miR-1-3p and miR-206 sensitizes HGF-induced gefitinib-resistant human lung cancer cells through inhibition of c-Met signalling and EMT.

Abstract

Hepatocyte growth factor (HGF) overexpression is an important mechanism in acquired epidermal growth factor receptor (EGFR) kinase inhibitor gefitinib resistance in lung cancers with EGFR activating mutations. MiR-1-3p and miR-206 act as suppressors in lung cancer proliferation and metastasis. However, whether miR-1-3p and miR-206 can overcome HGF-induced gefitinib resistance in EGFR mutant lung cancer is not clear. In this study, we showed that miR-1-3p and miR-206 restored the sensitivities of lung cancer cells PC-9 and HCC-827 to gefitinib in present of HGF. For the mechanisms, we demonstrated that both miR-1-3p and miR-206 directly target HGF receptor c-Met in lung cancer. Knockdown of c-Met mimicked the effects of miR-1-3p and miR-206 transfections Meanwhile, c-Met overexpression attenuated the effects of miR-1-3p and miR-206 in HGF-induced gefitinib resistance of lung cancers. Furthermore, we showed that miR-1-3p and miR-206 inhibited c-Met downstream Akt and Erk pathway and blocked HGF-induced epithelial-mesenchymal transition (EMT). Finally, we demonstrated that miR-1-3p and miR-206 can increase gefitinib sensitivity in xenograft mouse models in vivo. Our study for the first time indicated the new function of miR-1-3p and miR-206 in overcoming HGF-induced gefitinib resistance in EGFR mutant lung cancer cell.

• Authors: Demin Jiao, Jun Chen, Yu Li, Xiali Tang, Jian Wang, Wei Xu, Jia Song, You Li, Huimin Tao, Qingyong Chen
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 22 Issue 7 Pg. 3526-3536 (07 2018) ISSN: 1582-4934 [Electronic] England
• PMID: 29664235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Antineoplastic Agents
• HGF protein, human
• MIRN1 microRNA, human
• MIRN206 microRNA, human
• MicroRNAs
• Hepatocyte Growth Factor
• EGFR protein, human
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met
• Gefitinib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, genetics)
• Epithelial-Mesenchymal Transition (drug effects)
• ErbB Receptors (genetics)
• Gefitinib (pharmacology)
• Gene Expression Regulation, Neoplastic
• Hepatocyte Growth Factor (genetics, metabolism, pharmacology)
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Male
• Mice, Inbred BALB C
• MicroRNAs (genetics)
• Proto-Oncogene Proteins c-met (genetics, metabolism)
• Signal Transduction
• Xenograft Model Antitumor Assays