The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation
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Le résumé fourni par la source
The transcription factor caudal-type homeobox 1 (CDX1) is a key regulator of differentiation in the normal colon and in colorectal cancer (CRC). CDX1 activates the expression of enterocyte genes, but it is not clear how the concomitant silencing of stem cell genes is achieved. MicroRNAs (miRNAs) are important mediators of gene repression and have been implicated in tumor suppression and carcinogenesis, but the roles of miRNAs in differentiation, particularly in CRC, remain poorly understood. Here, we identified microRNA-215 (miR-215) as a direct transcriptional target of CDX1 by using high-throughput small RNA sequencing to profile miRNA expression in two pairs of CRC cell lines: CDX1-low HCT116 and HCT116 with stable CDX1 overexpression, and CDX1-high LS174T and LS174T with stable CDX1 knockdown. Validation of candidate miRNAs identified by RNA-seq in a larger cell-line panel revealed miR-215 to be most significantly correlated with CDX1 expression. Quantitative ChIP-PCR and promoter luciferase assays confirmed that CDX1 directly activates miR-215 transcription. miR-215 expression is depleted in FACS-enriched cancer stem cells compared with unsorted samples. Overexpression of miR-215 in poorly differentiated cell lines causes a decrease in clonogenicity, whereas miR-215 knockdown increases clonogenicity and impairs differentiation in CDX1-high cell lines. We identified the genome-wide targets of miR-215 and found that miR-215 mediates the repression of cell cycle and stemness genes downstream of CDX1. In particular, the miR-215 target gene BMI1 has been shown to promote stemness and self-renewal and to vary inversely with CDX1. Our work situates miR-215 as a link between CDX1 expression and BMI1 repression that governs differentiation in CRC.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation
- Date Crossref
- 16/03/2015
- Éditeur
- National Academy of Sciences
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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John Radcliffe Hospital pays non établi dans la noticeÉtablissement de santé
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University of Oxford Cancer and Immunogenetics Laboratory pays non établi dans la noticeUniversité ou école supérieure
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MRC Weatherall Institute of Molecular Medicine pays non établi dans la noticeStructure de recherche
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MRC Human Immunology Unit pays non établi dans la noticeStructure de recherche
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National Institutes of Health pays non établi dans la noticeOrganisme public
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National Cancer Institute Center for Cancer Research pays non établi dans la noticeOrganisme public
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Center for Cancer Research pays non établi dans la noticeStructure de recherche
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Regulatory RNAs and Cancer Section and pays non établi dans la noticeInstitution
John Radcliffe Hospital, Cancer and Immunogenetics Laboratory — University of Oxford et MRC Weatherall Institute of Molecular Medicine, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.