CCAT2, a novel non-coding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer
- Hui Ling1,
- Riccardo Spizzo1,
- Yaser Atlasi2,
- Milena Nicoloso1,
- Masayoshi Shimizu1,
- Roxana Redis1,
- Naohiro Nishida1,
- Roberta Gafà3,
- Jian Song1,
- Zhiyi Guo1,
- Cristina Ivan1,
- Elisa Barbarotto1,
- Ingrid De Vries2,
- Xinna Zhang1,
- Manuela Ferracin3,
- Mike Churchman4,
- Janneke van Galen2,
- Berna Beverloo2,
- Maryam Shariati1,
- Franziska Haderk1,
- Marcos R Estecio1,
- Guillermo Garcia-Manero1,
- Gijs Patijn2,
- David Gotley5,
- Vikas Bhardwaj1,
- Shureiqi Imad1,
- Subrata Sen1,
- Asha Multani1,
- James Welsh1,
- Ken Yamamoto6,
- Itsuki Taniguchi6,
- Min-Ae Song7,
- Steven Gallinger8,
- Graham Casey9,
- Stephen Thibodeau10,
- Loic Le Marchand7,
- Maarit Tiirikainen7,
- Sendurai Mani1,
- Wei Zhang1,
- Ramana Davuluri11,
- Koshi Mimori12,
- Masaki Mori13,
- Anieta Sieuwerts14,
- John Martens14,
- Ian Tomlinson15,
- Ioana Neagoe16,
- Massimo Negrini3,
- John Foekens14,
- Stanley Hamilton1,
- Giovanni Lanza3,
- Scott Kopetz1,
- Riccardo Fodde2 and
- George Calin1,17
- 1 The University of Texas MD Anderson Cancer Center;
- 2 Josephine Nefkens Institute, Erasmus Medical Center;
- 3 University of Ferrara;
- 4 Welcome Trust Centre for Human Genetics,University of Oxford;
- 5 Princess Alexandra Hospital;
- 6 Kyushu University;
- 7 University of Hawaii Cancer Center;
- 8 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Ontario Canada;
- 9 Keck School of Medicine, University of Southern California;
- 10 Mayo Clinic;
- 11 The Wistar Institute;
- 12 Kyushu University Beppu Hospital;
- 13 Osaka University;
- 14 Erasmus University Medical Center;
- 15 Welcome Trust Centre for Human Genetics, University of Oxford;
- 16 University of Medicine and Pharmacy 'I. Hatieganu'
- ↵* Corresponding author; email: gcalin{at}mdanderson.org
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 non-coding 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 demonstrated 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 on the SNP-conferred cancer risk.
- Received December 3, 2012.
- Accepted June 17, 2013.
- © 2013, Published by Cold Spring Harbor Laboratory Press
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