Unveiling the role of microRNA‐7 in linking TGF‐β‐Smad‐mediated epithelial‐mesenchymal transition with negative regulation of trophoblast invasion

ABSTRACTSeveral pregnancy complications result from abnormal trophoblast invasion. The dichotomous effect of TGF‐β on epithelial‐mesenchymal transition (EMT) between trophoblast invasion and cancer progression remains unknown and a critical concern. We attenuated the expression of TGF‐β type 1 receptor (coding by TGFBR1) with RNA interference in trophoblastic cells and significantly enhanced the trophoblastic invasion. Analysis of micro‐RNA profiles in trophoblasts indicated microRNA‐7 as a key molecule linking TGF‐β 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‐β–induced miR‐7 expression negatively modulated the TGF‐β–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‐β 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‐β–Smad‐mediated epithelial‐mesenchymal transition with negative regulation of trophoblast invasion. FASEB J. 33, 6281–6295 (2019). www.fasebj.org