DOI QR코드

DOI QR Code

Identification of potential candidate genes for lip and oral cavity cancer using network analysis

  • Mathavan, Sarmilah (Faculty of Health and Life Sciences, Management and Science University) ;
  • Kue, Chin Siang (Faculty of Health and Life Sciences, Management and Science University) ;
  • Kumar, Suresh (Faculty of Health and Life Sciences, Management and Science University)
  • Received : 2020.10.27
  • Accepted : 2021.01.04
  • Published : 2021.03.31

Abstract

Lip and oral cavity cancer, which can occur in any part of the mouth, is the 11th most common type of cancer worldwide. The major obstacles to patients' survival are the poor prognosis, lack of specific biomarkers, and expensive therapeutic alternatives. This study aimed to identify the main genes and pathways associated with lip and oral cavity carcinoma using network analysis and to analyze its molecular mechanism and prognostic significance further. In this study, 472 genes causing lip and oral cavity carcinoma were retrieved from the DisGeNET database. A protein-protein interaction network was developed for network analysis using the STRING database. VEGFA, IL6, MAPK3, INS, TNF, MAPK8, MMP9, CXCL8, EGF, and PTGS2 were recognized as network hub genes using the maximum clique centrality algorithm available in cytoHubba, and nine potential drug candidates (ranibizumab, siltuximab, sulindac, pomalidomide, dexrazoxane, endostatin, pamidronic acid, cetuximab, and apricoxib) for lip and oral cavity cancer were identified from the DGIdb database. Gene enrichment analysis was also performed to identify the gene ontology categorization of cellular components, biological processes, molecular functions, and biological pathways. The genes identified in this study could furnish a new understanding of the underlying molecular mechanisms of carcinogenesis and provide more reliable biomarkers for early diagnosis, prognostication, and treatment of lip and oral cavity cancer.

Keywords

References

  1. Liu J, Lian X, Liu F, Yan X, Cheng C, Cheng L, et al. Identification of novel key targets and candidate drugs in oral squamous cell carcinoma. Curr Bioinform 2020;15:328-337. https://doi.org/10.2174/1574893614666191127101836
  2. Maruccia M, Onesti MG, Parisi P, Cigna E, Troccola A, Scuderi N. Lip cancer: a 10-year retrospective epidemiological study. Anticancer Res 2012;32:1543-1546.
  3. Kerawala C, Roques T, Jeannon JP, Bisase B. Oral cavity and lip cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130(S2):S83-S89.
  4. Montero PH, Patel SG. Cancer of the oral cavity. Surg Oncol Clin N Am 2015;24:491-508. https://doi.org/10.1016/j.soc.2015.03.006
  5. Shield KD, Ferlay J, Jemal A, Sankaranarayanan R, Chaturvedi AK, Bray F, et al. The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA Cancer J Clin 2017;67: 51-64. https://doi.org/10.3322/caac.21384
  6. Gupta B, Bray F, Kumar N, Johnson NW. Associations between oral hygiene habits, diet, tobacco and alcohol and risk of oral cancer: a case-control study from India. Cancer Epidemiol 2017;51: 7-14. https://doi.org/10.1016/j.canep.2017.09.003
  7. Gupta B, Kumar N, Johnson NW. Relationship of lifetime exposure to tobacco, alcohol and second hand tobacco smoke with upper aero-digestive tract cancers in India: a case-control study with a life-course perspective. Asian Pac J Cancer Prev 2017; 18:347-356.
  8. Salehiniya H, Raei M. Oral cavity and lip cancer in the world: an epidemiological review. Biomed Res Ther 2020;7:3898-3905. https://doi.org/10.15419/bmrat.v7i8.619
  9. Merchant A, Husain SS, Hosain M, Fikree FF, Pitiphat W, Siddiqui AR, et al. Paan without tobacco: an independent risk factor for oral cancer. Int J Cancer 2000;86:128-131. https://doi.org/10.1002/(SICI)1097-0215(20000401)86:1<128::AID-IJC20>3.0.CO;2-M
  10. Pinero J, Queralt-Rosinach N, Bravo A, Deu-Pons J, Bauer-Mehren A, Baron M, et al. DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes. Database (Oxford) 2015;2015:bav028. https://doi.org/10.1093/database/bav028
  11. Shen LI, Liu L, Yang Z, Jiang N. Identification of genes and signaling pathways associated with squamous cell carcinoma by bioinformatics analysis. Oncol Lett 2016;11:1382-1390. https://doi.org/10.3892/ol.2015.4051
  12. Chin CH, Chen SH, Wu HH, Ho CW, Ko MT, Lin CY. cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol 2014;8 Suppl 4:S11. https://doi.org/10.1186/1752-0509-8-S4-S11
  13. Wang J, Duncan D, Shi Z, Zhang B. WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res 2013;41:W77-W83. https://doi.org/10.1093/nar/gkt439
  14. Pathan M, Keerthikumar S, Ang CS, Gangoda L, Quek CY, Williamson NA, et al. FunRich: an open access standalone functional enrichment and interaction network analysis tool. Proteomics 2015;15:2597-2601. https://doi.org/10.1002/pmic.201400515
  15. von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res 2003;31:258-261. https://doi.org/10.1093/nar/gkg034
  16. Baschieri F, Confalonieri S, Bertalot G, Di Fiore PP, Dietmaier W, Leist M, et al. Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis. Nat Commun 2014;5:4839. https://doi.org/10.1038/ncomms5839
  17. Prior SL, Griffiths AP, Baxter JM, Baxter PW, Hodder SC, Silvester KC, et al. Mitochondrial DNA mutations in oral squamous cell carcinoma. Carcinogenesis 2006;27:945-950. https://doi.org/10.1093/carcin/bgi326
  18. Park EM, Park YM, Gwak YS. Oxidative damage in tissues of rats exposed to cigarette smoke. Free Radic Biol Med 1998;25:79-86. https://doi.org/10.1016/S0891-5849(98)00041-0
  19. Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A 1988;85:6465-6467. https://doi.org/10.1073/pnas.85.17.6465
  20. van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 2018;19: 213-228. https://doi.org/10.1038/nrm.2017.125
  21. Kujan O, van Schaijik B, Farah CS. Immune checkpoint inhibitors in oral cavity squamous cell carcinoma and oral potentially malignant disorders: a systematic review. Cancers (Basel) 2020;12:1937. https://doi.org/10.3390/cancers12071937
  22. Weng LP, Wu CC, Hsu BL, Chi LM, Liang Y, Tseng CP, et al. Secretome-based identification of Mac-2 binding protein as a potential oral cancer marker involved in cell growth and motility. J Proteome Res 2008;7:3765-3775. https://doi.org/10.1021/pr800042n
  23. Nagler RM, Lischinsky S, Diamond E, Klein I, Reznick AZ. New insights into salivary lactate dehydrogenase of human subjects. J Lab Clin Med 2001;137:363-369. https://doi.org/10.1067/mlc.2001.114710
  24. Bahar G, Feinmesser R, Shpitzer T, Popovtzer A, Nagler RM. Salivary analysis in oral cancer patients: DNA and protein oxidation, reactive nitrogen species, and antioxidant profile. Cancer 2007; 109:54-59. https://doi.org/10.1002/cncr.22386
  25. Jourenkova-Mironova N, Mitrunen K, Bouchardy C, Dayer P, Benhamou S, Hirvonen A. High-activity microsomal epoxide hydrolase genotypes and the risk of oral, pharynx, and larynx cancers. Cancer Res 2000;60:534-536.
  26. Jourenkova-Mironova N, Voho A, Bouchardy C, Wikman H, Dayer P, Benhamou S, et al. Glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes and the risk of smoking-related oral and pharyngeal cancers. Int J Cancer 1999;81:44-48. https://doi.org/10.1002/(SICI)1097-0215(19990331)81:1<44::AID-IJC9>3.0.CO;2-A
  27. Lopez-Lazaro M. The Warburg effect: why and how do cancer cells activate glycolysis in the presence of oxygen? Anticancer Agents Med Chem 2008;8:305-312. https://doi.org/10.2174/187152008783961932
  28. Todd R, Donoff RB, Wong DT. The molecular biology of oral carcinogenesis: toward a tumor progression model. J Oral Maxillofac Surg 1997;55:613-623. https://doi.org/10.1016/S0278-2391(97)90495-X
  29. Weiner T, Cance WG. Molecular mechanisms involved in tumorigenesis and their surgical implications. Am J Surg 1994;167:428-434. https://doi.org/10.1016/0002-9610(94)90129-5
  30. Spangle JM, Roberts TM, Zhao JJ. The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer. Biochim Biophys Acta Rev Cancer 2017;1868:123-131. https://doi.org/10.1016/j.bbcan.2017.03.002
  31. Patel KR, Vajaria BN, Begum R, Patel JB, Shah FD, Joshi GM, et al. VEGFA isoforms play a vital role in oral cancer progression. Tumour Biol 2015;36:6321-6332. https://doi.org/10.1007/s13277-015-3318-1
  32. Supic G, Jovic N, Zeljic K, Kozomara R, Magic Z. Association of VEGF-A genetic polymorphisms with cancer risk and survival in advanced-stage oral squamous cell carcinoma patients. Oral Oncol 2012;48:1171-1177. https://doi.org/10.1016/j.oraloncology.2012.05.023
  33. Nibali L, Fedele S, D'Aiuto F, Donos N. Interleukin-6 in oral diseases: a review. Oral Dis 2012;18:236-243. https://doi.org/10.1111/j.1601-0825.2011.01867.x
  34. Gasche JA, Hoffmann J, Boland CR, Goel A. Interleukin-6 promotes tumorigenesis by altering DNA methylation in oral cancer cells. Int J Cancer 2011;129:1053-1063. https://doi.org/10.1002/ijc.25764
  35. Peng Q, Deng Z, Pan H, Gu L, Liu O, Tang Z. Mitogen-activated protein kinase signaling pathway in oral cancer. Oncol Lett 2018;15:1379-1388.
  36. Goutzanis L, Vairaktaris E, Yapijakis C, Kavantzas N, Nkenke E, Derka S, et al. Diabetes may increase risk for oral cancer through the insulin receptor substrate-1 and focal adhesion kinase pathway. Oral Oncol 2007;43:165-173. https://doi.org/10.1016/j.oraloncology.2006.02.004
  37. Sahibzada HA, Khurshid Z, Khan RS, Naseem M, Siddique KM, Mali M, et al. Salivary IL-8, IL-6 and TNF-alpha as potential diagnostic biomarkers for oral cancer. Diagnostics (Basel) 2017;7:21. https://doi.org/10.3390/diagnostics7020021
  38. Peisker A, Raschke GF, Fahmy MD, Guentsch A, Roshanghias K, Hennings J, et al. Salivary MMP-9 in the detection of oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal 2017;22: e270-e275.
  39. Ha NH, Park DG, Woo BH, Kim DJ, Choi JI, Park BS, et al. Porphyromonas gingivalis increases the invasiveness of oral cancer cells by upregulating IL-8 and MMPs. Cytokine 2016;86:64-72. https://doi.org/10.1016/j.cyto.2016.07.013
  40. Xu Q, Zhang Q, Ishida Y, Hajjar S, Tang X, Shi H, et al. EGF induces epithelial-mesenchymal transition and cancer stem-like cell properties in human oral cancer cells via promoting Warburg effect. Oncotarget 2017;8:9557-9571. https://doi.org/10.18632/oncotarget.13771
  41. Peng X, Li W, Johnson WD, Torres KE, McCormick DL. Overexpression of lipocalins and pro-inflammatory chemokines and altered methylation of PTGS2 and APC2 in oral squamous cell carcinomas induced in rats by 4-nitroquinoline-1-oxide. PLoS One 2015;10:e0116285. https://doi.org/10.1371/journal.pone.0116285
  42. Yang B, Dong K, Guo P, Guo P, Jie G, Zhang G, et al. Identification of key biomarkers and potential molecular mechanisms in oral squamous cell carcinoma by bioinformatics analysis. J Comput Biol 2020;27:40-54. https://doi.org/10.1089/cmb.2019.0211
  43. Huang GZ, Wu QQ, Zheng ZN, Shao TR, Lv XZ. Identification of candidate biomarkers and analysis of prognostic values in oral squamous cell carcinoma. Front Oncol 2019;9:1054. https://doi.org/10.3389/fonc.2019.01054
  44. Wang J, Wang Y, Kong F, Han R, Song W, Chen D, et al. Identification of a six-gene prognostic signature for oral squamous cell carcinoma. J Cell Physiol 2020;235:3056-3068. https://doi.org/10.1002/jcp.29210