Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma

• Published in: Molecular cancer therapeutics 2011-01, Vol.10 (1), p.169-177
• Main Authors: Nagai, Tomoyuki, Arao, Tokuzo, Furuta, Kazuyuki, Sakai, Kazuko, Kudo, Kanae, Kaneda, Hiroyasu, Tamura, Daisuke, Aomatsu, Keiichi, Kimura, Hideharu, Fujita, Yoshihiko, Matsumoto, Kazuko, Saijo, Nagahiro, Kudo, Masatoshi, Nishio, Kazuto
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Benzenesulfonates - pharmacology; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Down-Regulation; Epithelial-Mesenchymal Transition - drug effects; Hepatocyte Growth Factor - antagonists & inhibitors; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Niacinamide - analogs & derivatives; Phenylurea Compounds; Pyridines - pharmacology; Signal Transduction; Transfection
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-10-0544

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.