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