The ncx1/trpc6 complex mediates tgfb-driven migration and invasion of human hepatocellular carcinoma cells

Abstract

TGFb 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 Naþ/ Ca2þ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFb in human HCC. In HepG2 and Huh7 cells, TGFb-stimulated intracellular Ca2þ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex-mediated Ca2þ signaling regulated the effect of TGFb on the migration, invasion, and intrahepatic metastasis of human HCC cells in nude mice. TGFb 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 TGFb signaling, and they implicate TRPC6 and NCX1 as potential targets for therapy in HCC. Significance: TGFb induces the formation and activation of a TRPC6/NCX1 molecular complex, which mediates the effects of TGFb on the migration, invasion, and intrahepatic metastasis of HCC.