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Open Access Inhibition of ERK1/2 Signaling Impairs the Promoting Effects of TGF-β1 on Hepatocellular Carcinoma Cell Invasion and Epithelial‐Mesenchymal Transition

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Transforming growth factor-β (TGF-β) and ERK signaling have been implicated in various human cancers including hepatocellular carcinoma, but the underlying mechanism remains largely unclear. In this study, we aimed to explore the role of ERK1/2 in the regulation of TGF-β’s promoting and suppressive activities in HCC cells. Our data showed that treatment with TGF-β1 enhanced invasion and epithelial‐mesenchymal transition (EMT) in HCC HepG2 cells, accompanied with increased MMP9 production and activation of Smad2/3 and ERK1/2, but inhibited tumor cell proliferation. These effects were eliminated by treatment with SB431542, a TGF-β inhibitor. Afterward, treatment with the MEK1/2 inhibitor U0126 reduced the TGF-β1-induced invasion and vimentin and MMP9 secretion in HepG2 cells, without affecting the inhibitory effects of TGF-β1 on HepG2 cell proliferation. Moreover, inhibition of Smad2/3 expression attenuated TGF-β1-induced cell invasion, ERK1/2 phosphorylation, and MMP9 production in HepG2 cells. However, knockdown of Slug only reduced cell invasion but did not affect ERK1/2 activation and MMP9 secretion in HepG2 cells. These data indicate that TGF-β1 activates ERK1/2 in HepG2 cells through the Smad2/3 pathway but not the Slug pathway. In summary, our study demonstrates that inhibition of ERK1/2 signaling attenuates the promoting effects of TGF-β1 on the metastatic phenotypes of HCC cells without affecting its suppressive effects on HCC cell proliferation. Therefore, we suggest that ERK1/2 may be used as a molecular target for the treatment of TGF-β-responsive HCC.
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Keywords: ERK1/2; Epithelial‐mesenchymal transition (EMT); Hepatocellular carcinoma (HCC); Migration; Transforming growth factor-β1 (TGF-β1)

Document Type: Research Article

Affiliations: Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China

Publication date: November 2, 2017

This article was made available online on May 11, 2017 as a Fast Track article with title: "Inhibition of ERK1/2 Signaling Impairs the Promoting Effects of TGF-ß1 on Hepatocellular Carcinoma Cell Invasion and Epithelial-Mesenchymal Transition".

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