Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132, Genova, Italy; DIMES Sez. Biochimica-Università di Genova, 16132, Genova, Italy; Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132, Genova, Italy; Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Biochim Biophys Acta Gene Regul Mech. 2017 Mar;1860(3):291-298. doi: 10.1016/j.bbagrm.2017.01.001. Epub 2017 Jan 11.
Resveratrol (RESV) is a natural polyphenolic compound endowed with anti-inflammatory, anti-proliferative, as well as pro-apoptotic activities that make it a potential anti-tumor compound. Here we show that RESV counteracts the TGF-β-induced Epithelial to Mesenchymal Transition (EMT) phenotype in mammary gland cells and affects the alternative exon usage of pre-mRNAs that encode crucial factors in adhesion and migration -including CD44, ENAH, and FGFR2- in a panel of immortalized and transformed mammary gland cells. RESV causes a shift from the mesenchymal-specific forms of these factors to the respective epithelial forms and increases the expression of the RNA-binding proteins KHSRP and hnRNPA1. From a mechanistic point of view, we show that the combined silencing of KHSRP and hnRNPA1 prevents the RESV-dependent inclusion of the epithelial-type exons in the Cd44 pre-mRNA. Our findings support an unexpected regulatory mechanism where RESV limits EMT by controlling gene expression at post-transcriptional level.
白藜芦醇（RESV）是一种天然多酚化合物，具有抗炎、抗增殖和促凋亡活性，使其成为一种潜在的抗肿瘤化合物。在这里，我们表明 RESV 可抵抗 TGF-β诱导的乳腺细胞上皮间质转化（EMT）表型，并影响包括 CD44、ENAH 和 FGFR2 在内的粘附和迁移关键因子的前体 mRNA 的选择性外显子使用在一组永生化和转化的乳腺细胞中。RESV 导致这些因子的间充质特异性形式向各自的上皮形式转变，并增加 RNA 结合蛋白 KHSRP 和 hnRNPA1 的表达。从机制上讲，我们表明，KHSRP 和 hnRNPA1 的联合沉默可防止 RESV 依赖性包含 CD44 前体 mRNA 中的上皮型外显子。我们的研究结果支持一种意想不到的调节机制，其中 RESV 通过在转录后水平控制基因表达来限制 EMT。
