<i>CCAT2</i>, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer
Hui LingDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USARiccardo Spizzo1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Yaser Atlasi2Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands;Milena S. Nicoloso1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Masayoshi Shimizu1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Roxana S. Redis1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Naohiro Nishida1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Roberta Gafà5Department of Experimental and Diagnostic Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy;Jian H. Song6Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Zhiyi Guo1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Cristina Ivan7Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Elisa Barbarotto1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Ingrid de Vries2Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands;Xinna Zhang7Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Manuela Ferracin5Department of Experimental and Diagnostic Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy;Mike Churchman8Welcome Trust Centre for Human Genetics, NIHR Comprehensive Biomedical Research Center, University of Oxford, Oxford OX1 2JD, United Kingdom;Janneke F. van Galen9Department of Clinical Genetics, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands;Berna Beverloo9Department of Clinical Genetics, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands;Maryam Shariati10Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Franziska Haderk1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Marcos R. Estecio11Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Guillermo Garcia‐Manero13Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Gijs A. Patijn2Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands;D. C. Gotley14Department of Surgery, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia;Vikas Bhardwaj15Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Imad Shureiqi6Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Subrata Sen10Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Asha S. Multani16Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;James Welsh15Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Ken Yamamoto17Division of Genome Analysis, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;Itsuki Taniguchi17Division of Genome Analysis, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;Min‐Ae Song18Department of Molecular Biosciences and Bioengineering, University of Hawaii-Manoa, Honolulu, Hawaii 96822, USA;Steven Gallinger19Department of Surgery, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Ontario M5G 1X5, Canada;Graham Casey20Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA;Stephen N. Thibodeau21Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA;Loı̈c Le Marchand22Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA;Maarit Tiirikainen23Genomics Shared Resource, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA;Sendurai A. Mani10Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Wei Zhang24Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Ramana V. Davuluri25Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;Koshi Mimori26Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan;Masaki Mori4Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan;Anieta M. Sieuwerts27 Department of Medical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center and Cancer Genomics Center, Rotterdam 3000 CA, The Netherlands;John W.M. Martens27 Department of Medical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center and Cancer Genomics Center, Rotterdam 3000 CA, The Netherlands;Ian Tomlinson8Welcome Trust Centre for Human Genetics, NIHR Comprehensive Biomedical Research Center, University of Oxford, Oxford OX1 2JD, United Kingdom;Massimo Negrini5Department of Experimental and Diagnostic Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy;Ioana Berindan‐Neagoe28Department of Immunology, University of Medicine and Pharmacy “I. Hatieganu” Cluj-Napoca 400023, Romania;John A. Foekens27 Department of Medical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center and Cancer Genomics Center, Rotterdam 3000 CA, The Netherlands;Stanley R. Hamilton24Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Giovanni Lanza5Department of Experimental and Diagnostic Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara 44121, Italy;Scott Kopetz6Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;Riccardo Fodde2Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands;George A. Călin1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
2013en
ABI
Аннотация
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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