Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

LincRNA-uc002yug.2 involves in alternative splicing of RUNX1 and serves as a predictor for esophageal cancer and prognosis

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

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Szumilo J . Epidemiology and risk factors of the esophageal squamous cell carcinoma. Pol Merkur Lekarski 2009; 26: 82–85.

    PubMed  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. 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.

    Article  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. Manolio TA, Brooks LD, Collins FS . A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008; 118: 1590–1605.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. Ponting CP, Oliver PL, Reik W . Evolution and functions of long noncoding RNAs. Cell 2009; 136: 629–641.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. 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.

    Article  CAS  Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. 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.

    Article  CAS  Google Scholar 

  21. 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.

    Article  CAS  Google Scholar 

  22. Huarte M, Rinn JL . Large non-coding RNAs: missing links in cancer? Hum Mol Genet 2010; 19: R152–R161.

    Article  CAS  Google Scholar 

  23. Gibb EA, Brown CJ, Lam WL . The functional role of long non-coding RNA in human carcinomas. Mol Cancer 2011; 10: 38.

    Article  CAS  Google Scholar 

  24. Prensner JR, Chinnaiyan AM . The emergence of lncRNAs in cancer biology. Cancer Discov 2011; 1: 391–407.

    Article  CAS  Google Scholar 

  25. 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.

    Article  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. 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.

    Article  CAS  Google Scholar 

  29. 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.

    Article  Google Scholar 

  30. 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.

    Article  CAS  Google Scholar 

  31. 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.

    Article  CAS  Google Scholar 

  32. 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.

    Article  CAS  Google Scholar 

  33. 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.

    Article  CAS  Google Scholar 

  34. 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.

    Article  CAS  Google Scholar 

  35. Chimge NO, Frenkel B . The RUNX family in breast cancer: relationships with estrogen signaling. Oncogene 2013; 32: 2121–2130.

    Article  CAS  Google Scholar 

  36. 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.

    Article  CAS  Google Scholar 

  37. 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.

    Article  CAS  Google Scholar 

  38. Ito Y . Oncogenic potential of the RUNX gene family: 'overview'. Oncogene 2004; 23: 4198–4208.

    Article  CAS  Google Scholar 

  39. 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.

    Article  Google Scholar 

  40. Chen M, Manley JL . Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 2009; 10: 741–754.

    Article  CAS  Google Scholar 

  41. 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.

    Article  CAS  Google Scholar 

  42. 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.

    Article  CAS  Google Scholar 

  43. 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.

    Article  CAS  Google Scholar 

  44. 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.

    Article  CAS  Google Scholar 

  45. 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.

    Article  Google Scholar 

Download references

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

Authors

Corresponding author

Correspondence to Y Zhou.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.400

This article is cited by

Search

Quick links