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

Hui Ling, Riccardo Spizzo, Yaser Atlasi, Milena Nicoloso, Masayoshi Shimizu, Roxana S. Redis, Naohiro Nishida, Roberta Gafà, Jian Song, Zhiyi Guo, Cristina Ivan, Elisa Barbarotto, Ingrid De Vries, Xinna Zhang, Manuela Ferracin, Mike Churchman, Janneke F. Van Galen, Berna H. Beverloo, Maryam Shariati, Franziska HaderkMarcos R. Estecio, Guillermo Garcia-Manero, Gijs A. Patijn, David C. Gotley, Vikas Bhardwaj, Imad Shureiqi, Subrata Sen, Asha S. Multani, James Welsh, Ken Yamamoto, Itsuki Taniguchi, Min Ae Song, Steven Gallinger, Graham Casey, Stephen N. Thibodeau, Loic Le Marchand, Maarit Tiirikainen, Sendurai A. Mani, Wei Zhang, Ramana V. Davuluri, Koshi Mimori, Masaki Mori, Anieta M. Sieuwerts, John W M Martens, Ian Tomlinson, Massimo Negrini, Ioana Berindan-Neagoe, John A. Foekens, Stanley R. Hamilton, Giovanni Lanza, Scott Kopetz, Riccardo Fodde, George A. Calin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

384 Scopus citations

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 (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 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 CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.

Original languageEnglish (US)
Pages (from-to)1446-1461
Number of pages16
JournalGenome research
Volume23
Issue number9
DOIs
StatePublished - Sep 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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