miR-1/133a and miR-206/133b clusters overcome HGF induced gefitinib resistance in non-small cell lung cancers with EGFR sensitive mutations.

It has been reported that clustered miRNAs can be transcribed coordinately and exhibit similar functions by regulating the same targets. miR-1/133a and miR-206/133b are well characterized miRNA clusters. However, the effect of these clusters on EGFR-TKI resistance is not clear. In this study, we demonstrated that lentivirus-mediated HGF overexpression was able to induce gefitinib resistance in non-small cell lung cancers with EGFR sensitive mutations. miR-1/133a and miR-206/133b clusters could overcome HGF induced gefitinib resistance. Furthermore, the clusters were more effective than individual miRNA. Transcriptome RNA sequencing and bioinformatics analysis revealed that multiple pathways, including "EGFR tyrosine kinase inhibitor resistance" pathway, were involved in anti-resistance mechanisms of miR-1/133a and miR-206/133b clusters. Western blotting results confirmed the inhibitory effect of miRNA clusters on MET expression and downstream pathway activation. In conclusion, miR-1/133a and miR-206/133b clusters are able to exhibit the synergetic effect on overcoming HGF-induced gefitinib resistance in NSCLC and the mechanisms are through targeting multiple genes related to gefitinib resistance.