Research

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

    • 1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
    • 2Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands;
    • 3Department of Medical Genetics, University of Medicine and Pharmacy “I. Hatieganu,” Cluj-Napoca 400023, Romania;
    • 4Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan;
    • 5Department of Experimental and Diagnostic Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy;
    • 6Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
    • 7Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
    • 8Welcome Trust Centre for Human Genetics, NIHR Comprehensive Biomedical Research Center, University of Oxford, Oxford OX1 2JD, United Kingdom;
    • 9Department of Clinical Genetics, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands;
    • 10Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
    • 11Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
    • 12Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
    • 13Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
    • 14Department of Surgery, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia;
    • 15Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
    • 16Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
    • 17Division of Genome Analysis, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
    • 18Department of Molecular Biosciences and Bioengineering, University of Hawaii-Manoa, Honolulu, Hawaii 96822, USA;
    • 19Department of Surgery, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Ontario M5G 1X5, Canada;
    • 20Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA;
    • 21Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA;
    • 22Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA;
    • 23Genomics Shared Resource, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA;
    • 24Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
    • 25Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
    • 26Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan;
    • 27 Department of Medical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center and Cancer Genomics Center, Rotterdam 3000 CA, The Netherlands;
    • 28Department of Immunology, University of Medicine and Pharmacy “I. Hatieganu” Cluj-Napoca 400023, Romania;
    • 29Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy “I. Hatieganu” Cluj-Napoca 400023, Romania
    • Present addresses: 30Division of Experimental Oncology B, CRO, National Cancer Institute, Aviano 33081, Italy;
    • 31 German Cancer Research Center, Heidelberg 69120, Germany.
    • 32 These authors contributed equally to this work.
    • 33 Corresponding author E-mail [email protected]
Published June 24, 2013. Vol 23 Issue 9, pp. 1446-1461. https://doi.org/10.1101/gr.152942.112
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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 (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.

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