Peroxisome proliferator-activated receptor γ-mediated induction of microRNA-145 opposes tumor phenotype in colorectal cancer

Anna Panza, Carolina Votino, Annamaria Gentile, Maria Rosaria Valvano, Tommaso Colangelo, Massimo Pancione, Lucia Micale, Giuseppe Merla, Angelo Andriulli, Lina Sabatino, Manlio Vinciguerra, Clelia Prattichizzo, Gianluigi Mazzoccoli, Vittorio Colantuoni, Ada Piepoli

Research output: Contribution to journalArticlepeer-review

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/ 1194. bp 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.

Original languageEnglish
Pages (from-to)1225-1236
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1843
Issue number6
DOIs
Publication statusPublished - 2014

Keywords

  • Colorectal cancer
  • Invasiveness
  • MiR-145
  • PPARγ
  • SOX9

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Peroxisome proliferator-activated receptor γ-mediated induction of microRNA-145 opposes tumor phenotype in colorectal cancer'. Together they form a unique fingerprint.

Cite this