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Potential biomarkers and signaling pathways associated with the pathogenesis of primary salivary gland carcinoma: a bioinformatics study

  • Bayat, Zeynab (Department of Oral and Maxillofacial Medicine, Faculty of Dentistry, Hamadan University of Medical Sciences) ;
  • Ahmadi-Motamayel, Fatemeh (Dental Implants Research Center and Dental Research Center, Department of Oral Medicine, Hamadan University of Medical Sciences) ;
  • Salimi Parsa, Mohadeseh (Department of Oral and Maxillofacial Medicine, Faculty of Dentistry, Hamadan University of Medical Sciences) ;
  • Taherkhani, Amir (Research Center for Molecular Medicine, Hamadan University of Medical Sciences)
  • 투고 : 2021.09.13
  • 심사 : 2021.12.08
  • 발행 : 2021.12.31

초록

Salivary gland carcinoma (SGC) is rare cancer, constituting 6% of neoplasms in the head and neck area. The most responsible genes and pathways involved in the pathology of this disorder have not been fully understood. We aimed to identify differentially expressed genes (DEGs), the most critical hub genes, transcription factors, signaling pathways, and biological processes (BPs) associated with the pathogenesis of primary SGC. The mRNA dataset GSE153283 in the Gene Expression Omnibus database was re-analyzed for determining DEGs in cancer tissue of patients with primary SGC compared to the adjacent normal tissue (adjusted p-value < 0.001; |Log2 fold change| > 1). A protein interaction map (PIM) was built, and the main modules within the network were identified and focused on the different pathways and BP analyses. The hub genes of PIM were discovered, and their associated gene regulatory network was built to determine the master regulators involved in the pathogenesis of primary SGC. A total of 137 genes were found to be differentially expressed in primary SGC. The most significant pathways and BPs that were deregulated in the primary disease condition were associated with the cell cycle and fibroblast proliferation procedures. TP53, EGF, FN1, NOTCH1, EZH2, COL1A1, SPP1, CDKN2A, WNT5A, PDGFRB, CCNB1, and H2AFX were demonstrated to be the most critical genes linked with the primary SGC. SPIB, FOXM1, and POLR2A significantly regulate all the hub genes. This study illustrated several hub genes and their master regulators that might be appropriate targets for the therapeutic aims of primary SGC.

키워드

과제정보

The authors would like to appreciate the Dental Research Center, Deputy of Research and Technology, and Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan - Iran for their supports. This paper was extracted from the thesis of Mohadaseh Salimi Parsa.

참고문헌

  1. Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer 2005;114:806-816. https://doi.org/10.1002/ijc.20740
  2. Lassche G, van Engen-van Grunsven AC, Honings J, Dijkema T, Weijs WL, van Herpen CM. Salivary gland carcinoma. Ned Tijdschr Geneeskd 2020;164:D4760.
  3. Speight PM, Takata T. New tumour entities in the 4th edition of the World Health Organization classification of head and neck tumours: odontogenic and maxillofacial bone tumours. Virchows Arch 2018;472:331-339. https://doi.org/10.1007/s00428-017-2182-3
  4. Jones AV, Craig GT, Speight PM, Franklin CD. The range and demographics of salivary gland tumours diagnosed in a UK population. Oral Oncol 2008;44:407-417. https://doi.org/10.1016/j.oraloncology.2007.05.010
  5. Meinrath J, Haak A, Igci N, Dalvi P, Arolt C, Meemboor S, et al. Expression profiling on subclasses of primary parotid gland carcinomas. Oncotarget 2020;11:4123-4137. https://doi.org/10.18632/oncotarget.27797
  6. Witte HM, Gebauer N, Lappohn D, Umathum VG, Riecke A, Arndt A, et al. Prognostic impact of PD-L1 expression in malignant salivary gland tumors as assessed by established scoring criteria: Tumor Proportion Score (TPS), Combined Positivity Score (CPS), and Immune Cell (IC) infiltrate. Cancers (Basel) 2020;12:873. https://doi.org/10.3390/cancers12040873
  7. Wang X, Luo Y, Li M, Yan H, Sun M, Fan T. Management of salivary gland carcinomas: a review. Oncotarget 2017;8:3946-3956. https://doi.org/10.18632/oncotarget.13952
  8. Acauan MD, Figueiredo MA, Cherubini K, Gomes AP, Salum FG. Radiotherapy-induced salivary dysfunction: structural changes, pathogenetic mechanisms and therapies. Arch Oral Biol 2015;60:1802-1810. https://doi.org/10.1016/j.archoralbio.2015.09.014
  9. Sroussi HY, Epstein JB, Bensadoun RJ, Saunders DP, Lalla RV, Migliorati CA, et al. Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis. Cancer Med 2017;6:2918-2931. https://doi.org/10.1002/cam4.1221
  10. Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel) 2020;12:738. https://doi.org/10.3390/cancers12030738
  11. Kuchar M, Strizova Z, Capkova L, Komarc M, Skrivan J, Bartunkova J, et al. The periphery of salivary gland carcinoma tumors reveals a PD-L1/PD-1 biomarker niche for the evaluation of disease severity and tumor-immune system interplay. Biomedicines 2021;9:97. https://doi.org/10.3390/biomedicines9020097
  12. Frierson HF Jr, El-Naggar AK, Welsh JB, Sapinoso LM, Su AI, Cheng J, et al. Large scale molecular analysis identifies genes with altered expression in salivary adenoid cystic carcinoma. Am J Pathol 2002;161:1315-1323. https://doi.org/10.1016/S0002-9440(10)64408-2
  13. Aalto Y, El-Rifa W, Vilpo L, Ollila J, Nagy B, Vihinen M, et al. Distinct gene expression profiling in chronic lymphocytic leukemia with 11q23 deletion. Leukemia 2001;15:1721-1728. https://doi.org/10.1038/sj/leu/2402282
  14. Warrington JA, Todd R, Wong D. Microarrays and Cancer Research. Westborough: Eaton Publishing, 2002.
  15. Li J, Wang Y, Wang X, Yang Q. CDK1 and CDC20 overexpression in patients with colorectal cancer are associated with poor prognosis: evidence from integrated bioinformatics analysis. World J Surg Oncol 2020;18:50. https://doi.org/10.1186/s12957-020-01817-8
  16. Leal-Calvo T, Moraes MO. Reanalysis and integration of public microarray datasets reveals novel host genes modulated in leprosy. Mol Genet Genomics 2020;295:1355-1368. https://doi.org/10.1007/s00438-020-01705-6
  17. Junker BH, Schreiber F. Analysis of Biological Networks. Hoboken: John Wiley & Sons, 2011.
  18. Clough E, Barrett T. The gene expression omnibus database. Methods Mol Biol 2016;1418:93-110. https://doi.org/10.1007/978-1-4939-3578-9_5
  19. Davis S, Meltzer PS. GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics 2007;23:1846-1847. https://doi.org/10.1093/bioinformatics/btm254
  20. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 2017;45:D362-D368. https://doi.org/10.1093/nar/gkw937
  21. Su G, Morris JH, Demchak B, Bader GD. Biological network exploration with Cytoscape 3. Curr Protoc Bioinformatics 2014;47:8.13.11-24.
  22. Zali H, Rezaei Tavirani M. Meningioma protein-protein interaction network. Arch Iran Med 2014;17:262-272.
  23. Bader GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 2003;4:2. https://doi.org/10.1186/1471-2105-4-2
  24. Taherkhani A, Kalantari S, Arefi Oskouie A, Nafar M, Taghizadeh M, Tabar K. Network analysis of membranous glomerulonephritis based on metabolomics data. Mol Med Rep 2018;18:4197-4212.
  25. 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;25:25-29. https://doi.org/10.1038/75556
  26. Vastrik I, D'Eustachio P, Schmidt E, Gopinath G, Croft D, de Bono B, et al. Reactome: a knowledge base of biologic pathways and processes. Genome Biol 2007;8:R39. https://doi.org/10.1186/gb-2007-8-3-r39
  27. Fabregat A, Jupe S, Matthews L, Sidiropoulos K, Gillespie M, Garapati P, et al. The reactome pathway knowledgebase. Nucleic Acids Res 2018;46:D649-D655. https://doi.org/10.1093/nar/gkx1132
  28. Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, et al. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res 2007;35:W169-W175. https://doi.org/10.1093/nar/gkm415
  29. Diekmann Y, Seixas E, Gouw M, Tavares-Cadete F, Seabra MC, Pereira-Leal JB. Thousands of rab GTPases for the cell biologist. PLoS Comput Biol 2011;7:e1002217. https://doi.org/10.1371/journal.pcbi.1002217
  30. Taherkhani A, Kalantari S, Nafar M. Prediction of molecular signature, potential biomarkers, and molecular pathways associated with membranous nephropathy based on protein protein interactions. Rev Invest Clin 2018;70:184-191.
  31. Hong W, Hu Y, Fan Z, Gao R, Yang R, Bi J, et al. In silico identification of EP400 and TIA1 as critical transcription factors involved in human hepatocellular carcinoma relapse. Oncol Lett 2020;19:952-964.
  32. Bryne JC, Valen E, Tang MH, Marstrand T, Winther O, da Piedade I, et al. JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update. Nucleic Acids Res 2008;36:D102-D106. https://doi.org/10.1093/nar/gkm955
  33. Xiong J. Essential Bioinformatics. New York: Cambridge University Press, 2006.
  34. Gentleman R. R Programming for Bioinformatics. Boca Raton: CRC Press, 2008.
  35. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res 2019;47:W556-W560. https://doi.org/10.1093/nar/gkz430
  36. Tomczak K, Czerwinska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn) 2015;19:A68-A77.
  37. GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet 2013;45:580-585. https://doi.org/10.1038/ng.2653
  38. Andersson MK, Afshari MK, Andren Y, Wick MJ, Stenman G. Targeting the oncogenic transcriptional regulator MYB in adenoid cystic carcinoma by inhibition of IGF1R/AKT signaling. J Natl Cancer Inst 2017;109:djx017.
  39. Fu JY, Wu CX, Shen SK, Zheng Y, Zhang CP, Zhang ZY. Salivary gland carcinoma in Shanghai (2003-2012): an epidemiological study of incidence, site and pathology. BMC Cancer 2019;19:350. https://doi.org/10.1186/s12885-019-5564-x
  40. Suzuki T. p53 abnormality in salivary gland carcinoma and its relation to tumor DNA aneuploidy and AgNOR. Nihon Jibiinkoka Gakkai Kaiho 1994;97:2279-2286. https://doi.org/10.3950/jibiinkoka.97.2279
  41. Nachtsheim L, Arolt C, Dreyer T, Meyer MF, Brobeil A, Gamerdinger U, et al. Mucoepidermoidcarcinoma: importance in molecular pathology. Laryngorhinootologie 2020;99:144-148. https://doi.org/10.1055/a-1083-6805
  42. Ferrarotto R, Mitani Y, Diao L, Guijarro I, Wang J, Zweidler-McKay P, et al. Activating NOTCH1 mutations define a distinct subgroup of patients with adenoid cystic carcinoma who have poor prognosis, propensity to bone and liver metastasis, and potential responsiveness to Notch1 inhibitors. J Clin Oncol 2017;35:352-360.
  43. Labat-Robert J. Fibronectin in malignancy. Semin Cancer Biol 2002;12:187-195. https://doi.org/10.1016/S1044-579X(02)00022-6
  44. Leivo I, Jee KJ, Heikinheimo K, Laine M, Ollila J, Nagy B, et al. Characterization of gene expression in major types of salivary gland carcinomas with epithelial differentiation. Cancer Genet Cytogenet 2005;156:104-113. https://doi.org/10.1016/j.cancergencyto.2004.04.016
  45. Zhou L, Mudianto T, Ma X, Riley R, Uppaluri R. Targeting EZH2 enhances antigen presentation, antitumor immunity, and circumvents anti-PD-1 resistance in head and neck cancer. Clin Cancer Res 2020;26:290-300. https://doi.org/10.1158/1078-0432.ccr-19-1351
  46. Mishra R. Biomarkers of oral premalignant epithelial lesions for clinical application. Oral Oncol 2012;48:578-584. https://doi.org/10.1016/j.oraloncology.2012.01.017
  47. Du W, Xu X, Niu Q, Zhang X, Wei Y, Wang Z, et al. Spi-B-mediated silencing of claudin-2 promotes early dissemination of lung cancer cells from primary tumors. Cancer Res 2017;77:4809-4822. https://doi.org/10.1158/0008-5472.CAN-17-0020
  48. Zhang H, Wang G, Zhou R, Li X, Sun Y, Li Y, et al. SPIB promotes anoikis resistance via elevated autolysosomal process in lung cancer cells. FEBS J 2020;287:4696-4709. https://doi.org/10.1111/febs.15272
  49. Wood O, Woo J, Seumois G, Savelyeva N, McCann KJ, Singh D, et al. Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors. Oncotarget 2016;7:56781-56797. https://doi.org/10.18632/oncotarget.10788
  50. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24-35. https://doi.org/10.1056/NEJMoa0912217
  51. Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, et al. TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature 2015;520:697-701. https://doi.org/10.1038/nature14418
  52. Roh V, Hiou-Feige A, Misetic V, Rivals JP, Sponarova J, Teh MT, et al. The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma. J Pathol 2020;250:107-119. https://doi.org/10.1002/path.5342
  53. Piechocki MP, Lonardo F, Ensley JF, Nguyen T, Kim H, Yoo GH. Anticancer activity of docetaxel in murine salivary gland carcinoma. Clin Cancer Res 2002;8:870-877.
  54. Bhoora S, Punchoo R. Policing cancer: vitamin D arrests the cell cycle. Int J Mol Sci 2020;21:9296. https://doi.org/10.3390/ijms21239296
  55. Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 2008;68:918-926. https://doi.org/10.1158/0008-5472.CAN-07-5714
  56. Yashiro M, Nakazawa K, Tendo M, Kosaka K, Shinto O, Hirakawa K. Selective cyclooxygenase-2 inhibitor downregulates the paracrine epithelial-mesenchymal interactions of growth in scirrhous gastric carcinoma. Int J Cancer 2007;120:686-693. https://doi.org/10.1002/ijc.22329
  57. Tendo M, Yashiro M, Nakazawa K, Yamada N, Hirakawa K. Inhibitory effect of a selective cyclooxygenase inhibitor on the invasion-stimulating activity of orthotopic fibroblasts for scirrhous gastric cancer cells. Cancer Sci 2005;96:451-455. https://doi.org/10.1111/j.1349-7006.2005.00066.x
  58. Nakazawa K, Yashiro M, Hirakawa K. Keratinocyte growth factor produced by gastric fibroblasts specifically stimulates proliferation of cancer cells from scirrhous gastric carcinoma. Cancer Res 2003;63:8848-8852.
  59. Postlethwaite AE, Keski-Oja J, Moses HL, Kang AH. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exp Med 1987;165:251-256. https://doi.org/10.1084/jem.165.1.251
  60. Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, et al. TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 1996;86:531-542. https://doi.org/10.1016/S0092-8674(00)80127-0
  61. Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol 2000;148:779-790. https://doi.org/10.1083/jcb.148.4.779
  62. Semba S, Kodama Y, Ohnuma K, Mizuuchi E, Masuda R, Yashiro M, et al. Direct cancer-stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells. Br J Cancer 2009;101:1365-1373. https://doi.org/10.1038/sj.bjc.6605309
  63. Gospodarowicz D, Neufeld G, Schweigerer L. Fibroblast growth factor: structural and biological properties. J Cell Physiol Suppl 1987;Suppl 5:15-26.
  64. Burgess WH, Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem 1989;58:575-606. https://doi.org/10.1146/annurev.bi.58.070189.003043
  65. Basilico C, Moscatelli D. The FGF family of growth factors and oncogenes. Adv Cancer Res 1992;59:115-165. https://doi.org/10.1016/S0065-230X(08)60305-X
  66. Tanaka A, Miyamoto K, Minamino N, Takeda M, Sato B, Matsuo H, et al. Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells. Proc Natl Acad Sci U S A 1992;89:8928-8932. https://doi.org/10.1073/pnas.89.19.8928
  67. Miyamoto M, Naruo K, Seko C, Matsumoto S, Kondo T, Kurokawa T. Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property. Mol Cell Biol 1993;13:4251-4259. https://doi.org/10.1128/MCB.13.7.4251
  68. Miyake A, Konishi M, Martin FH, Hernday NA, Ozaki K, Yamamoto S, et al. Structure and expression of a novel member, FGF-16, on the fibroblast growth factor family. Biochem Biophys Res Commun 1998;243:148-152. https://doi.org/10.1006/bbrc.1998.8073
  69. Hughes SE, Hall PA. Immunolocalization of fibroblast growth factor receptor 1 and its ligands in human tissues. Lab Invest 1993;69:173-182.
  70. Chao HH, Yang VC, Chen JK. Acidic FGF and EGF are involved in the autocrine growth stimulation of a human nasopharyngeal carcinoma cell line and sub-line cells. Int J Cancer 1993;54:807-812. https://doi.org/10.1002/ijc.2910540515
  71. Penault-Llorca F, Bertucci F, Adelaide J, Parc P, Coulier F, Jacquemier J, et al. Expression of FGF and FGF receptor genes in human breast cancer. Int J Cancer 1995;61:170-176. https://doi.org/10.1002/ijc.2910610205
  72. Myoken Y, Myoken Y, Okamoto T, Kan M, McKeehan WL, Sato JD, et al. Expression of fibroblast growth factor-1 (FGF-1), FGF-2 and FGF receptor-1 in a human salivary-gland adenocarcinoma cell line: evidence of growth. Int J Cancer 1996;65:650-657. https://doi.org/10.1002/(SICI)1097-0215(19960301)65:5<650::AID-IJC15>3.0.CO;2-B
  73. Okamoto T, Myoken Y, Yabumoto M, Osaki T, Fujita Y, Whitney RG, et al. Androgen-dependent expression of fibroblast growth factor-1 in submaxillary gland of mouse. Biochem Biophys Res Commun 1996;221:795-802. https://doi.org/10.1006/bbrc.1996.0676
  74. Matsushita F, Daa T, Nakayama I, Mogi G. Effects of acidic and basic fibroblast growth factors on cell proliferation in pleomorphic adenoma of the parotid gland. Acta Otolaryngol 1997;117:634-639. https://doi.org/10.3109/00016489709113451
  75. Kusafuka K, Yamaguchi A, Kayano T, Takemura T. Immunohistochemical localization of fibroblast growth factors (FGFs) and FGF receptor-1 in human normal salivary glands and pleomorphic adenomas. J Oral Pathol Med 1998;27:287-292.
  76. Yura Y, Yoshioka Y, Yamamoto S, Kusaka J, Bando T, Yoshida H, et al. Enhancing effects of fibroblast growth factor on the proliferation of salivary gland carcinoma cells and salivary gland carcinogenesis. J Oral Pathol Med 2001;30:159-167. https://doi.org/10.1034/j.1600-0714.2001.300306.x