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.

SUBMITTER: Jiao D 

PROVIDER: S-EPMC6010770 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature