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

  1. George A. Calin1,7,33
  1. 1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  2. 2Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands;
  3. 3Department of Medical Genetics, University of Medicine and Pharmacy “I. Hatieganu,” Cluj-Napoca 400023, Romania;
  4. 4Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan;
  5. 5Department of Experimental and Diagnostic Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy;
  6. 6Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  7. 7Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  8. 8Welcome Trust Centre for Human Genetics, NIHR Comprehensive Biomedical Research Center, University of Oxford, Oxford OX1 2JD, United Kingdom;
  9. 9Department of Clinical Genetics, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands;
  10. 10Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  11. 11Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  12. 12Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  13. 13Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  14. 14Department of Surgery, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia;
  15. 15Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  16. 16Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  17. 17Division of Genome Analysis, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
  18. 18Department of Molecular Biosciences and Bioengineering, University of Hawaii-Manoa, Honolulu, Hawaii 96822, USA;
  19. 19Department of Surgery, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Ontario M5G 1X5, Canada;
  20. 20Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA;
  21. 21Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA;
  22. 22Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA;
  23. 23Genomics Shared Resource, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA;
  24. 24Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  25. 25Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
  26. 26Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan;
  27. 27 Department of Medical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center and Cancer Genomics Center, Rotterdam 3000 CA, The Netherlands;
  28. 28Department of Immunology, University of Medicine and Pharmacy “I. Hatieganu” Cluj-Napoca 400023, Romania;
  29. 29Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy “I. Hatieganu” Cluj-Napoca 400023, Romania

    1. ↵32 These authors contributed equally to this work.

    • ↵Present addresses: 30Division of Experimental Oncology B, CRO, National Cancer Institute, Aviano 33081, Italy;

    • ↵31 German Cancer Research Center, Heidelberg 69120, Germany.

    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.

    Footnotes

    • Received December 3, 2012.
    • Accepted June 17, 2013.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.

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    1. Published in Advance June 24, 2013, doi: 10.1101/gr.152942.112 Genome Res. 23: 1446-1461 © 2013, Published by Cold Spring Harbor Laboratory Press

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