title: miRNA-Mediated KHSRP Silencing Rewires Distinct Post-transcriptional Programs during TGF-β-Induced Epithelial-to-Mesenchymal Transition.
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.
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132 Genova, Italy; DIMES Sezione Biochimica-Università di Genova, 16132 Genova, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Puppo
authors.affiliation: Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, 20132 Milano, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bucci
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132 Genova, Italy; DIMES Sezione Biochimica-Università di Genova, 16132 Genova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132 Genova, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Giovarelli
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132 Genova, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Bordo
authors.affiliation: 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 198396-3113, Iran.
authors.forename: Arfa
authors.initials: A
authors.lastname: Moshiri
authors.affiliation: S.C. Ginecologia e Ostetricia Galliera Hospital, 16128 Genova, Italy; School of Medicine, DINOGMI, University of Genova, 16128 Genova, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Gorlero
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132 Genova, Italy. Electronic address: roberto.gherzi@hsanmartino.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gherzi
authors.affiliation: Gene Expression Regulation Laboratory, IRCCS AOU San Martino-IST, 16132 Genova, Italy. Electronic address: paola.briata@hsanmartino.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Briata
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D008321:Mammary Glands, Animal; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C105789:KHSRP protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2