title: Adenomatous polyposis coli (APC) regulates miR17-92 cluster through β-catenin pathway in colorectal cancer.
abstract: Adenomatous polyposis coli (APC) mutation is the most common genetic change in sporadic colorectal cancer (CRC). Although deregulations of miRNAs have been frequently reported in this malignancy, APC-regulated miRNAs have not been extensively documented. Here, by using an APC-inducible cell line and array analysis, we identified a total of 26 deregulated miRNAs. Among them, members of miR-17-92 cluster were dramatically inhibited by APC and induced by enforced expression of β-catenin. Furthermore, we demonstrate that activated β-catenin resulted from APC loss binds to and activates the miR-17-92 promoter. Notably, enforced expression of miR-19a overrides APC tumor suppressor activity, and knockdown of miR-19a in cancer cells with compromised APC function reduced their aggressive features in vitro. Finally, we observed that expression of miR-19a significantly correlates with β-catenin levels in colorectal cancer specimens, and it is associated to the aggressive stage of tumor progression. Thus, our study reveals that miR-17-92 cluster is directly regulated by APC/β-catenin pathway and could be a potential therapeutic target in colon cancers with aberrant APC/β-catenin signaling.
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.|Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, via Massarenti, 9, 40138 Bologna, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Lauriola
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Donghwa
authors.initials: D
authors.lastname: Kim
authors.affiliation: EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Mirko
authors.initials: M
authors.lastname: Francesconi
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, via Massarenti, 9, 40138 Bologna, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: D'Uva
authors.affiliation: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Dave
authors.initials: D
authors.lastname: Shibata
authors.affiliation: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Mokenge P
authors.initials: MP
authors.lastname: Malafa
authors.affiliation: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Yeatman
authors.affiliation: Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, via Massarenti, 9, 40138 Bologna, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Solmi
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D011401:Promoter Regions, Genetic; D046888:Tissue Array Analysis; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051176:beta Catenin