title: Multifaceted enrichment analysis of RNA-RNA crosstalk reveals cooperating micro-societies in human colorectal cancer.
abstract: Alterations in the balance of mRNA and microRNA (miRNA) expression profiles contribute to the onset and development of colorectal cancer. The regulatory functions of individual miRNA-gene pairs are widely acknowledged, but group effects are largely unexplored. We performed an integrative analysis of mRNA-miRNA and miRNA-miRNA interactions using high-throughput mRNA and miRNA expression profiles obtained from matched specimens of human colorectal cancer tissue and adjacent non-tumorous mucosa. This investigation resulted in a hypernetwork-based model, whose functional backbone was fulfilled by tight micro-societies of miRNAs. These proved to modulate several genes that are known to control a set of significantly enriched cancer-enhancer and cancer-protection biological processes, and that an array of upstream regulatory analyses demonstrated to be dependent on miR-145, a cell cycle and MAPK signaling cascade master regulator. In conclusion, we reveal miRNA-gene clusters and gene families with close functional relationships and highlight the role of miR-145 as potent upstream regulator of a complex RNA-RNA crosstalk, which mechanistically modulates several signaling pathways and regulatory circuits that when deranged are relevant to the changes occurring in colorectal carcinogenesis.
authors.affiliation: Bioinformatics Unit, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy t.mazza@css-mendel.it.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mazza
authors.affiliation: Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy g.mazzoccoli@operapadrepio.it.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mazzoccoli
authors.affiliation: Bioinformatics Unit, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fusilli
authors.affiliation: Bioinformatics Unit, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Capocefalo
authors.affiliation: Department of Medical Sciences, Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Panza
authors.affiliation: Bioinformatics Unit, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Biagini
authors.affiliation: Bioinformatics Unit, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Castellana
authors.affiliation: Department of Medical Sciences, Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Gentile
authors.affiliation: Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: De Cata
authors.affiliation: Medical Genetics, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Palumbo
authors.affiliation: Medical Genetics, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Stallone
authors.affiliation: Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rubino
authors.affiliation: Medical Genetics, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.affiliation: Division of Epidemiology and Health Statistics, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo (FG), Italy a.piepoli@operapadrepio.it.
authors.forename: Ada
authors.initials: A
authors.lastname: Piepoli
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005810:Multigene Family / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger