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: Tomoyuki Nagai, Tokuzo Arao, Kazuyuki Furuta, Kazuko Sakai, Kanae Kudo, Hiroyasu Kaneda, Daisuke Tamura, Keiichi Aomatsu, Hideharu Kimura, Yoshihiko Fujita, Kazuko Matsumoto, Nagahiro Saijo, Masatoshi Kudo, Kazuto Nishio
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 1 Pg. 169-77 (Jan 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21220499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• Antineoplastic Agents
• Benzenesulfonates
• Phenylurea Compounds
• Pyridines
• Niacinamide
• Hepatocyte Growth Factor
• Sorafenib

Topics

• Antineoplastic Agents (pharmacology)
• Benzenesulfonates (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Down-Regulation
• Epithelial-Mesenchymal Transition (drug effects)
• Hepatocyte Growth Factor (antagonists & inhibitors, genetics, metabolism)
• Humans
• Liver Neoplasms (drug therapy, genetics, metabolism, pathology)
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Pyridines (pharmacology)
• Signal Transduction
• Sorafenib
• Transfection