title: miRNA profiling in colorectal cancer highlights miR-1 involvement in MET-dependent proliferation.
abstract: Altered expression of miRNAs is associated with development and progression of various human cancers by regulating the translation of oncogenes and tumor suppressor genes. In colorectal cancer, these regulators complement the Vogelstein multistep model of pathogenesis and have the potential of becoming a novel class of tumor biomarkers and therapeutic targets. Using quantitative real-time PCR, we measured the expression of 621 mature miRNAs in 40 colorectal cancers and their paired normal tissues and identified 23 significantly deregulated miRNAs. We subsequently evaluated their association with clinical characteristics of the samples and presence of alterations in the molecular markers of colorectal cancer progression. Expression levels of miR-31 were correlated with CA19-9 and miR-18a, miR-21, and miR-31 were associated with mutations in APC gene. To investigate the downstream regulation of the differentially expressed miRNAs identified, we integrated putative mRNA target predictions with the results of a meta-analysis of seven public gene expression datasets of normal and tumor samples of colorectal cancer patients. Many of the colorectal cancer deregulated miRNAs computationally mapped to targets involved in pathways related to progression. Here one promising candidate pair (miR-1 and MET) was studied and functionally validated. We show that miR-1 can have a tumor suppressor function in colorectal cancer by directly downregulating MET oncogene both at RNA and protein level and that reexpression of miR-1 leads to MET-driven reduction of cell proliferation and motility, identifying the miR-1 downmodulation as one of the events that could enhance colorectal cancer progression.
authors.affiliation: Departments of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy.
authors.forename: James F
authors.initials: JF
authors.lastname: Reid
authors.forename: Viktorija
authors.initials: V
authors.lastname: Sokolova
authors.forename: Eugenio
authors.initials: E
authors.lastname: Zoni
authors.forename: Andrea
authors.initials: A
authors.lastname: Lampis
authors.forename: Sara
authors.initials: S
authors.lastname: Pizzamiglio
authors.forename: Claudia
authors.initials: C
authors.lastname: Bertan
authors.forename: Susanna
authors.initials: S
authors.lastname: Zanutto
authors.forename: Federica
authors.initials: F
authors.lastname: Perrone
authors.forename: Tiziana
authors.initials: T
authors.lastname: Camerini
authors.forename: Gianfrancesco
authors.initials: G
authors.lastname: Gallino
authors.forename: Paolo
authors.initials: P
authors.lastname: Verderio
authors.forename: Ermanno
authors.initials: E
authors.lastname: Leo
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.forename: Manuela
authors.initials: M
authors.lastname: Gariboldi
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
mesh_terms: D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C544547:MIRN1 microRNA, human; D035683:MicroRNAs; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met