CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

H Ling, R Spizzo, Yaser Atlasi, M Nicoloso, M Shinnizu, RS Redis, N Nishida, R Gafa, J Song, ZY Guo, C Ivan, E Barbarotto, I de Vries, XN Zhang, M Ferracin, M Churchman, Janneke Galen, BH Beverloo, M Shariati, F HaderkMR Estecio, G Garcia-Manero, GA Patijn, DC Gotley, V Bhardwaj, I Shureiqi, S Sen, AS Multani, J Welsh, K Yamamoto, I Taniguchi, MA Song, S Gallinger, G Casey, SN Thibodeau, L Le Marchand, M Tiirikainen, SA Mani, W Zhang, RV Davuluri, K Mimori, M Mori, Anieta Sieuwerts, John Martens, I Tomlinson, M Negrini, I Berindan-Neagoe, John Foekens, SR Hamilton, G Lanza, S Kopetz, Riccardo Fodde, GA Calin

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Abstract

The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (IncRNA) encompassing the rs6983267 SNP, is highly over-expressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MY, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CC4T2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CC4T2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel IncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.
Original languageUndefined/Unknown
Pages (from-to)1446-1461
Number of pages16
JournalGenome Research
Volume23
Issue number9
DOIs
Publication statusPublished - 2013

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