression of both TRPC6 and NCX1 were markedly increased in native human HCC tissues, and their expression levels positively correlated with advancement of HCC in patients. These data reveal the role of the TRPC6/NCX1 molecular complex in HCC and in regulating TGFβ signaling, and they implicate TRPC6 and NCX1 as potential targets for therapy in HCC.Significance: TGFβ induces the formation and activation of a TRPC6/NCX1 molecular complex, which mediates the effects of TGFβ on the migration, invasion, and intrahepatic metastasis of HCC. Cancer Res; 78(10); 2564-76. ©2018 AACR.

Highlights

TGFb is a multifunctional cytokine that exerts a wide range of biological activities such as cell growth and apoptosis, differentiation, angiogenesis, wound healing, and immune modulation [1, 2]
We demonstrate that TGFb induces the formation of transient receptor potential channel 6 (TRPC6)/Naþ/ Ca2þ exchanger 1 (NCX1) molecular complex and activates the functional activity of TRPC6/NCX1 complex, promotes the migration, invasion, and intrahepatic metastasis of human hepatocellular carcinoma (HCC) cells, which reveals the role of TRPC6/NCX1 molecular complex in tumor and a novel TGFb signaling mechanism
These results demonstrate that TGFb stimulates [Ca2þ]i increases in human HCC cells through TRPC6 and NCX1

Summary

Introduction

TGFb is a multifunctional cytokine that exerts a wide range of biological activities such as cell growth and apoptosis, differentiation, angiogenesis, wound healing, and immune modulation [1, 2]. There is an increasing evidence that TGFb signaling is a key driver in tumorigenesis and tumor progression, which controls many different cell functions and regulates many critical cellular processes during tumor progression, including proliferative signaling, apoptosis, invasion, metastasis, and angiogenesis [3,4,5]. The cellular and molecular mechanisms of TGFb action on tumor are not completely understood. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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