Sorafenib inhibits migration and invasion of hepatocellular carcinoma cells through suppression of matrix metalloproteinase expression

• Published in: Anticancer research 2015-04, Vol.35 (4), p.1967-1976
• Main Authors: Ha, Tae-Yong, Hwang, Shin, Moon, Ki-Myeong, Won, You-Jin, Song, Gi-Won, Kim, Nayoung, Tak, Eunyoung, Ryoo, Baek-Yeol, Hong, Hea-Nam
• Format: Article
• Language: English
• Subjects: Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Movement - drug effects; Epithelial-Mesenchymal Transition - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Hep G2 Cells; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; MAP Kinase Signaling System - drug effects; Matrix Metalloproteinase 2 - biosynthesis; Matrix Metalloproteinase 9 - biosynthesis; Neoplasm Invasiveness - genetics; Niacinamide - administration & dosage; Niacinamide - analogs & derivatives; Phenylurea Compounds - administration & dosage; Proto-Oncogene Proteins c-met - biosynthesis
• ISSN: 0250-7005; 1791-7530

Sorafenib increases survival of patients with advanced hepatocellular carcinoma (HCC) by inhibiting RAF kinase and receptor tyrosine kinase activity, but involvement of sorafenib in fibrosis and epithelial-mesenchymal transition (EMT) remains unclear. To elucidate effects of sorafenib on EMT progression and matrix metalloproteinase (MMP) activity, levels of E-cadherin, N-cadherin, and MMPs were evaluated in HepG2 human HCC cells induced by hepatocyte growth factor (HGF). Scratching cell migration assay, matrigel cell invasion assay, and immuno histochemistry were performed to examine effects of sorafenib on tumor metastasis and MMP expression. Sorafenib inhibited HGF-induced EMT and suppressed cell migration and invasion. Treatment with sorafenib significantly reduced HGF-enhanced expression of MMPs, suggesting that inhibition of MMP activity contributes to suppression of cellular motility and invasiveness of HepG2 cells. Neutralization of MMP activity by antibodies to MMP2/9, broad-spectrum MMP inhibitor or selective gelatinase inhibitor resulted in significant suppression of HGF-induced EMT and cell migration/invasion. Sorafenib treatment and MMP inactivation inhibited HGF-induced c-MET and MEK/ERK pathways. Sorafenib reduced MMP activity in this HGF-induced tumorigenic model of HCC. These findings provide in vitro evidence that sorafenib suppresses HGF-induced EMT and cell migration/invasion, as well as HGF-induced c-MET and MEK/ERK pathways.