Investigation on the Differentially Expressed Genes in HIGK Cells Treated with T.denticola and their Putative Association with HNSCC
Objectives: Treponema denticola (Td) is a bacterium commonly linked to periodontal diseases, but its role in head and neck squamous cell carcinoma (HNSCC) is not well understood. This study aimed to explore the role of differentially expressed genes (DEGs) in HNSCC HIGK cells treated with T. denticola.
Methods: An observational study design using computational tools was employed to identify associations between DEGs in HIGK cells infected with T. denticola. The GEOmnibus dataset GSE207003 was used to pinpoint DEGs in Td-infected HIGK cells. Gene expression profiling and survival analysis for the top 25 genes were performed using the UALCAN database.
Results: Numerous DEGs were identified in HIGK cells infected with T. denticola. Among the top 25 genes, LAMC2 (p- value < 10-12), FN1 (p-value = 1.62 × 10-12), and TGFBI (p-value = 1.11 × 10-16) showed significant overexpression. These genes significantly impacted HNSCC patient survival, with high expression correlating with poor prognosis.
Conclusion: This study identified three key genes—LAMC2, FN1, and TGFB1—potentially linked to HNSCC develop- ment. While LAMC2 and FN1 are known oncogenes, TGFB1, typically a tumor suppressor, was found to act as an onco-gene in this context. Experimental validation is needed to confirm the role of T. denticola in carcinogenesis
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of inci- dence and mortality worldwide for 36 cancers in 185 coun- tries. CA Cancer J Clin 2018;68:394–424.
2. Prabhash K, Babu G, Chaturvedi P, Kuriakose M, Birur P, Anand A, et al. Indian clinical practice consensus guidelines for the management of squamous cell carcinoma of head and neck. Indian J Cancer 2020;57:1.
3. Panda M, Rai AK, Rahman T, Das A, Das R, Sarma A, et al. Alter- ations of salivary microbial community associated with oro- pharyngeal and hypopharyngeal squamous cell carcinoma patients. Arch Microbiol 2020;202:785–805.
4. Peng RT, SunY, Zhou XD, Liu SY, Han Q, Cheng L, et al. Trepo- nema denticola promotes OSCC development via the TGF-β signaling pathway. J Dent Res 2022;101:704–13.
5. Kajihara R, Sakai H, HanY, Amari K, Kawamoto M, HakoyamaY, et al. Presence of periodontitis may synergistically contribute to cancer progression viaTregand IL-6. Sci Rep 2022;12:11584.
6. Listyarifah D, Nieminen MT, Mäkinen LK, Haglund C, Grenier D, Häyry V, et al. Treponema denticolachymotrypsin-like pro- teinase is present in early-stage mobile tonguesquamous cell carcinoma and related to the clinicopathological features. J Oral Pathol Med 2018;47:764–72.
7. Aditya J, Smiline Girija AS, Paramasivam A, Vijayashree Priyad- harsini J. Genetic alterations in Wnt family of genes and their putative association with head and neck squamous cell carci- noma. Genomics Inform 2021;19:e5.
8. Jaikumarr Ram A, Girija AS, Jayaseelan VP, Arumugam P. Overexpression of BASP1 indicates a poor prognosis in head and neck squamous cell carcinoma. Asian Pac J Cancer Prev 2020;21:3435–9.
9. Jayaseelan VP, Arumugam P. Exosomal microRNAs targeting TP53 gene as promising prognostic markers for head and neck squamous cell carcinoma. Glob Med Genet 2022;9:277–86.
10. Hinson AN, Hawkes CG, Blake CS, Fitzsimonds ZR, Zhu B, Buck G, et al. Treponema denticola induces interleukin-36γ expres- sion in human oral gingival keratinocytes via the parallel ac- tivation of NF-κB and mitogen-activated protein kinase path- ways. Infect Immun 2022;90:e0024722.
11. Chandrashekar DS, Karthikeyan SK, Korla PK, Patel H, Shovon AR, Athar M, et al. UALCAN: An update to the integrated can- cer data analysis platform. Neoplasia 2022;25:18–27.
12. Hunt GP, Grassi L, Henkin R, Smeraldi F, SpargoTP, Kabiljo R, et al. GEOexplorer: A webserver for gene expression analysis and visualisation. Nucleic Acids Res 2022;50:W367–74.
13. StasiewiczM, KarpińskiTM. The oral microbiota and its role in carcinogenesis. Semin Cancer Biol 2022;86:633–42.
14. Handfield M, Mans JJ, Zheng G, Lopez MC, Mao S, Progulske- Fox A, et al. Distinct transcriptional profiles characterize oral epithelium-microbiota interactions. Cell Microbiol 2005;7:811–23.
15. Fitzsimonds ZR, Rodriguez-Hernandez CJ, Bagaitkar J, Lamont RJ. From beyond the pale to the pale riders: The emerging as- sociation of bacteria with oral cancer. J Dent Res 2020;99:604– 12.
16. Fu T, Liu J-X, Xie J, Gao Z, Yang Z. LAMC2 as a prognostic bio- marker in human cancer: A systematic review and meta-anal- ysis. BMJ Open 2022;12:e063682.
17. Cave DD, Buonaiuto S, Sainz B Jr, Fantuz M, Mangini M, Carrer A, et al. LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer. J ExpClin Cancer Res 2022;41:315.
18. Wang QY, Liu YC, Zhou SH, Chen HH. LAMC2 acts as a novel therapeutic target of cetuximabin laryngeal cancer. Neoplas- ma 2021;68:1257–64.
19. Singh B, Fleury C, Jalalvand F, Riesbeck K. Human pathogens utilize host extracellular matrix proteinslaminin and collagen for adhesion and invasion of the host. FEMS Microbiol Rev 2012;36:1122–80.
20. Shan F. LAMC2 regulates proliferation, migration, and inva- sion mediated by the Pl3K/AKT/mTOR pathway in oral squa- mous carcinoma. Oncol Res 2023;31:481–93.
21. Tong D, Wang X, Liu L, Wen T, Chen Q, Huang C. LAMC2 pro- motes EGFR cell membrane localization and acts as a novel biomarker for tyrosine kinase inhibitors (TKIs) sensitivity in lung cancer. Cancer GeneTher 2023;30:1498–512.
22. Emingil G, KuulaH, Pirilä E, AtillaG,SorsaT. Gingival crevicular fluid laminin-5 γ2-chain levels in periodontal disease. J Clin Periodontol 2006;33:462–8.
23. Song JS, Hwang DH, Kim SO, Jeon M, Choi BJ, Jung HS, et al. Comparative gene expression analysis of the human peri- odontal ligament in deciduous and permanent teeth. PLoS One 2013;8:e61231.
24. Wang H, Zhang J, Li H, Yu H, Chen S, Liu S, et al. FN1 is a prog- nostic biomarker and correlated with immune infiltrates in gastric cancers. Front Oncol 2022;12:918719.
25. Zhou Y, Cao G, Cai H, Huang H, Zhu X. The effect and clinical significance of FN1 expression on biological functions of gas- tric cancer cells. Cell Mol Biol (Noisy-Le-Grand) 2020;66:191–5.
26. Huynh QN, Wang S, Tafolla E, Gansky SA, Kapila S, Armitage GC, et al. Specific fibronectin fragments as markers of peri- odontal disease status. J Periodontol 2002;73:1101–10.
27. Dawson JR, Ellen RP. Tip-oriented adherence of Treponema denticola to fibronectin. Infect Immun 1990;58:3924–8.
28. Nüchel J, Ghatak S, Zuk AV, Illerhaus A, Mörgelin M, Schön- born K, et al. TGFB1 is secreted through an unconventional pathway dependent on the autophagic machinery and cyto- skeletal regulators. Autophagy 2018;14:465–86.
29. Zhang F, Wang H, Wang X, Jiang G, Liu H, Zhang G, et al. TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget 2016;7:52294–306.
30. Wodziński D, Wosiak A, Pietrzak J, Świechowski R, Kordek R, Balcerczak E. Assessment of the TGFB1 gene expression and methylation status of the promoter region in patients with colorectal cancer. Sci Rep 2022;12:11488.
31. Mize TW, Sundararaj KP, Leite RS, Huang Y. Increased and cor- related expression of connective tissue growth factor and transforming growth factor beta 1 in surgically removed peri- odontal tissues with chronic periodontitis. J Periodontal Res 2015;50:315–19.
32. González CR, Amer MA, Vitullo AD, González-Calvar SI, Vacas MI. Immunolocalization of the TGFB1 system in submandibu- largland fibrosis after experimental periodontitis in rats. Acta Odontol Latinoam 2016;29:138–43.
33. Selvakumar SC, Preethi KA, Ross K, Tusubira D, Khan MWA, Mani P, et al. CRISPR/Cas9 and next-generation sequencing in the personalized treatment of cancer. Mol Cancer 2022;21:83.
34. Gajbhiye KR, Salve R, Narwade M, Sheikh A, Kesharwani P, Gajbhiye V. Lipid polymer hybrid nanoparticles: A custom-tai- lored next-generation approach for cancer therapeutics. Mol Cancer 2023;22:160.
35. Qin W, Chandra J, Abourehab MAS, Gupta N, Chen ZS, Keshar- wani P, et al. New opportunities for RGD-engineered metal nanoparticles in cancer. Mol Cancer 2023;22:87.