Abstract
Long intergenic noncoding RNAs (lincRNAs) have critical regulatory roles in cancer biology; however, the contributions of lincRNAs to esophageal squamous cell carcinoma (ESCC) have been infrequently explored. The aim of this study was to explore the contribution of lincRNAs, located at ESCC susceptibility loci identified by genome-wide association studies, to the risk and prognosis of ESCC. The associations between lincRNAs and the risk and prognosis of ESCC were analyzed in 358 diagnosed patients from eastern China, and the findings were validated in 326 additional patients from southern China. Functional relevance of lincRNAs was further examined by biochemical assays. We found that lincRNA-uc002yug.2 was commonly overexpressed in ESCC compared with paired peritumoral tissue in eastern and southern Chinese populations. The expression levels of lincRNA-uc002yug.2 in ESCC might be a prognostic factor for survival. Moreover, lincRNA-uc002yug.2 promoted a combination of RUNX1 and alternative splicing (AS) factors in the nucleus to produce more RUNX1a, the short isoform and inhibitor of RUNX1, and reduce CEBPα (CCAAT/enhancer-binding protein-α) gene expression, thereby promoting ESCC progression. These results indicated that lincRNA-uc002yug.2 might involve in AS of RUNX1/AML1 and serve as a predictor for esophageal cancer and prognosis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Szumilo J . Epidemiology and risk factors of the esophageal squamous cell carcinoma. Pol Merkur Lekarski 2009; 26: 82–85.
Wu C, Li D, Jia W, Hu Z, Zhou Y, Yu D et al. Genome-wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-cell carcinoma. Nat Genet 2013; 45: 632–638.
Kuwano H, Kato H, Miyazaki T, Fukuchi M, Masuda N, Nakajima M et al. Genetic alterations in esophageal cancer. Surg Today 2005; 35: 7–18.
Cui R, Kamatani Y, Takahashi A, Usami M, Hosono N, Kawaguchi T et al. Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. Gastroenterology 2009; 137: 1768–1775.
Hu N, Wang C, Hu Y, Yang HH, Giffen C, Tang ZZ et al. Genome-wide association study in esophageal cancer using GeneChip mapping 10 K array. Cancer Res 2005; 65: 2542–2546.
Wang LD, Zhou FY, Li XM, Sun LD, Song X, Jin Y et al. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat Genet 2010; 42: 759–763.
Abnet CC, Freedman ND, Hu N, Wang Z, Yu K, Shu XO et al. A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat Genet 2010; 42: 764–767.
Jin G, Ma H, Wu C, Dai J, Zhang R, Shi Y et al. Genetic variants at 6p21.1 and 7p15.3 are associated with risk of multiple cancers in Han Chinese. Am J Hum Genet 2012; 91: 928–934.
Yang HH, Hu N, Taylor PR, Lee MP . Whole genome-wide association study using affymetrix SNP chip: a two-stage sequential selection method to identify genes that increase the risk of developing complex diseases. Methods Mol Med 2008; 141: 23–35.
Yamabuki T, Daigo Y, Kato T, Hayama S, Tsunoda T, Miyamoto M et al. Genome-wide gene expression profile analysis of esophageal squamous cell carcinomas. Int J Oncol 2006; 28: 1375–1384.
Wu C, Hu Z, He Z, Jia W, Wang F, Zhou Y et al. Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations. Nat Genet 2011; 43: 679–684.
Wu C, Kraft P, Zhai K, Chang J, Wang Z, Li Y et al. Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene–environment interactions. Nat Genet 2012; 44: 1090–1097.
Manolio TA, Brooks LD, Collins FS . A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008; 118: 1590–1605.
Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007; 447: 799–816.
Dinger ME, Amaral PP, Mercer TR, Mattick JS . Pervasive transcription of the eukaryotic genome: functional indices and conceptual implications. Brief Funct Genomic Proteomic 2009; 8: 407–423.
Ponting CP, Oliver PL, Reik W . Evolution and functions of long noncoding RNAs. Cell 2009; 136: 629–641.
Kapranov P St, Laurent G, Raz T, Ozsolak F, Reynolds CP, Sorensen PH et al. The majority of total nuclear-encoded non-ribosomal RNA in a human cell is 'dark matter' un-annotated RNA. BMC Biol 2010; 8: 149.
Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 2005; 309: 1570–1573.
Martianov I, Ramadass A, Serra Barros A, Chow N, Akoulitchev A . Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 2007; 445: 666–670.
Wang X, Arai S, Song X, Reichart D, Du K, Pascual G et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 2008; 454: 126–130.
Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP . A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 2010; 465: 1033–1038.
Huarte M, Rinn JL . Large non-coding RNAs: missing links in cancer? Hum Mol Genet 2010; 19: R152–R161.
Gibb EA, Brown CJ, Lam WL . The functional role of long non-coding RNA in human carcinomas. Mol Cancer 2011; 10: 38.
Prensner JR, Chinnaiyan AM . The emergence of lncRNAs in cancer biology. Cancer Discov 2011; 1: 391–407.
Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 2003; 22: 8031–8041.
Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 2010; 329: 689–693.
Yap KL, Li S, Munoz-Cabello AM, Raguz S, Zeng L, Mujtaba S et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 2010; 38: 662–674.
Ulitsky I, Shkumatava A, Jan CH, Sive H, Bartel DP . Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell 2011; 147: 1537–1550.
Sun M, Liu XH, Wang KM, Nie FQ, Kong R, Yang JS et al. Downregulation of BRAF activated non-coding RNA is associated with poor prognosis for non-small cell lung cancer and promotes metastasis by affecting epithelial-mesenchymal transition. Mol Cancer 2014; 13: 68.
Liu X, Zhang Q, Zhang DE, Zhou C, Xing H, Tian Z et al. Overexpression of an isoform of AML1 in acute leukemia and its potential role in leukemogenesis. Leukemia 2009; 23: 739–745.
Guo H, Ma O, Speck NA, Friedman AD . Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis. Blood 2012; 119: 4408–4418.
Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ et al. C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Mol Cell 2001; 8: 817–828.
Sato A, Yamada N, Ogawa Y, Ikegami M . CCAAT/enhancer-binding protein-alpha suppresses lung tumor development in mice through the p38alpha MAP kinase pathway. PLoS One 2013; 8: e57013.
Girard N, Tremblay M, Humbert M, Grondin B, Haman A, Labrecque J et al. RARalpha-PLZF oncogene inhibits C/EBPalpha function in myeloid cells. Proc Natl Acad Sci USA 2013; 110: 13522–13527.
Chimge NO, Frenkel B . The RUNX family in breast cancer: relationships with estrogen signaling. Oncogene 2013; 32: 2121–2130.
Scheitz CJ, Lee TS, McDermitt DJ, Tumbar T . Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J 2012; 31: 4124–4139.
Dulak AM, Schumacher SE, van Lieshout J, Imamura Y, Fox C, Shim B et al. Gastrointestinal adenocarcinomas of the esophagus, stomach, and colon exhibit distinct patterns of genome instability and oncogenesis. Cancer Res 2012; 72: 4383–4393.
Ito Y . Oncogenic potential of the RUNX gene family: 'overview'. Oncogene 2004; 23: 4198–4208.
Tsuzuki S, Hong D, Gupta R, Matsuo K, Seto M, Enver T . Isoform-specific potentiation of stem and progenitor cell engraftment by AML1/RUNX1. PLoS Med 2007; 4: e172.
Chen M, Manley JL . Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 2009; 10: 741–754.
Luco RF, Misteli T . More than a splicing code: integrating the role of RNA, chromatin and non-coding RNA in alternative splicing regulation. Curr Opin Genet Dev 2011; 21: 366–372.
Sun S, Zhang Z, Sinha R, Karni R, Krainer AR . SF2/ASF autoregulation involves multiple layers of post-transcriptional and translational control. Nat Struct Mol Biol 2010; 17: 306–312.
Han H, Irimia M, Ross PJ, Sung HK, Alipanahi B, David L et al. MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature 2013; 498: 241–245.
Kumar M, Witt B, Knippschild U, Koch S, Meena JK, Heinlein C et al. CEBP factors regulate telomerase reverse transcriptase promoter activity in whey acidic protein-T mice during mammary carcinogenesis. Int J Cancer 2013; 132: 2032–2043.
Muller C, Calkhoven CF, Sha X, Leutz A . The CCAAT enhancer-binding protein alpha (C/EBPalpha) requires a SWI/SNF complex for proliferation arrest. J Biol Chem 2004; 279: 7353–7358.
Acknowledgements
This study was supported by the National Scientific Foundation of China grants 81001278, 81171895, 81472630 and 81072366; a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, Jiangsu Provincial Natural Science Foundation (No. BK2011297); Jiangsu Province Science and Technology Support Program (No. BE2012648) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (No. 20101561).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Rights and permissions
About this article
Cite this article
Wu, H., Zheng, J., Deng, J. et al. LincRNA-uc002yug.2 involves in alternative splicing of RUNX1 and serves as a predictor for esophageal cancer and prognosis. Oncogene 34, 4723–4734 (2015). https://doi.org/10.1038/onc.2014.400
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2014.400
This article is cited by
-
MicroRNAs and long non-coding RNAs during transcriptional regulation and latency of HIV and HTLV
Retrovirology (2024)
-
miR-575/RIPK4 axis modulates cell cycle progression and proliferation by inactivating the Wnt/β-catenin signaling pathway through inhibiting RUNX1 in colon cancer
Molecular and Cellular Biochemistry (2024)
-
RUN(X) out of blood: emerging RUNX1 functions beyond hematopoiesis and links to Down syndrome
Human Genomics (2023)
-
A micropeptide XBP1SBM encoded by lncRNA promotes angiogenesis and metastasis of TNBC via XBP1s pathway
Oncogene (2022)
-
Long non-coding RNAs are involved in alternative splicing and promote cancer progression
British Journal of Cancer (2022)