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.

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

FERRACIN, MANUELA;
2013

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.
H. Ling; R. Spizzo; Y. Atlasi; M. Nicoloso; M. Shimizu; R. S. Redis; N. Nishida; R. Gafa; J. Song; Z. Guo; C. Ivan; E. Barbarotto; I. De Vries; X. Zhang; M. Ferracin; M. Churchman; J. F. van Galen; B. H. Beverloo; M. Shariati; F. Haderk; M. R. Estecio; G. Garcia-Manero; G. A. Patijn; D. C. Gotley; V. Bhardwaj; I. Shureiqi; S. Sen; A. S. Multani; J. Welsh; K. Yamamoto; I. Taniguchi; M.-A. Song; S. Gallinger; G. Casey; S. N. Thibodeau; L. Le Marchand; M. Tiirikainen; S. A. Mani; W. Zhang; R. V. Davuluri; K. Mimori; M. Mori; A. M. Sieuwerts; J. W. M. Martens; I. Tomlinson; M. Negrini; I. Berindan-Neagoe; J. A. Foekens; S. R. Hamilton; G. Lanza; S. Kopetz; R. Fodde; G. A. Calin
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/542199
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