title: Interplay between SOX9, β-catenin and PPARγ activation in colorectal cancer.
abstract: Colorectal carcinogenesis relies on loss of homeostasic mechanisms regulating cell proliferation, differentiation and survival. These cell processes have been reported to be influenced independently by transcription factors activated downstream of the Wnt pathway, such as SOX9 and β-catenin, and by the nuclear receptor PPARγ. The purpose of this study was to explore the expression levels and functional link between SOX9, β-catenin and PPARγ in the pathogenesis of colorectal cancer (CRC). We evaluated SOX9, β-catenin and PPARγ expression levels on human CRC specimens by qPCR and immunoblot detection. We tested the hypothesis that PPARγ activation might affect SOX9 and β-catenin expression using four colon cancer cell lines (CaCo2, SW480, HCT116, and HT29 cells). In CRC tissues SOX9 resulted up-regulated at both mRNA and protein levels when compared to matched normal mucosa, β-catenin resulted up-regulated at protein levels, while PPARG mRNA and PPARγ protein levels were down-regulated. A significant relationship was observed between high PPARG and SOX9 expression levels in the tumor tissue and female gender (p=0.005 and p=0.04, respectively), and between high SOX9 expression in the tumor tissue and age (p=0.04) and microsatellite instability (MSI), in particular with MSI-H (p=0.0002). Moreover, treatment with the synthetic PPARγ ligand rosiglitazone induced different changes of SOX9 and β-catenin expression and subcellular localization in the colon cancer cell lines examined. In conclusion, SOX9, β-catenin and PPARγ expression levels are deregulated in the CRC tissue, and in colon cancer cell lines ligand-dependent PPARγ activation unevenly influences SOX9 and β-catenin expression and subcellular localization, suggesting a variable mechanistic role in colon carcinogenesis.
authors.affiliation: Department of Medical Sciences, IRCCS Scientific Institute and Regional General Hospital, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Panza
authors.forename: Valerio
authors.initials: V
authors.lastname: Pazienza
authors.forename: Maria
authors.initials: M
authors.lastname: Ripoli
authors.forename: Giorgia
authors.initials: G
authors.lastname: Benegiamo
authors.forename: Annamaria
authors.initials: A
authors.lastname: Gentile
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Valvano
authors.forename: Bartolomeo
authors.initials: B
authors.lastname: Augello
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Merla
authors.forename: Clelia
authors.initials: C
authors.lastname: Prattichizzo
authors.forename: Francesca
authors.initials: F
authors.lastname: Tavano
authors.forename: Elena
authors.initials: E
authors.lastname: Ranieri
authors.forename: Pierluigi
authors.initials: P
authors.lastname: di Sebastiano
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
authors.forename: Angelo
authors.initials: A
authors.lastname: Andriulli
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mazzoccoli
authors.forename: Ada
authors.initials: A
authors.lastname: Piepoli
mesh_terms: D000368:Aged; D018938:Caco-2 Cells; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D047495:PPAR gamma; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D051176:beta Catenin