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Variations of chromosome 2 gene expressions among patients with lung cancer or non-cancer

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Abstract

Lung cancer is one of the most common malignancies worldwide. The present study aimed to investigate specific genotypes of different subtypes or stages of lung cancer through gene expression variations of chromosome 2 genes, trying to identify predictors for diagnosis or prognosis of lung cancer. About 537 patients with lung adenocarcinoma (ADC), 140 patients with lung squamous carcinoma (SQC), 9 patients with lung large cell carcinoma (LCC), 56 patients with small cell lung cancer (SCLC), and 590 patients without cancer were analyzed in present study. Co-expressed, subtype-specific, and stage-specific chromosome 2 genes were identified and further analyzed by bioinformatic methods. As a result, 15 or 10 genes were significantly up- or down-regulated in all four subtypes of lung cancer. GKN1, LOC100131510, prominin-2 (PROM2), IL37, and SNORA41 were identified as ADC-specific up-regulated genes; SQC-specific up-regulated genes included HOXD family (HOXD1, HOXD3, HOXD4, HOXD8, and HOXD9) and UGT1A family (UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A7, UGT1A8, UGT1A9, and UGT1A10); and LCC- or SCLC-specific genes were also identified. Nine genes were significantly up-expressed at all four stages of ADC while 230 genes at all three stages of SQC. MFSD2B, CCL20 and STAT1, or STARD7 and ZNF512 genes may be risk or protect factors in prognosis of ADC, while HTR2B, DPP4, and TGFBRAP1 genes may be risk factors in prognosis of SQC. Our results suggested that a number of altered chromosome 2 genes have the subtype or stage specificities of lung cancer and may be considered as diagnostic and prognostic biomarkers.

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References

  • Albig AR, Neil JR, Schiemann WP. Fibulins 3 and 5 antagonize tumor angiogenesis in vivo. Cancer Res. 2006;66:2621–9.

    Article  CAS  PubMed  Google Scholar 

  • Asada Y, Aratake Y, Kotani T, Marutsuka K, Araki Y, Ohtaki S, et al. Expression of dipeptidyl aminopeptidase IV activity in human lung carcinoma. Histopathology. 1993;23:265–70.

    Article  CAS  PubMed  Google Scholar 

  • Avarello R, Pedicini A, Caiulo A, Zuffardi O, Fraccaro M. Evidence for an ancestral alphoid domain on the long arm of human chromosome 2. Hum Genet. 1992;89:247–9.

    Article  CAS  PubMed  Google Scholar 

  • Baeuerle PA, Gires O. EpCAM (CD326) finding its role in cancer. Br J Cancer. 2007;96:417–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baum L, Haerian BS, Ng HK, Wong VC, Ng PW, Lui CH, et al. Case–control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy. Hum Genet. 2014;133:651–9.

    Article  CAS  PubMed  Google Scholar 

  • Beer DG, Kardia SL, Huang CC, Giordano TJ, Levin AM, Misek DE, et al. Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med. 2002;8:816–24.

    CAS  PubMed  Google Scholar 

  • Bornancin F, Mechtcheriakova D, Stora S, Graf C, Wlachos A, Devay P, et al. Characterization of a ceramide kinase-like protein. Biochim Biophys Acta. 2005;1687:31–43.

    Article  CAS  PubMed  Google Scholar 

  • Carpenter G, Red Brewer M. EpCAM: another surface-to-nucleus missile. Cancer Cell. 2009;15:165–6.

    Article  CAS  PubMed  Google Scholar 

  • Cross SA, Salomao DR, Parisi JE, Kryzer TJ, Bradley EA, Mines JA, et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol. 2003;54:38–50.

    Article  PubMed  Google Scholar 

  • Dimitrova M, Ivanov I, Todorova R, Stefanova N, Moskova-Doumanova V, Topouzova-Hristova T, et al. Comparison of the activity levels and localization of dipeptidyl peptidase IV in normal and tumor human lung cells. Tissue Cell. 2012;44:74–9.

    Article  CAS  PubMed  Google Scholar 

  • Eberlein C, Rooney C, Ross SJ, Farren M, Weir HM, Barry ST. E-cadherin and EpCAM expression by NSCLC tumour cells associate with normal fibroblast activation through a pathway initiated by integrin αvβ6 and maintained through TGFbeta signalling. Oncogene. 2015;34:704–16.

    Article  CAS  PubMed  Google Scholar 

  • Gastl G, Spizzo G, Obrist P, Dunser M, Mikuz G. Ep-CAM overexpression in breast cancer as a predictor of survival. Lancet. 2000;356:1981–2.

    Article  CAS  PubMed  Google Scholar 

  • Goldkorn T, Chung S, Filosto S. Lung cancer and lung injury: the dual role of ceramide. Handbook of experimental pharmacology. 2013 93–113.

  • Hamada J, Omatsu T, Okada F, Furuuchi K, Okubo Y, Takahashi Y, et al. Overexpression of homeobox gene HOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells. Int J Cancer Journal international du cancer. 2001;93:516–25.

    Article  CAS  Google Scholar 

  • Hayes DN, Monti S, Parmigiani G, Gilks CB, Naoki K, Bhattacharjee A, et al. Gene expression profiling reveals reproducible human lung adenocarcinoma subtypes in multiple independent patient cohorts. J Clin Oncol: Off J Am Soc Clin Oncol. 2006;24:5079–90.

    Article  CAS  Google Scholar 

  • Huang ZX, Tian HY, Hu ZF, Zhou YB, Zhao J, Yao KT. GenCLiP: a software program for clustering gene lists by literature profiling and constructing gene co-occurrence networks related to custom keywords. BMC Bioinforma. 2008;9:308.

    Article  Google Scholar 

  • Iwamoto S, Tanimoto K, Nishio Y, Putra AC, Fuchita H, Ohe M, et al. Association of EPAS1 gene rs4953354 polymorphism with susceptibility to lung adenocarcinoma in female Japanese non-smokers. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer. 2014;9:1709–13.

    Article  CAS  Google Scholar 

  • JW IJ, Baldini A, Ward DC, Reeders ST, Wells RA. Origin of human chromosome 2: an ancestral telomere-telomere fusion. Proc Natl Acad Sci U S A. 1991;88:9051–5.

    Article  Google Scholar 

  • Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M. The KEGG resource for deciphering the genome. Nucleic Acids Res. 2004;32:D277–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larrayoz M, Pio R, Pajares MJ, Zudaire I, Ajona D, Casanovas O, et al. Contrasting responses of non-small cell lung cancer to antiangiogenic therapies depend on histological subtype. EMBO Mol Med. 2014;6:539–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee G, Blenis J. Akt-ivation of RNA splicing. Mol Cell. 2014; 53.

  • Litvinov SV, Velders MP, Bakker HAM, Fleuren GJ, Warnaar SO. Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. JCell Biol. 1994;125:437–46.

    Article  CAS  Google Scholar 

  • Liu PJ, Chen CD, Wang CL, Wu YC, Hsu CW, Lee CW, et al. In-depth proteomic analysis of six types of exudative pleural effusions for nonsmall cell lung cancer biomarker discovery. Mol Cell Proteomics: MCP. 2015;14:917–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Margolin E, Flint A, Trobe JD. High-titer collapsin response-mediating protein-associated (CRMP-5) paraneoplastic optic neuropathy and Vitritis as the only clinical manifestations in a patient with small cell lung carcinoma. J Neuro-ophthalmol: Off J North Am Neuro-Ophthalmol Soc. 2008;28:17–22.

    Article  Google Scholar 

  • Meyer M, Kircher M, Gansauge MT, Li H, Racimo F, Mallick S, et al. A high-coverage genome sequence from an archaic Denisovan individual. Science (New York, NY). 2012;338:222–6.

    Article  CAS  Google Scholar 

  • Meyerson M, Carbone D. Genomic and proteomic profiling of lung cancers: lung cancer classification in the age of targeted therapy. J Clin Oncol: Off J Am Soc Clin Oncol. 2005;23:3219–26.

    Article  CAS  Google Scholar 

  • Miyazaki YJ. HOXD3 enhances motility and invasiveness through the TGF-β-dependent and -independent pathways in A549 cells. Oncogene. 2002;21:798–808.

    Article  CAS  PubMed  Google Scholar 

  • Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA. IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol. 2010;11:1014–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohta H, Hamada J, Tada M, Aoyama T, Furuuchi K, Takahashi Y, et al. HOXD3-overexpression increases integrin alpha v beta 3 expression and deprives E-cadherin while it enhances cell motility in A549 cells. Clin Exp Metastasis. 2006;23:381–90.

    Article  CAS  PubMed  Google Scholar 

  • Pastukhov O, Schwalm S, Zangemeister-Wittke U, Fabbro D, Bornancin F, Japtok L, et al. The ceramide kinase inhibitor NVP-231 inhibits breast and lung cancer cell proliferation by inducing M phase arrest and subsequent cell death. Br J Pharmacol. 2014;171:5829–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saddoughi SA, Ogretmen B. Diverse functions of ceramide in cancer cell death and proliferation. Adv Cancer Res. 2013; 117.

  • Sanidas I, Polytarchou C, Hatziapostolou M, Ezell SA, Kottakis F, Hu L, et al. Phosphoproteomics screen reveals akt isoform-specific signals linking RNA processing to lung cancer. Mol Cell. 2014;53:577–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sato M, Tanaka T, Maeno T, Sando Y, Suga T, Maeno Y, et al. Inducible expression of endothelial PAS domain protein-1 by hypoxia in human lung adenocarcinoma A549 cells role of Src family kinases-dependent pathway. Am J Respir Cell Mol Biol. 2002a;26:127–34.

    Article  CAS  PubMed  Google Scholar 

  • Sato M, Tanaka T, Maeno T, Sando Y, Suga T, Maeno Y, et al. Inducible expression of endothelial PAS domain protein-1 by hypoxia in human lung adenocarcinoma A549 cells. Role of Src family kinases-dependent pathway. Am J Respir Cell Mol Biol. 2002b;26:127–34.

    Article  CAS  PubMed  Google Scholar 

  • Schmiedl A, Grutzner D, Hoffmann T, von Horsten S, Stephan M. DPP4 inhibitors increase differentially the expression of surfactant proteins in Fischer 344 rats. Acta Physiol. 2014;212:248–61.

    Article  CAS  Google Scholar 

  • Sebastian M, Passlick B, Friccius-Quecke H, Jager M, Lindhofer H, Kanniess F, et al. Treatment of non-small cell lung cancer patients with the trifunctional monoclonal antibody catumaxomab (anti-EpCAM x anti-CD3): a phase I study. Cancer Immunol Immunother: CII. 2007;56:1637–44.

    Article  CAS  PubMed  Google Scholar 

  • Sheorajpanday R, Slabbynck H, Van De Sompel W, Galdermans D, Neetens I, De Deyn PP. Small cell lung carcinoma presenting as collapsin response-mediating protein (CRMP) -5 paraneoplastic optic neuropathy. J Neuro-ophthalmol: Off J North Am Neuro-Ophthalmol Soc. 2006;26:168–72.

    Article  Google Scholar 

  • Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  • Silvestri GA, Patricia Rivera M. Targeted therapy for the treatment of advanced non-small cell lung cancer: a review of the epidermal growth factor receptor antagonists. CHEST. 2005;128:3975–84.

    Article  CAS  PubMed  Google Scholar 

  • Simboeck E, Gutierrez A, Cozzuto L, Beringer M, Caizzi L, Keyes WM, et al. DPY30 regulates pathways in cellular senescence through ID protein expression. EMBO J. 2013;32:2217–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447–52.

    Article  PubMed  Google Scholar 

  • Takahashi YH, Westfield GH, Oleskie AN, Trievel RC, Shilatifard A, Skiniotis G. Structural analysis of the core COMPASS family of histone H3K4 methylases from yeast to human. Proc Natl Acad Sci U S A. 2011;108:20526–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tas F, Karabulut S, Duranyildiz D. Clinical significance of serum epithelial cell adhesion molecule (EPCAM) levels in patients with lung cancer. Mol Cell Biochem. 2014;396:307–12.

    Article  CAS  PubMed  Google Scholar 

  • Therneau T. A package for survival analysis in S. R package version 2.37-7, http://CRAN.R-project.org/package=survival. 2014.

  • Vanoye CG, Gurnett CA, Holland KD, George Jr AL, Kearney JA. Novel SCN3A variants associated with focal epilepsy in children. Neurobiol Dis. 2014;62:313–22.

    Article  CAS  PubMed  Google Scholar 

  • Wang R, Zhang YW, Chen LB. Aberrant promoter methylation of FBLN-3 gene and clinicopathological significance in non-small cell lung carcinoma. Lung Cancer. 2010;69:239–44.

    Article  PubMed  Google Scholar 

  • Wesley UV, Tiwari S, Houghton AN. Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells. Int J Cancer Journal international du cancer. 2004;109:855–66.

    Article  CAS  PubMed  Google Scholar 

  • Wu XH, Qian C, Yuan K. Correlations of hypoxia-inducible factor-1alpha/hypoxia-inducible factor-2alpha expression with angiogenesis factors expression and prognosis in non-small cell lung cancer. Chin Med J (Engl). 2011;124:11–8.

    Google Scholar 

  • Xu S, Yang Y, Sun YB, Wang HY, Sun CB, Zhang X. Role of fibulin-3 in lung cancer: in vivo and in vitro analyses. Oncol Rep. 2014;31:79–86.

    CAS  PubMed  Google Scholar 

  • Yang Z, Augustin J, Chang C, Hu J, Shah K, Chang CW, et al. The DPY30 subunit in SET1/MLL complexes regulates the proliferation and differentiation of hematopoietic progenitor cells. Blood. 2014;124:2025–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoo S, Takikawa S, Geraghty P, Argmann C, Campbell J, Lin L, et al. Integrative analysis of DNA methylation and gene expression data identifies EPAS1 as a key regulator of COPD. PLoS Genet. 2015;11, e1004898.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by Zhongshan Distinguished Professor Grant (XDW), the National Nature Science Foundation of China (91230204, 81270099, 81320108001, 81270131, 81300010), the Shanghai Committee of Science and Technology (12JC1402200, 12431900207, 11410708600, 14431905100), the Zhejiang Provincial Natural Science Foundation (Z2080988), the Zhejiang Provincial Science Technology Department Foundation (2010C14011), and the Ministry of Education, Academic Special Science and Research Foundation for PhD Education (20130071110043).

Authors’ contributions

LMB contributed the data analyses and writing of the manuscript. YZ contributed the study design, collection of information, and data mining. HYW contributed the prognosis prediction analyses. XDW contributed the study design and preparation of the manuscript.

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Correspondence to Xiangdong Wang.

Electronic supplementary material

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Supplement Fig. 1

The pathways of targeted co-expressed genes in lung cancer. (GIF 45 kb)

High resolution image (TIF 348 kb)

Supplement Fig. 2

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(GIF 96 kb)

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Supplement Table 1

Genes up-regulated in four subtypes of lung cancer compared with non-cancer. (XLSX 87 kb)

Supplement Table 2

Co-expressed genes in four subtypes of lung cancer. (XLSX 13 kb)

Supplement Table 3

Subtype-specific up or down genes in ADC, SQC, LCC, and SCLC. (XLSX 46 kb)

Supplement Table 4

Stage-specific up or down genes in ADC and SQC. (XLSX 22 kb)

Supplement Table 5

Identified genes of ADC or SQC predicted poor overall survival through TCGA survival model. (XLSX 11 kb)

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Bao, L., Zhang, Y., Wang, J. et al. Variations of chromosome 2 gene expressions among patients with lung cancer or non-cancer. Cell Biol Toxicol 32, 419–435 (2016). https://doi.org/10.1007/s10565-016-9343-z

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