Journal
GENOME RESEARCH
Volume 23, Issue 9, Pages 1446-1461Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.152942.112
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Funding
- NIH/NCI [CA135444]
- Department of Defense Breast Cancer Idea Award
- Developmental Research Awards in Breast Cancer, Ovarian Cancer, Brain Cancer, Prostate Cancer, Multiple Myeloma, and Leukemia SPOREs
- MDACC Sister Institution Network Fund grant in colorectal cancer
- Laura and John Arnold Foundation
- RGK Foundation
- Estate
- Dutch Cancer Society [(EMCR 2001-2482]
- Netherlands Organisation for Scientific Research [NWO/Vici 016.036.636]
- BSIK (Kennisinfrastructuur) program of the Dutch Government [03038]
- Netherlands Institute for Regenerative Medicine (NIRM)
- EU
- Funding Program for Next Generation World-Leading Researchers [LS094]
- Core Research for Evolutional Science and Technology
- NCI [CA016672, CA16672]
- National Cancer Institute, National Institutes of Health [CA-95-011]
- University of Hawaii Colorectal Cancer Family Registry [U01 CA074806]
- Mayo Clinic Cooperative Family Registry for Colon Cancer Studies [1101 CA074800]
- Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]
- University of Southern California Familial Colorectal Neoplasia Collaborative Group [U01 CA074799]
- Affymetrix Collaborations in Cancer Research Program
- [2P30CA071789-13]
- Cancer Research UK [16459] Funding Source: researchfish
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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.
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