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

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/Ca 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 Ca increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex-mediated Ca 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. 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. .

TRPC6 Channels Are Required for Proliferation, Migration and Invasion of Breast Cancer Cell Lines by Modulation of Orai1 and Orai3 Surface Exposure

“…TRPC6 has been reported to play a relevant role in the proliferation of gastric [ 24 ], prostate [ 25 ], esophageal squamous cell carcinoma [ 26 ] and hepatome cells [ 27 ]. Furthermore, TRPC6 is required for migration and invasion of hepatocellular carcinoma cells [ 28 ]. TRPC6 channels have been shown to be overexpressed in human breast ductal adenocarcinoma compared to non-tumoral tissue [ 29 , 30 ] and both, TRPC3 and TRPC6, have been reported to be significantly up-regulated in breast cancer biopsies compared to normal tissue [ 31 ]; however, the molecular basis of the functional role of TRPC6 in breast cancer cells and its involvement in the cancer hallmarks remains unclear.…”

TRP Channels in Digestive Tract Cancers

“…In addition, TGF-β has been shown to induce a formation of the complex between TRPC6 and the type1 Na + /Ca 2+ exchanger (NCX1), leading to an increased migration and invasion of HCC. Moreover, a positive correlation was found between the severity of HCC progression and the expression of TRPC6 and NCX1 [80]. Both the inhibition and RNAi downregulation of TRPC6 or NCX1 was able to attenuate TGF-β induced cell migration or the intrahepatic metastasis of human HCC in an in vivo xenograft mouse model [80].…”

“…Moreover, a positive correlation was found between the severity of HCC progression and the expression of TRPC6 and NCX1 [80]. Both the inhibition and RNAi downregulation of TRPC6 or NCX1 was able to attenuate TGF-β induced cell migration or the intrahepatic metastasis of human HCC in an in vivo xenograft mouse model [80]. Moreover, Wen and colleagues recently reported a significantly increased TRPC6 mRNA expression in HCC cells upon hypoxia stimulation, doxorubicin treatment, or ionizing radiation [88].…”

“…TRPC6 is weakly expressed on mRNA and protein level in normal hepatocytes but strongly expressed in liver carcinoma samples. Moreover, high TRPC6 expression has been suggested to be associated with a higher Tumor Node Metastasis (TNM) classification of tumors [76,80]. TRPC6 overexpression in Huh-7 cells leads to increased proliferation [76].…”

Novel insights into ion channels in cancer stem cells (Review)

“…At present, few reports have focused on the association between ion channels and CSCs. Our recent work indicated that solute carrier family 8 member A1 and transient receptor potential cation channel subfamily C member 6 are expressed in cluster of differentiation (CD)133 + stem cells in Huh7 hepatic cancer cells, thus indicating that ion channels may be involved in the occurrence and development of cancer (30). Furthermore, ion channel inhibitors can reduce drug resistance of tumor cells via regulation of CSC function (31,32).…”