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

被引：550

作者：

Ling, Hui ^{[1
]}

Spizzo, Riccardo ^{[1
]}

Atlasi, Yaser ^{[2
]}

Nicoloso, Milena ^{[1
]}

Shinnizu, Masayoshi ^{[1
]}

Redis, Roxana S. ^{[1
,3
]}

Nishida, Naohiro ^{[1
,4
]}

Gafa, Roberta ^{[5
,6
]}

Song, Jian ^{[7
]}

Guo, Zhiyi ^{[1
]}

Ivan, Cristina ^{[8
]}

Barbarotto, Elisa ^{[1
]}

De Vries, Ingrid ^{[2
]}

Zhang, Xinna ^{[8
]}

Ferracin, Manuela ^{[5
,6
]}

Churchman, Mike ^{[9
]}

van Galen, Janneke F. ^{[10
]}

Beverloo, Berna H. ^{[10
]}

Shariati, Maryam ^{[11
]}

Haderk, Franziska ^{[1
]}

Estecio, Marcos R. ^{[12
,13
]}

Garcia-Manero, Guillermo ^{[14
]}

Patijn, Gijs A. ^{[2
]}

Gotley, David C. ^{[15
]}

Bhardwaj, Vikas ^{[16
]}

Shureiqi, Imad ^{[7
]}

Sen, Subrata ^{[11
]}

Multani, Asha S. ^{[17
]}

Welsh, James ^{[16
]}

Yamamoto, Ken ^{[18
]}

Taniguchi, Itsuki ^{[18
]}

Song, Min-Ae ^{[19
]}

Gallinger, Steven ^{[20
]}

Casey, Graham ^{[21
]}

Thibodeau, Stephen N. ^{[22
]}

Le Marchand, Loic ^{[23
]}

Tiirikainen, Maarit ^{[24
]}

Mani, Sendurai A. ^{[11
]}

Zhang, Wei ^{[25
]}

Davuluri, Ramana V. ^{[26
]}

Mimori, Koshi ^{[27
]}

Mori, Masaki ^{[4
]}

Sieuwerts, Anieta M. ^{[28
]}

Martens, John W. M. ^{[28
]}

Tomlinson, Ian ^{[9
]}

Negrini, Massimo ^{[5
,6
]}

Berindan-Neagoe, Ioana ^{[29
,30
]}

Foekens, John A. ^{[28
]}

Hamilton, Stanley R. ^{[25
]}

Lanza, Giovanni ^{[5
,6
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA

[2] Erasmus MC, Josephine Nefkens Inst, Dept Pathol, NL-3000 CA Rotterdam, Netherlands

[3] Univ Med & Pharm I Hatieganu, Dept Med Genet, Cluj Napoca 400023, Romania

[4] Osaka Univ, Grad Sch Med, Dept Surg Gastroenterol, Suita, Osaka 5650871, Japan

[5] Univ Ferrara, Dept Expt & Diagnost Med, I-44121 Ferrara, Italy

[6] Univ Ferrara, LTTA, I-44121 Ferrara, Italy

[7] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Houston, TX 77030 USA

[9] Univ Oxford, NIHR Comprehens Biomed Res Ctr, Welcome Trust Ctr Human Genet, Oxford OX1 2JD, England

[10] Erasmus MC, Dept Clin Genet, Josephine Nefkens Inst, NL-3000 CA Rotterdam, Netherlands

[11] Univ Texas MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Mol Carcinogenesis, Houston, TX 77030 USA

[13] Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[15] Princess Alexandra Hosp, Dept Surg, Brisbane, Qld 4102, Australia

[16] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

[17] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA

[18] Kyushu Univ, Div Genome Anal, Res Ctr Genet Informat, Med Inst Bioregulat, Fukuoka 8128582, Japan

[19] Univ Hawaii Manoa, Dept Mol Biosci & Bioengn, Honolulu, HI 96822 USA

[20] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Surg, Toronto, ON MSG 1X5, Canada

[21] Univ So Calif, Keck Sch Med, Dept Prevent Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90089 USA

[22] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[23] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96813 USA

[24] Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA

[25] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Div Pathol & Lab Med, Houston, TX 77030 USA

[26] Wistar Inst Anat & Biol, Ctr Syst & Computat Biol, Philadelphia, PA 19104 USA

[27] Kyushu Univ, Beppu Hosp, Dept Surg, Beppu, Oita 8740838, Japan

[28] Erasmus Univ, Dept Med Oncol, Med Ctr, Dr Daniel Den Hoed Canc Ctr, NL-3000 CA Rotterdam, Netherlands

[29] Univ Med & Pharm I Hatieganu, Dept Immunol, Cluj Napoca 400023, Romania

[30] Univ Med & Pharm I Hatieganu, Res Ctr Funct Genom Biomed & Translat Med, Cluj Napoca 400023, Romania

来源：

GENOME RESEARCH | 2013年 / 23卷 / 09期

基金：

美国国家卫生研究院;

关键词：

C-MYC; COLORECTAL-CANCER; SNP RS6983267; BETA-CATENIN; APC; TRANSCRIPTION; EXPRESSION; MICRORNAS; PROTEIN; TARGET;

D O I：

10.1101/gr.152942.112

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (IncRNA) encompassing the rs6983267 SNP, is highly over-expressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MY, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CC4T2 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 CC4T2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel IncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.

引用

页码：1446 / 1461

页数：16

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