Abstract
MicroRNAs (miRNAs), a novel class of gene regulators, have been associated with tumorigenesis. Aberrant expression and function of epidermal growth factor receptor (EGFR) are reported in most lung cancer cases and are correlated with poor prognosis. Through a miRNA microarray screen for miRNAs regulated by EGFR signaling in lung cancer, we discovered that EGFR induces miR-7 expression. Overexpression of the active EGFR mutant (L858R) enhanced the miR-7 expression. Once transfected in lung cancer cells, Ras and c-Myc promoted miR-7 level; whereas blocking the ERK pathway with inhibitors decreased the miR-7 level, suggesting that the EGFR induces miR-7 expression through the Ras/ERK/c-Myc pathway. Ectopic expression of miR-7 in lung cancer cells promoted cell growth and tumor formation, and significantly increased the mortality of nude mice, indicating miR-7 is an oncomiR. Using a SILAC (stable isotope labeling with amino acids in cell culture) analysis, we found that miR-7 decreases the levels of ERF, suggesting the downstream target of miR-7 is ERF. Furthermore, a miR-7 complementary sequence was identified in the coding sequence of ERF. miR-7 inhibited ectopic expression of the wild-type but not the mutated ERF coding sequence, supporting that ERF is the direct target of miR-7 in lung cancer. Overexpression of miR-7 inhibited ERF expression and rescued ERF-mediated cell growth arrest. Our finding that miR-7 is overexpressed in primary lung cancer and correlated positively with EGFR mutation indicates an important role for miR-7 in the modulation of EGFR-mediated oncogenesis and can serves as a novel biomarker for cancer prognosis.