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Mirna-Mediated Khsrp Silencing Rewires Distinct Post-Transcriptional Programs During Tgf-Β-Induced Epithelial-To-Mesenchymal Transition Publisher Pubmed



Puppo M1, 2 ; Bucci G3 ; Rossi M1, 2 ; Giovarelli M1 ; Bordo D1 ; Moshiri A1, 6 ; Gorlero F4, 5 ; Gherzi R1 ; Briata P1
Authors
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Authors Affiliations
  1. 1. Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, Genova, 16132, Italy
  2. 2. DIMES Sezione Biochimica-Universita di Genova, Genova, 16132, Italy
  3. 3. Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milano, 20132, Italy
  4. 4. S.C. Ginecologia e Ostetricia Galliera Hospital, 16128, Genova, Italy
  5. 5. School of Medicine, DINOGMI, University of Genova, Genova, 16128, Italy
  6. 6. Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 198396-3113, Iran

Source: Cell Reports Published:2016


Abstract

Epithelial-to-mesenchymal transition (EMT) confers several traits to cancer cells that are required for malignant progression. Here, we report that miR-27b-3p-mediated silencing of the single-strand RNA binding protein KHSRP is required for transforming growth factor β (TGF-β)-induced EMT in mammary gland cells. Sustained KHSRP expression limits TGF-β-dependent induction of EMT factors and cell migration, whereas its knockdown in untreated cells mimics TGF-β-induced EMT. Genome-wide sequencing analyses revealed that KHSRP controls (1) levels of mature miR-192-5p, a microRNA that targets a group of EMT factors, and (2) alternative splicing of a cohort of pre-mRNAs related to cell adhesion and motility including Cd44 and Fgfr2. KHSRP belongs to a ribonucleoprotein complex that includes hnRNPA1, and the two proteins cooperate in promoting epithelial-type exon usage of select pre-mRNAs. Thus, TGF-β-induced KHSRP silencing is central in a pathway leading to gene-expression changes that contribute to the cellular changes linked to EMT. © 2016 The Author(s)