Abstract
Activated KRAS is frequently observed and paralleled by inactivating of tumor suppressors in lung cancer, while the mechanisms remained elusive. Here, our study revealed a microRNA was involved in KRAS overexpression, activation of KRAS signaling and its synergy with inactivating of tumor suppressor genes. miR-1205 was selected by its sequence-dependent inhibition on KRAS and negative clinical correlation with KRAS. A549 and H460 cells carrying mutant KRAS, were sensitive to the growth inhibition and G1/S arrest induced by miR-1205. Target analysis revealed that miR-1205 could simultaneously downregulate the expression levels of MDM4 and E2F1, which were downstream of KRAS and synergistic with KRAS. Silencing of MDM4 or E2F1 inhibited cellular proliferation. MiR-1205 decreased the protein levels of MDM4 and E2F1 via directly binding to the coding sequence of E2F1 and 3'UTR of MDM4. Meanwhile, blocking RAS-MAPK signaling using KRAS siRNA or ERK1/2 inhibitor exerted similar inhibitory effects on MDM4 and E2F1. Forced expression of KRAS partially restored the inhibition of miR-1205 on MDM4 and E2F1. Overexpression of KRAS, MDM4 or E2F1 could partially rescued the growth inhibition of miR-1205 in vitro. More importantly, miR-1205 strongly inhibited the tumor growth of A549 xenografts in nude mice and decreased the protein levels of KRAS, MDM4 and E2F1 in tumor tissues. Together, our study firstly confirmed a potential synergy between KRAS and MDM4/E2F1 which are p53/RB inactivators in non-small cell lung cancer, and identified miR-1205 as a potent destructor of this synergy, making miR-1205 function as a tumor suppressor in vitro and in vivo.