title: Sorafenib inhibits migration and invasion of hepatocellular carcinoma cells through suppression of matrix metalloproteinase expression.
abstract: 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.
authors: Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Tae-Yong
authors: TY
authors: Ha
authors: Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea shwang@amc.seoul.kr.
authors: Shin
authors: S
authors: Hwang
authors: Department of Surgery, Busan National University Yangsan Hospital, Yangsan, Republic of Korea.
authors: Ki-Myeong
authors: KM
authors: Moon
authors: Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: You-Jin
authors: YJ
authors: Won
authors: Department of Surgery, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Gi-Won
authors: GW
authors: Song
authors: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Nayoung
authors: N
authors: Kim
authors: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Eunyoung
authors: E
authors: Tak
authors: Department of Oncology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Baek-Yeol
authors: BY
authors: Ryoo
authors: Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Hea-Nam
authors: HN
authors: Hong
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D000077157:Sorafenib
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D019859:Proto-Oncogene Proteins c-met; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Sorafenib; epithelial–mesenchymal transition; hepatocellular carcinoma; matrix metalloproteinase