title: Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma.
abstract: The epithelial mesenchymal transition (EMT) has emerged as a pivotal event in the development of the invasive and metastatic potentials of cancer progression. Sorafenib, a VEGFR inhibitor with activity against RAF kinase, is active against hepatocellular carcinoma (HCC); however, the possible involvement of sorafenib in the EMT remains unclear. Here, we examined the effect of sorafenib on the EMT. Hepatocyte growth factor (HGF) induced EMT-like morphologic changes and the upregulation of SNAI1 and N-cadherin expression. The downregulation of E-cadherin expression in HepG2 and Huh7 HCC cell lines shows that HGF mediates the EMT in HCC. The knockdown of SNAI1 using siRNA canceled the HGF-mediated morphologic changes and cadherin switching, indicating that SNAI1 is required for the HGF-mediated EMT in HCC. Interestingly, sorafenib and the MEK inhibitor U0126 markedly inhibited the HGF-induced morphologic changes, SNAI1 upregulation, and cadherin switching, whereas the PI3 kinase inhibitor wortmannin did not. Collectively, these findings indicate that sorafenib downregulates SNAI1 expression by inhibiting mitogen-activated protein kinase (MAPK) signaling, thereby inhibiting the EMT in HCC cells. In fact, a wound healing and migration assay revealed that sorafenib completely canceled the HGF-mediated cellular migration in HCC cells. In conclusion, we found that sorafenib exerts a potent inhibitory activity against the EMT by inhibiting MAPK signaling and SNAI1 expression in HCC. Our findings may provide a novel insight into the anti-EMT effect of tyrosine kinase inhibitors in cancer cells.
authors.affiliation: Kazuto Nishio, Department of Genome Biology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nagai
authors.forename: Tokuzo
authors.initials: T
authors.lastname: Arao
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Furuta
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.forename: Kanae
authors.initials: K
authors.lastname: Kudo
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kaneda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tamura
authors.forename: Keiichi
authors.initials: K
authors.lastname: Aomatsu
authors.forename: Hideharu
authors.initials: H
authors.lastname: Kimura
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Fujita
authors.forename: Kazuko
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction; D000077157:Sorafenib; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D017228:Hepatocyte Growth Factor; D000077157:Sorafenib