Unveiling the role of microRNA-7 in linking TGF-ß-Smad-mediated epithelial-mesenchymal transition with negative regulation of trophoblast invasion.

Several pregnancy complications result from abnormal trophoblast invasion. The dichotomous effect of TGF-ß on epithelial-mesenchymal transition (EMT) between trophoblast invasion and cancer progression remains unknown and a critical concern. We attenuated the expression of TGF-ß type 1 receptor (coding by TGFBR1) with RNA interference in trophoblastic cells and significantly enhanced the trophoblastic invasion. Analysis of microRNA profiles in trophoblasts indicated microRNA-7 as a key molecule linking TGF-ß with the negative regulation of trophoblast invasion. We then attenuated TGFBR1 and miR-7 transcription by transducing either short hairpin RNA targeting TGFBR1 or anti-miR-7-locked nucleonic acid, and we observed an up-regulation of EMT-related transcription factors (TFs) and their downstream effectors, causing a mesenchymal transition of trophoblasts. Conversely, overexpression of TGFBR1 or miR-7 led to the epithelial transition of trophoblasts. Our results showed that TGF-ß-induced miR-7 expression negatively modulated the TGF-ß-SMAD family member 2-mediated EMT pathway via targeting EMT-related TFs and down-regulating their mesenchymal markers. These findings possibly explain, at least in part, why TGF-ß exerts an opposite effect on EMT during trophoblast invasion and cancer progression.-Shih, J.-C., Lin, H.-H., Hsiao, A.-C., Su, Y.-T., Tsai, S., Chien, C.-L., Kung, H.-N. Unveiling the role of microRNA-7 in linking TGF-ß-Smad-mediated epithelial-mesenchymal transition with negative regulation of trophoblast invasion.

EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF.

MicroRNAs (miRNA) mediate distinct gene regulatory pathways triggered by epidermal growth factor receptor (EGFR) activation, which occurs commonly in lung cancers with poor prognosis. In this study, we report the discovery and mechanistic characterization of the miRNA miR-7 as an oncogenic "oncomiR" and its role as a key mediator of EGFR signaling in lung cancer cells. EGFR activation or ectopic expression of Ras as well as c-Myc stimulated miR-7 expression in an extracellular signal-regulated kinase (ERK)-dependent manner, suggesting that EGFR induces miR-7 expression through a Ras/ERK/Myc pathway. In support of this likelihood, c-Myc bound to the miR-7 promoter and enhanced its activity. Ectopic miR-7 promoted cell growth and tumor formation in lung cancer cells, significantly increasing the mortality of nude mice hosts, which were orthotopically implanted with lung cancers. Quantitative proteomic analysis revealed that miR-7 decreased levels of the Ets2 transcriptional repression factor ERF, the coding sequence of which was found to contain a miR-7 complementary sequence. Indeed, ectopic miR-7 inhibited production of ERF messages with a wild-type but not a silently mutated coding sequence, and ectopic miR-7 rescued growth arrest produced by wild-type but not mutated ERF. Together, these results identified that ERF is a direct target of miR-7 in lung cancer. Our findings suggest that miR-7 may act as an important modulator of EGFR-mediated oncogenesis, with potential applications as a novel prognostic biomarker and therapeutic target in lung cancer.