Tumor Biology

, Volume 36, Issue 3, pp 1849–1857 | Cite as

RETRACTED ARTICLE: A comprehensive analysis of candidate genes and pathways in pancreatic cancer

  • Jie Liu
  • Jun Li
  • Hali Li
  • Aidong Li
  • Biou Liu
  • Liou Han
Research Article


The study aimed to dissect the molecular mechanism of pancreatic cancer by a range of bioinformatics approaches. Three microarray datasets (GSE32676, GSE21654, and GSE14245) were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) with logarithm of fold change (|logFC|) >0.585 and p value <0.05 were identified between pancreatic cancer samples and normal controls. Transcription factors (TFs) were selected from the DEGs based on TRASFAC database. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed for the DEGs using The Database for Annotation, Visualization and Integrated Discovery (p value <0.05), followed by construction of protein-protein interaction (PPI) network using Search Tool for the Retrieval of Interacting Genes software. Latent pathway identification analysis was applied to analyze the DEGs-related pathways crosstalk and the pathways with high weight value were included in the pathway crosstalk network using Cytoscape. Sixty-five DEGs were screened out. CCAAT/enhancer-binding protein delta (CEBPD), FBJ osteosarcoma oncogene B (FOSB), Stratifin (SFN), Krüppel-like factor 5 (KLF5), Pentraxin 3 (PTX3), and nuclear receptor subfamily 4, group A, member 3 (NR4A3) were important TFs. Interleukin-6 (IL-6) was the hub node of the PPI network. DEGs were significantly enriched in NOD-like receptor signaling pathway which was primarily interacted with inflammation and immune related pathways (cytosolic DNA-sensing, hematopoietic cell lineage, intestinal immune network for IgA production and chemokine pathways). The study suggested CEBPD, FOSB, SFN, KLF5, PTX3, NR4A3, IL-6, and NOD-like receptor pathways were involved in pancreatic cancer.


Pancreatic cancer Pathway crosstalk Protein-protein interaction Differentially expressed genes Gene ontology 



transcription factor






V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog


tumor necrosis factor-alpha


epidermal growth factor


robust multiarray average


logarithm of fold change


The Database for Annotation, Visualization, and Integrated Discovery


gene ontology


Kyoto Encyclopedia of Genes and Genomes


biological process


cellular component


molecular function


The Search Tool for the Retrieval of Interacting Genes


protein-protein interaction


latent pathway identification analysis


differentially expressed genes






FBJ osteosarcoma oncogene B


pentraxin-related protein 3


nuclear receptor subfamily 4 group A, member 3

C/EBP delta

CCAAT/enhancer-binding protein delta


Krüppel-like factors


NOD-like receptors


mitogen-activated protein kinase



This study was supported by Overseas Scholars Funds (grant no. 1054HQ081) and National Natural Science Foundation of China (grant no. 30340058).

Conflicts of interest



  1. 1.
    Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24(14):2137–50.CrossRefPubMedGoogle Scholar
  2. 2.
    Seufferlein T, Bachet J, Van Cutsem E, Rougier P. Pancreatic adenocarcinoma: ESMO–ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 suppl 7:vii33–40.CrossRefPubMedGoogle Scholar
  3. 3.
    Loos M, Kleeff J, Friess H, Büchler MW. Surgical treatment of pancreatic cancer. Ann N Y Acad Sci. 2008;1138(1):169–80.CrossRefPubMedGoogle Scholar
  4. 4.
    Biankin AV, Waddell N, Kassahn KS, Gingras M-C, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491(7424):399–405.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Maupin KA, Sinha A, Eugster E, Miller J, Ross J, Paulino V, et al. Glycogene expression alterations associated with pancreatic cancer epithelial-mesenchymal transition in complementary model systems. PLoS One. 2010;5(9):e13002.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zhang L, Farrell JJ, Zhou H, Elashoff D, Akin D, Park NH, et al. Salivary transcriptomic biomarkers for detection of resectable pancreatic cancer. Gastroenterology. 2010;138(3):949–57. e7.CrossRefPubMedGoogle Scholar
  7. 7.
    Huang M, Tang S-N, Upadhyay G, Marsh JL, Jackman CP, Shankar S, et al. Embelin suppresses growth of human pancreatic cancer xenografts, and pancreatic cancer cells isolated from KrasG12D mice by inhibiting Akt and sonic hedgehog pathways. PLoS One. 2014;9(4):e92161.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Donahue TR, Tran LM, Hill R, Li Y, Kovochich A, Calvopina JH, et al. Integrative survival-based molecular profiling of human pancreatic cancer. Clin Cancer Res. 2012;18(5):1352–63.CrossRefPubMedGoogle Scholar
  9. 9.
    Pang H, Lin A, Holford M, Enerson BE, Lu B, Lawton MP, et al. Pathway analysis using random forests classification and regression. Bioinformatics. 2006;22(16):2028–36.CrossRefPubMedGoogle Scholar
  10. 10.
    Li Y, Agarwal P, Rajagopalan D. A global pathway crosstalk network. Bioinformatics. 2008;24(12):1442–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Basu A, Castle VP, Bouziane M, Bhalla K, Haldar S. Crosstalk between extrinsic and intrinsic cell death pathways in pancreatic cancer: synergistic action of estrogen metabolite and ligands of death receptor family. Cancer Res. 2006;66(8):4309–18.CrossRefPubMedGoogle Scholar
  12. 12.
    Young SH, Rozengurt E. Crosstalk between insulin receptor and G protein-coupled receptor signaling systems leads to Ca (2) + oscillations in pancreatic cancer PANC-1 cells. Biochem Biophys Res Commun. 2010;401(1):154–8. doi: 10.1016/j.bbrc.2010.09.036.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Maniati E, Bossard M, Cook N, Candido JB, Emami-Shahri N, Nedospasov SA, et al. Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice. J Clin Invest. 2011;121(121):4685–99. 12.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gautier L, Cope L, Bolstad BM, Irizarry RA. affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20(3):307–15.CrossRefPubMedGoogle Scholar
  15. 15.
    Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4(2):249–64.CrossRefPubMedGoogle Scholar
  16. 16.
    Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004;5(10):R80.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Leek JT. Surrogate variable analysis: University of Washington; 2007Google Scholar
  18. 18.
    Wingender E. The TRANSFAC project as an example of framework technology that supports the analysis of genomic regulation. Brief Bioinform. 2008;9(4):326–32.CrossRefPubMedGoogle Scholar
  19. 19.
    Dennis Jr G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol. 2003;4(5):3.CrossRefGoogle Scholar
  20. 20.
    Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene Ontology: tool for the unification of biology. Nat Genet. 2000;25(1):25–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Arakawa K, Kono N, Yamada Y, Mori H, Tomita M. KEGG-based pathway visualization tool for complex omics data. In silico biol. 2005;5(4):419–23.PubMedGoogle Scholar
  22. 22.
    Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, et al. STRING v9. 1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 2013;41(D1):D808–D15.CrossRefPubMedGoogle Scholar
  23. 23.
    Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Pham L, Christadore L, Schaus S, Kolaczyk ED. Network-based prediction for sources of transcriptional dysregulation using latent pathway identification analysis. Proc Natl Acad Sci. 2011;108(32):13347–52.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Becker AE, Hernandez YG, Frucht H, Lucas AL. Pancreatic ductal adenocarcinoma: risk factors, screening, and early detection. World J Gastroenterol : WJG. 2014;20(32):11182–98. doi: 10.3748/wjg.v20.i32.11182.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Moore F, Santin I, Nogueira TC, Gurzov EN, Marselli L, Marchetti P, et al. The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells. PLoS One. 2012;7(2):e31062.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kim JH, Lee JY, Lee KT, Lee JK, Lee KH, Jang K-T, et al. RGS16 and FosB underexpressed in pancreatic cancer with lymph node metastasis promote tumor progression. Tumor Biol. 2010;31(5):541–8.CrossRefGoogle Scholar
  28. 28.
    Guweidhi A, Kleeff J, Giese N, El Fitori J, Ketterer K, Giese T, et al. Enhanced expression of 14-3-3sigma in pancreatic cancer and its role in cell cycle regulation and apoptosis. Carcinogenesis. 2004;25(9):1575–85.CrossRefPubMedGoogle Scholar
  29. 29.
    Mori A, Moser C, Lang SA, Hackl C, Gottfried E, Kreutz M, et al. Up-regulation of Kruppel-like factor 5 in pancreatic cancer is promoted by interleukin-1beta signaling and hypoxia-inducible factor-1alpha. Mol Cancer Res : MCR. 2009;7(8):1390–8. doi: 10.1158/1541-7786.mcr-08-0525.CrossRefPubMedGoogle Scholar
  30. 30.
    Locatelli M, Ferrero S, Martinelli Boneschi F, Boiocchi L, Zavanone M, Maria Gaini S, et al. The long pentraxin PTX3 as a correlate of cancer-related inflammation and prognosis of malignancy in gliomas. J Neuroimmunol. 2013;260(1):99–106.CrossRefPubMedGoogle Scholar
  31. 31.
    Lee S-O, Abdelrahim M, Yoon K, Chintharlapalli S, Papineni S, Kim K, et al. Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth. Cancer Res. 2010;70(17):6824–36.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Guerra C, Schuhmacher AJ, Cañamero M, Grippo PJ, Verdaguer L, Pérez-Gallego L, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007;11(3):291–302.CrossRefPubMedGoogle Scholar
  33. 33.
    Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148(1):349–61.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Dima SO, Tanase C, Albulescu R, Herlea V, Chivu-Economescu M, Purnichescu-Purtan R, et al. An exploratory study of inflammatory cytokines as prognostic biomarkers in patients with ductal pancreatic adenocarcinoma. Pancreas. 2012;41(7):1001–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefPubMedGoogle Scholar
  36. 36.
    Rincon M. Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol. 2012;33(11):571–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Klöppel G, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011;19(4):456–69.CrossRefPubMedGoogle Scholar
  38. 38.
    Guan J, Zhang H, Wen Z, Gu Y, Cheng Y, Sun Y et al. Retinoic acid inhibits pancreatic cancer cell migration and EMT through the downregulation of IL-6 in cancer associated fibroblast cells. Cancer letters. 2013.Google Scholar
  39. 39.
    Hong DS, Angelo LS, Kurzrock R. Interleukin‐6 and its receptor in cancer. Cancer. 2007;110(9):1911–28.CrossRefPubMedGoogle Scholar
  40. 40.
    Song J, Singh M. How and when should interactome-derived clusters be used to predict functional modules and protein function? Bioinformatics. 2009;25(23):3143–50.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Fukata M, Vamadevan AS, Abreu MT, editors. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders. Seminars in immunology; 2009: Elsevier.Google Scholar
  42. 42.
    Huzarski T, Lener M, Domagała W, Gronwald J, Byrski T, Kurzawski G, et al. The 3020insC allele of NOD2 predisposes to early-onset breast cancer. Breast Cancer Res Treat. 2005;89(1):91–3.CrossRefPubMedGoogle Scholar
  43. 43.
    Papaconstantinou I, Theodoropoulos G, Gazouli M, Panoussopoulos D, Mantzaris GJ, Felekouras E, et al. Association between mutations in the CARD15/NOD2 gene and colorectal cancer in a Greek population. Int J Cancer. 2005;114(3):433–5.CrossRefPubMedGoogle Scholar
  44. 44.
    Tsuji M, Suzuki K, Kinoshita K, Fagarasan S, editors. Dynamic interactions between bacteria and immune cells leading to intestinal IgA synthesis. Seminars in immunology; 2008: Elsevier.Google Scholar
  45. 45.
    Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Nunez G, et al. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J. 2008;27(2):373–83. doi: 10.1038/sj.emboj.7601962.CrossRefPubMedGoogle Scholar
  46. 46.
    Park J-H, Kim Y-G, McDonald C, Kanneganti T-D, Hasegawa M, Body-Malapel M, et al. RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol. 2007;178(4):2380–6.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Jie Liu
    • 1
  • Jun Li
    • 1
  • Hali Li
    • 1
  • Aidong Li
    • 1
  • Biou Liu
    • 1
  • Liou Han
    • 1
  1. 1.Department of general surgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina

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