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

Hui Ling; Riccardo Spizzo; Yaser Atlasi; Milena Nicoloso; Masayoshi Shimizu; Roxana S. Redis; Naohiro Nishida; Roberta Gafà; Jian Song; Zhiyi Guo; Cristina Ivan; Elisa Barbarotto; Ingrid De Vries; Xinna Zhang; Manuela Ferracin; Mike Churchman; Janneke F. Van Galen; Berna H. Beverloo; Maryam Shariati; Franziska Haderk; Marcos R. Estecio; Guillermo Garcia-Manero; Gijs A. Patijn; David C. Gotley; Vikas Bhardwaj; Imad Shureiqi; Subrata Sen; Asha S. Multani; James Welsh; Ken Yamamoto; Itsuki Taniguchi; Min Ae Song; Steven Gallinger; Graham Casey; Stephen N. Thibodeau; Loic Le Marchand; Maarit Tiirikainen; Sendurai A. Mani; Wei Zhang; Ramana V. Davuluri; Koshi Mimori; Masaki Mori; Anieta M. Sieuwerts; John W.M. Martens; Ian Tomlinson; Massimo Negrini; Ioana Berindan-Neagoe; John A. Foekens; Stanley R. Hamilton; Giovanni Lanza; Scott Kopetz; Riccardo Fodde; George A. Calin

doi:10.1101/gr.152942.112

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

Hui Ling, Riccardo Spizzo, Yaser Atlasi, Milena Nicoloso, Masayoshi Shimizu, Roxana S. Redis, Naohiro Nishida, Roberta Gafà, Jian Song, Zhiyi Guo, Cristina Ivan, Elisa Barbarotto, Ingrid De Vries, Xinna Zhang, Manuela Ferracin, Mike Churchman, Janneke F. Van Galen, Berna H. Beverloo, Maryam Shariati, Franziska HaderkMarcos R. Estecio, Guillermo Garcia-Manero, Gijs A. Patijn, David C. Gotley, Vikas Bhardwaj, Imad Shureiqi, Subrata Sen, Asha S. Multani, James Welsh, Ken Yamamoto, Itsuki Taniguchi, Min Ae Song, Steven Gallinger, Graham Casey, Stephen N. Thibodeau, Loic Le Marchand, Maarit Tiirikainen, Sendurai A. Mani, Wei Zhang, Ramana V. Davuluri, Koshi Mimori, Masaki Mori, Anieta M. Sieuwerts, John W.M. Martens, Ian Tomlinson, Massimo Negrini, Ioana Berindan-Neagoe, John A. Foekens, Stanley R. Hamilton, Giovanni Lanza, Scott Kopetz, Riccardo Fodde, George A. Calin

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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.

Original language	English
Pages (from-to)	1446-1461
Number of pages	16
Journal	Genome Research
Volume	23
Issue number	9
DOIs	https://doi.org/10.1101/gr.152942.112
Publication status	Published - Sept 2013

All Science Journal Classification (ASJC) codes

Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1101/gr.152942.112

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Ling, H., Spizzo, R., Atlasi, Y., Nicoloso, M., Shimizu, M., Redis, R. S., Nishida, N., Gafà, R., Song, J., Guo, Z., Ivan, C., Barbarotto, E., De Vries, I., Zhang, X., Ferracin, M., Churchman, M., Van Galen, J. F., Beverloo, B. H., Shariati, M., ... Calin, G. A. (2013). CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Research, 23(9), 1446-1461. https://doi.org/10.1101/gr.152942.112

Ling, H, Spizzo, R, Atlasi, Y, Nicoloso, M, Shimizu, M, Redis, RS, Nishida, N, Gafà, R, Song, J, Guo, Z, Ivan, C, Barbarotto, E, De Vries, I, Zhang, X, Ferracin, M, Churchman, M, Van Galen, JF, Beverloo, BH, Shariati, M, Haderk, F, Estecio, MR, Garcia-Manero, G, Patijn, GA, Gotley, DC, Bhardwaj, V, Shureiqi, I, Sen, S, Multani, AS, Welsh, J, Yamamoto, K, Taniguchi, I, Song, MA, Gallinger, S, Casey, G, Thibodeau, SN, Le Marchand, L, Tiirikainen, M, Mani, SA, Zhang, W, Davuluri, RV, Mimori, K, Mori, M, Sieuwerts, AM, Martens, JWM, Tomlinson, I, Negrini, M, Berindan-Neagoe, I, Foekens, JA, Hamilton, SR, Lanza, G, Kopetz, S, Fodde, R & Calin, GA 2013, 'CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer', Genome Research, vol. 23, no. 9, pp. 1446-1461. https://doi.org/10.1101/gr.152942.112

@article{83b9afb274c54cdc831ebd731763dfa2,

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

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.",

author = "Hui Ling and Riccardo Spizzo and Yaser Atlasi and Milena Nicoloso and Masayoshi Shimizu and Redis, {Roxana S.} and Naohiro Nishida and Roberta Gaf{\`a} and Jian Song and Zhiyi Guo and Cristina Ivan and Elisa Barbarotto and {De Vries}, Ingrid and Xinna Zhang and Manuela Ferracin and Mike Churchman and {Van Galen}, {Janneke F.} and Beverloo, {Berna H.} and Maryam Shariati and Franziska Haderk and Estecio, {Marcos R.} and Guillermo Garcia-Manero and Patijn, {Gijs A.} and Gotley, {David C.} and Vikas Bhardwaj and Imad Shureiqi and Subrata Sen and Multani, {Asha S.} and James Welsh and Ken Yamamoto and Itsuki Taniguchi and Song, {Min Ae} and Steven Gallinger and Graham Casey and Thibodeau, {Stephen N.} and {Le Marchand}, Loic and Maarit Tiirikainen and Mani, {Sendurai A.} and Wei Zhang and Davuluri, {Ramana V.} and Koshi Mimori and Masaki Mori and Sieuwerts, {Anieta M.} and Martens, {John W.M.} and Ian Tomlinson and Massimo Negrini and Ioana Berindan-Neagoe and Foekens, {John A.} and Hamilton, {Stanley R.} and Giovanni Lanza and Scott Kopetz and Riccardo Fodde and Calin, {George A.}",

year = "2013",

month = sep,

doi = "10.1101/gr.152942.112",

language = "English",

volume = "23",

pages = "1446--1461",

journal = "Genome Research",

issn = "1088-9051",

publisher = "Cold Spring Harbor Laboratory Press",

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T1 - CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

AU - Ling, Hui

AU - Spizzo, Riccardo

AU - Atlasi, Yaser

AU - Nicoloso, Milena

AU - Shimizu, Masayoshi

AU - Redis, Roxana S.

AU - Nishida, Naohiro

AU - Gafà, Roberta

AU - Song, Jian

AU - Guo, Zhiyi

AU - Ivan, Cristina

AU - Barbarotto, Elisa

AU - De Vries, Ingrid

AU - Zhang, Xinna

AU - Ferracin, Manuela

AU - Churchman, Mike

AU - Van Galen, Janneke F.

AU - Beverloo, Berna H.

AU - Shariati, Maryam

AU - Haderk, Franziska

AU - Estecio, Marcos R.

AU - Garcia-Manero, Guillermo

AU - Patijn, Gijs A.

AU - Gotley, David C.

AU - Bhardwaj, Vikas

AU - Shureiqi, Imad

AU - Sen, Subrata

AU - Multani, Asha S.

AU - Welsh, James

AU - Yamamoto, Ken

AU - Taniguchi, Itsuki

AU - Song, Min Ae

AU - Gallinger, Steven

AU - Casey, Graham

AU - Thibodeau, Stephen N.

AU - Le Marchand, Loic

AU - Tiirikainen, Maarit

AU - Mani, Sendurai A.

AU - Zhang, Wei

AU - Davuluri, Ramana V.

AU - Mimori, Koshi

AU - Mori, Masaki

AU - Sieuwerts, Anieta M.

AU - Martens, John W.M.

AU - Tomlinson, Ian

AU - Negrini, Massimo

AU - Berindan-Neagoe, Ioana

AU - Foekens, John A.

AU - Hamilton, Stanley R.

AU - Lanza, Giovanni

AU - Kopetz, Scott

AU - Fodde, Riccardo

AU - Calin, George A.

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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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JO - Genome Research

JF - Genome Research

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ER -

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

Abstract

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