title: Peroxisome proliferator-activated receptor γ-mediated induction of microRNA-145 opposes tumor phenotype in colorectal cancer.
abstract: MicroRNAs (miRNAs) regulate diverse biological processes by inhibiting translation or inducing degradation of target mRNAs. miR-145 is a candidate tumor suppressor in colorectal carcinoma (CRC). Colorectal carcinogenesis involves deregulation of cellular processes controlled by a number of intertwined chief transcription factors, such as PPARγ and SOX9. Since PPAR family members are able to modulate complex miRNAs networks, we hypothesized a role of miRNA-145 in the interaction between PPARγ and SOX9 in colorectal carcinogenesis. To address this issue, we evaluated gene expression in tissue specimens of CRC patients and we took advantage of invitro models represented by CRC derived cell lines (CaCo2, SW480, HCT116, and HT-29), employing PPARγ activation and/or miRNA-145 ectopic overexpression to analyze how their interplay impact the expression of SOX9 and the development of a malignant phenotype.
  
  
  RESULTS
  PPARγ regulates the expression of miR-145 by directly binding to a PPAR response element (PPRE) in its promoter at -1207/-1194bp from the transcription start site. The binding is essential for miR-145 upregulation by PPARγ upon rosiglitazone treatment. Ectopic expression of miR-145, in turn, regulates SOX9 expression through the binding to specific seed motifs. The PPARγ-miR-145-SOX9 axis overarches cell cycle progression, invasiveness and differentiation of CRC derived cell lines. Together, these results suggest that miR-145 is a novel target of PPARγ, acts as a tumor suppressor in CRC cell lines and is a key regulator of intestinal cell differentiation by directly targeting SOX9, a marker of undifferentiated progenitors in the colonic crypts.
authors.affiliation: Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia 71013, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Panza
authors.affiliation: Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, Benevento 82100, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Votino
authors.affiliation: Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia 71013, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Gentile
authors.affiliation: Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia 71013, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Valvano
authors.affiliation: Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, Benevento 82100, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Colangelo
authors.affiliation: Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, Benevento 82100, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pancione
authors.affiliation: Medical Genetics Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia 71013, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Micale
authors.affiliation: Medical Genetics Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia 71013, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Merla
authors.affiliation: Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia 71013, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Andriulli
authors.affiliation: Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, Benevento 82100, Italy.
authors.forename: Lina
authors.initials: L
authors.lastname: Sabatino
authors.affiliation: University College London, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, London NW3 2PF, UK; Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia 71013, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
authors.affiliation: Department of Medical Science and Surgery, University of Foggia, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Prattichizzo
authors.affiliation: Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia 71013, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mazzoccoli
authors.affiliation: Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, Benevento 82100, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Colantuoni
authors.affiliation: Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia 71013, Italy. Electronic address: a.piepoli@operapadrepio.it.
authors.forename: Ada
authors.initials: A
authors.lastname: Piepoli
mesh_terms: D000368:Aged; D015153:Blotting, Western; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D015331:Cohort Studies; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D016296:Mutagenesis; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012007:Rectum / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D017931:DNA Primers; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D047495:PPAR gamma; D012333:RNA, Messenger; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D008156:Luciferases
keywords: Colorectal cancer; Invasiveness; PPARγ; SOX9; miR-145