Tumor Biology

, Volume 36, Issue 12, pp 9969–9978 | Cite as

Differentially expressed protein-coding genes and long noncoding RNA in early-stage lung cancer

Research Article

Abstract

Due to the application of low-dose computed tomography screening, more and more early-stage lung cancers have been diagnosed. Thus, it is essential to characterize the gene expression profile of early-stage lung cancer to develop potential biomarkers for early diagnosis and therapeutic targets. Here, we analyzed microarray data of 181 early-stage lung cancer patients. By comparing gene expression between different tumor and lymph node metastasis stages, we identified various differentially expressed protein-coding genes and long noncoding RNA (lncRNA) in the comparisons of T2 vs. T2 and N1- vs. N0-stage lung cancer. Functional analyses revealed that these differentially expressed genes were enriched in various tumorigenesis or metastasis-related pathways. Survival analysis indicated that two protein-coding genes, C7 and SCN7A, were significantly associated survival of lung cancer. Notably, a novel lncRNA, LINC00313, was highly expressed in both T2- and N1-stage lung cancers. On the other hand, LINC00313 was also upregulated in lung cancer and metastasized lung cancer tissues, compared with adjacent lung tissues and primary lung cancer tissues. Additionally, higher expression level of LINC00313 indicated poor prognosis of lung cancer (hazard ratio = 0.658). Overall, we characterized the expression profiles of protein-coding genes and lncRNA in early-stage lung cancer and found that LINC00313 could be a biomarker for lung cancer.

Keywords

Lung cancer lncRNA Biomarker Survival 

Notes

Acknowledgments

This study is founded by the Natural Science Foundation of China (81372321 to Lin Xu; 81201830 and 81472200 to Rong Yin), Natural Science Foundation for High Education of Jiangsu Province (13KJB320010 to Rong Yin), Jiangsu Provincial Special Program of Medical Science (BL2012030 to Lin Xu), and Jiangsu Province Ordinary University Graduate Student Research Innovation Project for 2013 (CXLX13_571 to Mantang Qiu).

Conflicts of interest

None

Supplementary material

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ESM 1 (PNG 110 kb)
13277_2015_3714_MOESM2_ESM.xlsx (125 kb)
ESM 2 (XLSX 124 kb)

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    National Lung Screening Trial Research T, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395–409.CrossRefGoogle Scholar
  3. 3.
    Senthi S, Lagerwaard FJ, Haasbeek CJ, Slotman BJ, Senan S. Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol. 2012;13(8):802–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Senan S, Paul MA, Lagerwaard FJ. Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy? Lancet Oncol. 2013;14(7):e270–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, Groen HJ, McRae SE, Widder J, Feng L, van den Borne BE, Munsell MF, Hurkmans C, Berry DA, van Werkhoven E, Kresl JJ, Dingemans AM, Dawood O, Haasbeek CJ, Carpenter LS, De Jaeger K, Komaki R, Slotman BJ, Smit EF, Roth JA. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015.Google Scholar
  6. 6.
    Zhu CQ, Pintilie M, John T, Strumpf D, Shepherd FA, Der SD, et al. Understanding prognostic gene expression signatures in lung cancer. Clin Lung Cancer. 2009;10(5):331–40.CrossRefPubMedGoogle Scholar
  7. 7.
    Subramanian J, Simon R. Gene expression-based prognostic signatures in lung cancer: ready for clinical use? J Natl Cancer Inst. 2010;102(7):464–74.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhu CQ, Ding K, Strumpf D, Weir BA, Meyerson M, Pennell N, et al. Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer. J Clin Oncol. 2010;28(29):4417–24.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Der SD, Sykes J, Pintilie M, Zhu CQ, Strumpf D, Liu N, et al. Validation of a histology-independent prognostic gene signature for early-stage, non-small-cell lung cancer including stage IA patients. J Thorac Oncol. 2014;9(1):59–64.CrossRefPubMedGoogle Scholar
  10. 10.
    Sandoval J, Mendez-Gonzalez J, Nadal E, Chen G, Carmona FJ, Sayols S, et al. A prognostic DNA methylation signature for stage I non-small-cell lung cancer. J Clin Oncol. 2013;31(32):4140–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136(4):629–41.CrossRefPubMedGoogle Scholar
  12. 12.
    Qiu MT, Hu JW, Yin R, Xu L. Long noncoding RNA: an emerging paradigm of cancer research. Tumour Biol. 2013;34(2):613–20.CrossRefPubMedGoogle Scholar
  13. 13.
    Tsai MC, Spitale RC, Chang HY. Long intergenic noncoding RNAs: new links in cancer progression. Cancer Res. 2011;71(1):3–7.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Dinger ME, Amaral PP, Mercer TR, Pang KC, Bruce SJ, Gardiner BB, et al. Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Res. 2008;18(9):1433–45.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ren S, Wang F, Shen J, Sun Y, Xu W, Lu J, et al. Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 derived miniRNA as a novel plasma-based biomarker for diagnosing prostate cancer. Eur J Cancer. 2013;49(13):2949–59.CrossRefPubMedGoogle Scholar
  16. 16.
    Su X, Malouf GG, Chen Y, Zhang J, Yao H, Valero V, et al. Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes. Oncotarget. 2014;5(20):9864–76.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yang J, Lin J, Liu T, Chen T, Pan S, Huang W, et al. Analysis of lncRNA expression profiles in non-small cell lung cancers (NSCLC) and their clinical subtypes. Lung Cancer. 2014;85(2):110–5.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang X, Sun S, Pu JK, Tsang AC, Lee D, Man VO, et al. Long non-coding RNA expression profiles predict clinical phenotypes in glioma. Neurobiol Dis. 2012;48(1):1–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Wettenhall JM, Smyth GK. limmaGUI: a graphical user interface for linear modeling of microarray data. Bioinformatics. 2004;20(18):3705–6.CrossRefPubMedGoogle Scholar
  20. 20.
    The Gene Ontology (GO) project in 2006. Nucleic Acids Res. 2006;34(Database issue):D322-326.Google Scholar
  21. 21.
    Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25(1):25–9.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Dupuy D, Bertin N, Hidalgo CA, Venkatesan K, Tu D, Lee D, et al. Genome-scale analysis of in vivo spatiotemporal promoter activity in Caenorhabditis elegans. Nat Biotechnol. 2007;25(6):663–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Schlitt T, Palin K, Rung J, Dietmann S, Lappe M, Ukkonen E, et al. From gene networks to gene function. Genome Res. 2003;13(12):2568–76.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M. The KEGG resource for deciphering the genome. Nucleic Acids Res. 2004;32(Database issue):D277–80.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Yi M, Horton JD, Cohen JC, Hobbs HH, Stephens RM. WholePathwayScope: a comprehensive pathway-based analysis tool for high-throughput data. BMC Bioinformatics. 2006;7:30.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Draghici S, Khatri P, Tarca AL, Amin K, Done A, Voichita C, et al. A systems biology approach for pathway level analysis. Genome Res. 2007;17(10):1537–45.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Louie AV, Senthi S, Palma DA. Surgery versus SABR for NSCLC. Lancet Oncol. 2013;14(12), e491.CrossRefPubMedGoogle Scholar
  28. 28.
    Tang H, Xiao G, Behrens C, Schiller J, Allen J, Chow CW, et al. A 12-gene set predicts survival benefits from adjuvant chemotherapy in non-small cell lung cancer patients. Clin Cancer Res. 2013;19(6):1577–86.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev. 2009;23(13):1494–504.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43(6):904–14.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642–55.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Srikantan V, Zou Z, Petrovics G, Xu L, Augustus M, Davis L, et al. PCGEM1, a prostate-specific gene, is overexpressed in prostate cancer. Proc Natl Acad Sci U S A. 2000;97(22):12216–21.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Schmidt LH, Spieker T, Koschmieder S, Schaffers S, Humberg J, Jungen D, et al. The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol. 2011;6(12):1984–92.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Ming Li
    • 1
  • Mantang Qiu
    • 1
    • 2
  • Youtao Xu
    • 1
    • 3
  • Qixing Mao
    • 1
    • 2
  • Jie Wang
    • 1
    • 4
  • Gaochao Dong
    • 1
    • 4
  • Wenjia Xia
    • 1
    • 2
  • Rong Yin
    • 1
  • Lin Xu
    • 1
  1. 1.Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjingChina
  2. 2.The Fourth Clinical College of Nanjing Medical UniversityNanjingChina
  3. 3.The First Clinical College of Nanjing Medical UniversityNanjingChina
  4. 4.Department of Scientific Research, Nanjing Medical University Affiliated Cancer HospitalCancer Institute of Jiangsu ProvinceNanjingChina

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