ENT Updates

Review

The Molecular Mechanisms of Tobacco-Related Oral Carcinogenesis

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https://doi.org/10.54963/entu.v15i1.897
Jiao Li, Suharni Mohamad, & Rahman, N. A. (2025). The Molecular Mechanisms of Tobacco-Related Oral Carcinogenesis. ENT Updates, 15(1). https://doi.org/10.54963/entu.v15i1.897
Volume 15 Issue 1 (2025)
Copyright (c) 2025 Jiao Li, Suharni Mohamad, Nurhayu Ab Rahman
Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors

  • Jiao Li School of Dental Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia https://orcid.org/0000-0003-0409-9338
  • Suharni Mohamad School of Dental Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
  • Nurhayu Ab Rahman
    Oral Medicine and Oral Pathology Unit, School of Dental Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia

Oral squamous cell carcinoma (OSCC) causes a serious loss of facial function or death, and its morbidity is highly related to the usage of tobacco products. Uncovering the mechanisms of tobacco-related OSCC plays a vital role in the prevention and treatment of OSCC. The present review systematically and comprehensively discusses the known mechanisms of tobacco-related OSCC and offer a foundation for the prevention, diagnosis, and treatment of tobacco-mediated OSCC. Scientific literature related to the incidence of tobacco-related OSCC and studies on mechanisms related to tobacco components are included, both in humans and animals. Among the 129 articles cited, three perspectives of the incidence of tobacco-related OSCC were evaluated: DNA adducts, receptor binding, and cocarcinogenic pathways. Tobacco-associated carcinogens cause OSCC by covalently binding to DNA to form DNA adducts or by binding to the receptors, and through the combined action of cocarcinogenic pathways. Three tobacco carcinogens that bind to DNA to form DNA adducts, two receptors that bind to carcinogens, five downstream pathways, and three cocarcinogen-related pathways were listed. This work evaluated the present research status of tobacco-related OSCC to enhance the pathogenesis knowledge of OSCC and offer a foundation for further research endeavours on the prevention, diagnosis, and treatment of tobacco mediated OSCC.

Keywords:

Cigarette Smoking Tobacco Carcinogen Signalling Pathways Oral Squamous Cell Carcinoma

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021, 71(3), 209–249.
  2. Gandini, S.; Botteri, E.; Iodice, S.; et al. Tobacco Smoking and Cancer: A Meta-Analysis. Int. J. Cancer 2008, 122(1), 155–164.
  3. Fauzi, F.H.; Hamzan, N.I.; Rahman, N.A.; et al. Detection of Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma. J. Zhejiang Univ. Sci. B 2020, 21(12), 961–976.
  4. Boffetta, P.; Hecht, S.; Gray, N.; et al. Smokeless Tobacco and Cancer. Lancet Oncol. 2008, 9(7), 667–675.
  5. Wild, C.P.; Weiderpass, E.; Stewart, B.W. World Cancer Report: Cancer Research for Cancer Prevention. 2020.
  6. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics, 2019. CA Cancer J. Clin. 2019, 69(1), 7–34.
  7. IARC, Tobacco Smoke and Involuntary Smoking. IARC Monogr. Eval. Carcinog. Risks Hum. 2004, 83, 1–1438.
  8. WHO. Agents Classified by the IARC Monographs, Volumes 1–132. 2022. Available online: https://monographs.iarc.who.int/agents-classified-by-the-iarc/
  9. Balbo, S.; James-Yi, S.; Johnson, C.S.; et al. (S)-N’-Nitrosonornicotine, a Constituent of Smokeless Tobacco, is a Powerful Oral Cavity Carcinogen in Rats. Carcinogenesis 2013, 34(9), 2178–2183.
  10. Chunxia, D.; Meifang, W.; Jianhua, Z.; et al. Tobacco Smoke Exposure and the Risk of Childhood Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia: A Meta-Analysis. Medicine (Baltimore) 2019, 98(28), e16454.
  11. Geng, H.; Guo, W.; Feng, L.; et al. Diallyl Trisulfide Inhibited Tobacco Smoke-Mediated Bladder EMT and Cancer Stem Cell Marker Expression via the NF-κB Pathway in Vivo. J. Int. Med. Res. 2021, 49(3), 300060521992900.
  12. Korc, M.; Jeon, C.Y.; Edderkaoui, M.; et al. Tobacco and Alcohol as Risk Factors for Pancreatic Cancer. Best Pract. Res. Clin. Gastroenterol. 2017, 31(5), 529–536.
  13. Li, W.; Zhang, L.; Guo, B.; et al. Exosomal FMR1-AS1 Facilitates Maintaining Cancer Stem-Like Cell Dynamic Equilibrium via TLR7/NFκB/c-Myc Signaling in Female Esophageal Carcinoma. Mol. Cancer 2019. 18(1), 22.
  14. Rudin, C.M.; Brambilla, E.; Faivre-Finn, C.; et al. Small-Cell Lung Cancer. Nat. Rev. Dis. Primers 2021, 7(1), 3.
  15. Xie, C.; Zhu, J.; Wang, X.; et al. Tobacco Smoke Induced Hepatic Cancer Stem Cell-Like Properties through IL-33/p38 Pathway. J. Exp. Clin. Cancer Res. 2019, 38(1), 39.
  16. Zhang, S.; Wang, M.; Villalta, P.W.; et al. Quantitation of Pyridyloxobutyl DNA Adducts in Nasal and Oral Mucosa of Rats Treated Chronically with Enantiomers of N’-Nitrosonornicotine. Chem. Res. Toxicol. 2009, 22(5), 949–56.
  17. Zhivagui, M.; Ng, A.W.T.; Ardin, M.; et al. Experimental and Pan-Cancer Genome Analyses Reveal Widespread Contribution of Acrylamide Exposure to Carcinogenesis in Humans. Genome Res. 2019, 29(4), 521–531.
  18. Catassi, A.; Servent, D.; Paleari, L.; et al. Multiple Roles of Nicotine on Cell Proliferation and Inhibition of Apoptosis: Implications on Lung Carcinogenesis. Mutat. Res. 2008. 659(3), 221–231.
  19. Ginzkey, C.; Kampfinger, K.; Friehs, G.; et al. Nicotine Induces DNA Damage in Human Salivary Glands. Toxicol. Lett. 2009, 184(1), 1–4.
  20. Ginzkey, C.; Friehs, G.; Koehler, C.; et al. Assessment of Nicotine-Induced DNA Damage in a Genotoxicological Test Battery. Mutat. Res. 2013. 751(1), 34–39.
  21. Ginzkey, C.; Stueber, T.; Friehs, G.; et al., Analysis of Nicotine-Induced DNA Damage in Cells of the Human Respiratory Tract. Toxicol. Lett. 2012, 208(1), 23–29.
  22. Galitovskiy, V.; Chernyavsky, A.I.; Edwards, R.A.; et al. Muscle Sarcomas and Alopecia in A/J Mice Chronically Treated with Nicotine. Life Sci. 2012, 91(21–22), 1109–1112.
  23. Sharma, M.; Shetty, S.S.; Radhakrishnan, R.A. Novel Pathways and Mechanisms of Nicotine-Induced Oral Carcinogenesis. Recent Pat. Anti-cancer Drug Discov. 2022, 17(1), 66–79.
  24. Hanahan, D.; Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022, 12(1), 31–46.
  25. Hecht, S.S.; Lung Carcinogenesis by Tobacco Smoke. Int. J. Cancer. 2012, 131(12), 2724–2732.
  26. Balbo, S.; Johnson, C.S.; Kovi, R.C.; et al. Carcinogenicity and DNA Adduct Formation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone and Enantiomers of Its Metabolite 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in F-344 Rats. Carcinogenesis 2014, 35(12), 2798–2806.
  27. Alexandrov, K.; Cascorbi, I.; Rojas, M.; et al. CYP1A1 and GSTM1 Genotypes affect Benzo[a]Pyrene DNA Adducts in Smokers’ Lung: Comparison with Aromatic/Hydrophobic Adduct Formation. Carcinogenesis 2002, 23(12), 1969–1977.
  28. Zhang, S.M.; Chen, K.M.; Aliaga, C.; et al. Identification and Quantification of DNA Adducts in the Oral Tissues of Mice Treated with the Environmental Carcinogen Dibenzo[a,l]Pyrene by HPLC-MS/MS. Chem. Res. Toxicol. 2011, 24(8), 1297–1303.
  29. Chen, K.M.; Sun, Y.W.; Krebs, N.M.; et al. Detection of DNA Adducts Derived from the Tobacco Carcinogens, Benzo[a]Pyrene and Dibenzo[def,p]Chrysene in Human Oral Buccal Cells. Carcinogenesis 2022, 43(8), 746–753.
  30. Zhang, S.M.; Chen, K.M.; Sun, Y.W.; et al. Simultaneous Detection of Deoxyadenosine and Deoxyguanosine Adducts in the Tongue and Other Oral Tissues of Mice Treated with Dibenzo[a,l]Pyrene. Chem. Res. Toxicol. 2014, 27(7), 1199–1206.
  31. Tsou, H.H.; Hu, C.H.; Liu, J.H.; et al. Acrolein is Involved in the Synergistic Potential of Cigarette Smoking- and Betel Quid Chewing-Related Human Oral Cancer. Cancer Epidemiol. Biomarkers Prev. 2019. 28(5), 954–962.
  32. Paiano, V.; Maertens, L.; Guidolin, V.; et al. Quantitative Liquid Chromatography-Nanoelectrospray Ionization-High-Resolution Tandem Mass Spectrometry Analysis of Acrolein-DNA Adducts and Etheno-DNA Adducts in Oral Cells from Cigarette Smokers and Nonsmokers. Chem. Res. Toxicol. 2020, 33(8), 2197–2207.
  33. Guengerich, F.P. Role of Cytochrome P450 Enzymes in Drug-Drug Interactions. Adv. Pharmacol. 1997, 43, 7–35.
  34. Hecht, S.S. Tobacco Carcinogens, Their Biomarkers and Tobacco-Induced Cancer. Nat. Rev. Cancer 2003, 3(10), 733–744.
  35. Li, Y.; Hecht, S.S. Metabolism and DNA Adduct Formation of Tobacco-Specific N-Nitrosamines. Int. J. Mol. Sci. 2022, 23(9), 5109.
  36. Murphy, S.E.; Heiblum, R.; Trushin, N. Comparative Metabolism of N’-Nitrosonornicotine and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone by Cultured F344 Rat Oral Tissue and Esophagus. Cancer Res. 1990, 50(15), 4685–4691.
  37. Yuan, J.M.; Gao, Y.T.; Murphy, S.E.; et al. Urinary Levels of Cigarette Smoke Constituent Metabolites are Prospectively Associated with Lung Cancer Development in smokers. Cancer Res. 2011, 71(21), 6749–6757.
  38. Yuan, J.M.; Knezevich, A.D.; Wang, R.; et al. Urinary Levels of the Tobacco-Specific Carcinogen N’-Nitrosonornicotine and Its Glucuronide are Strongly Associated with Esophageal Cancer Risk in Smokers. Carcinogenesis 2011, 32(9), 1366–1371.
  39. Hecht, S.S. Oral Cell DNA Adducts as Potential Biomarkers for Lung Cancer Susceptibility in Cigarette Smokers. Chem. Res. Toxicol. 2017, 30(1), 367–375.
  40. Stepanov, I.; Muzic, J.; Le, C.T.; et al. Analysis of 4-Hydroxy-1-(3-Pyridyl)-1-Butanone (HPB)-Releasing DNA Adducts in Human Exfoliated Oral Mucosa Cells by Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry. Chem. Res. Toxicol. 2013, 26(1), 37–45.
  41. Culp, S.J.; Gaylor, D.W.; Sheldon, W.G.; et al. A comparison of the Tumors Induced by Coal Tar and Benzo[a]Pyrene in a 2-year Bioassay. Carcinogenesis 1998, 19(1), 117–124.
  42. El-Bayoumy, K.; Chen, K.M.; Zhang, S.M.; et al. Carcinogenesis of the Oral Cavity: Environmental Causes and Potential Prevention by Black Raspberry. Chem. Res. Toxicol. 2017, 30(1), 126–144.
  43. Jin, Y., Xu, P.; Liu, X.; et al. Cigarette Smoking, BPDE-DNA Adducts, and Aberrant Promoter Methylations of Tumor Suppressor Genes (TSGs) in NSCLC from Chinese Population. Cancer Invest. 2016, 34(4), 173–180.
  44. Chuang, C.Y.; Tung, J.N.; Su, M.C.; et al. BPDE-Like DNA Adduct Level in Oral Tissue May Act as a Risk Biomarker of Oral Cancer. Arch. Oral Biol. 2013, 58(1), 102–109.
  45. Guttenplan, J.B.; Kosinska, W.; Zhao, Z.L.; et al. Mutagenesis and Carcinogenesis Induced by Dibenzo[a,l]Pyrene in the Mouse Oral Cavity: A Potential New Model for Oral Cancer. Int. J. Cancer 2012, 130(12), 2783–2790.
  46. Chen, K.M.; Guttenplan, J.B.; Zhang, S.M.; et al. Mechanisms of Oral Carcinogenesis Induced by Dibenzo[a,l]Pyrene: An Environmental Pollutant and a Tobacco Smoke Constituent. Int. J. Cancer 2013, 133(6), 1300–1309.
  47. Nath, R.G.; Chung, F.L. Detection of Exocyclic 1,N2-Propanodeoxyguanosine Adducts as Common DNA Lesions in Rodents and Humans. Proc. Natl. Acad. Sci. U S A 1994, 91(16), 7491–7495.
  48. Nath, R.G.; Ocando, J.E.; Guttenplan, J.B.; et al. 1,N2-Propanodeoxyguanosine Adducts: Potential New Biomarkers Of Smoking-Induced DNA Damage in Human Oral Tissue. Cancer Res. 1998, 58(4), 581–584.
  49. Hikisz, P.; Jacenik, D.; The Tobacco Smoke Component, Acrolein, as a Major Culprit in Lung Diseases and Respiratory Cancers: Molecular Mechanisms of Acrolein Cytotoxic Activity. Cells 2023, 12(6), 879.
  50. Gomes, R.; Meek, B.; Eggleton, M. Concise International Chemical Assessment Document 43: Acrolein. IPCS Concise International Chemical Assessment Documents, 2002(43).
  51. Feng, Z.; Hu, W.; Hu, Y.; et al. Acrolein is a Major Cigarette-Related Lung Cancer Agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair. Proc. Natl. Acad. Sci. U S A 2006. 103(42), 15404–15409.
  52. Cheng, G.; Guo, J.; Carmella, S.G.; et al. Increased Acrolein-DNA Adducts in Buccal Brushings of E-Cigarette Users. Carcinogenesis 2022, 43(5), 437–444.
  53. Batta, N.; Pandey, M. Mutational Spectrum of Tobacco Associated Oral Squamous Carcinoma and Its Therapeutic Significance. World J. Surg. Oncol. 2019, 17(1), 198.
  54. Zaid, K.; Azar-Maalouf, E.; Barakat, C.; et al. p53 Overexpression in Oral Mucosa in Relation to Shisha Smoking in Syria and Lebanon. Asian Pac. J. Cancer Prev. 2018. 19(7), 1879–1882.
  55. Solomon, B.; Young, R.J.; Rischin, D. Head and Neck Squamous Cell Carcinoma: Genomics and Emerging Biomarkers for Immunomodulatory Cancer Treatments. Semin. Cancer Biol. 2018, 52(Pt 2), 228–240.
  56. Hsieh, L.L.; Wang, P.F.; Chen, I.H.; et al. Characteristics of Mutations in the p53 Gene in Oral Squamous Cell Carcinoma Associated with Betel Quid Chewing and Cigarette Smoking in Taiwanese. Carcinogenesis 2001, 22(9), 1497–1503.
  57. Wong, Y.K.; Liu, T.Y.; Chang, K.W.; et al. p53 Alterations in Betel Quid- and Tobacco-Associated Oral Squamous Cell Carcinomas from Taiwan. J. Oral Pathol. Med. 1998, 27(6), 243–248.
  58. Blons, H.; Laurent-Puig, P. TP53 and Head and Neck Neoplasms. Hum. Mutat. 2003, 21(3), 252–257.
  59. Singh, R.D.; Patel, K.R.; Patel, P.S. p53 Mutation Spectrum and Its Role In Prognosis of Oral Cancer Patients: A Study from Gujarat, West India. Mutat. Res. 2016, 783, 15–26.
  60. Lee, H.J.; Guo, H.Y.; Lee, S.K.; et al. Effects of Nicotine on Proliferation, Cell Cycle, and Differentiation in Immortalized and Malignant Oral Keratinocytes. J. Oral Pathol. Med. 2005, 34(7), 436–443.
  61. Park, J.E.; Jang, Y.L.; Jang, C.Y. The Tobacco Carcinogen NNK Disturbs Mitotic Chromosome Alignment by Interrupting p53 Targeting to the Centrosome. Toxicol. Lett. 2017, 281, 110–118.
  62. Yoon, J.H.; Smith, L.E.; Feng, Z.; et al. Methylated CpG Dinucleotides are the Preferential Targets for G-to-T Transversion Mutations Induced by Benzo[a]Pyrene Diol Epoxide in Mammalian Cells: Similarities with the p53 Mutation Spectrum in Smoking-Associated Lung Cancers. Cancer Res. 2001, 61(19), 7110–7117.
  63. Tsou, H.H.; Tsai, H.C.; Chu, C.T.; et al. Cigarette Smoke Containing Acrolein Upregulates EGFR Signaling Contributing to Oral Tumorigenesis in Vitro and in Vivo. Cancers (Basel) 2021, 13(14), 3544.
  64. Wang, P.; Leng, J.; Wang, Y. DNA Replication Studies of N-Nitroso Compound-induced O (6)-Alkyl-2’-Deoxyguanosine Lesions in Escherichia Coli. J. Biol. Chem. 2019, 294(11), 3899–3908.
  65. Guttenplan, J.B.; Chen, K.M.; Sun, Y.W.; et al. Effects of the Tobacco Carcinogens N’-Nitrosonornicotine and Dibenzo[a,l]Pyrene Individually and in Combination on DNA Damage in Human Oral Leukoplakia and on Mutagenicity and Mutation Profiles in lacI Mouse Tongue. Chem. Res. Toxicol. 2019, 32(9), 1893–1899.
  66. Grando, S.A. Connections of Nicotine to Cancer. Nat. Rev. Cancer 2014, 14(6), 419–429.
  67. Arredondo, J.; Nguyen, V.T.; Chernyavsky, A.I.; et al. A Receptor-Mediated Mechanism of Nicotine Toxicity in Oral Keratinocytes. Lab. Invest. 2001, 81(12), 1653–1668.
  68. Arredondo, J.; Chernyavsky, A.I.; Jolkovsky, D.L.; et al. Receptor-Mediated Tobacco Toxicity: Cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 Pathways Downstream of Alpha7 Nicotinic Receptor in Oral Keratinocytes. FASEB J. 2006, 20(12), 2093–2101.
  69. Arredondo, J.; Chernyavsky, A.I.; Marubio, L.M.; et al. Receptor-Mediated Tobacco Toxicity: Regulation of Gene Expression through Alpha3beta2 Nicotinic Receptor in Oral Epithelial Cells. Am. J. Pathol. 2005, 166(2), 597–613.
  70. Arredondo, J.; Chernyavsky, A.I.; Jolkovsky, D.L.; et al. Receptor-Mediated Tobacco Toxicity: Acceleration of Sequential Expression of Alpha5 And Alpha7 Nicotinic Receptor Subunits in Oral Keratinocytes Exposed to Cigarette Smoke. FASEB J. 2008, 22(5), 1356–1368.
  71. Arredondo, J.; Chernyavsky, A.I.; Jolkovsky, D.L.; et al. Receptor-Mediated Tobacco Toxicity: Alterations of the NF-kappaB Expression and Activity Downstream of Alpha7 Nicotinic Receptor in Oral Keratinocytes. Life Sci. 2007, 80(24–25), 2191-4.
  72. Tsai, J.R.; Chong, I.W.; Chen, C.C.; et al. Mitogen-Activated Protein Kinase Pathway was Significantly Activated in Human Bronchial Epithelial Cells by Nicotine. DNA Cell Biol. 2006, 25(5), 312–322.
  73. Wang, C.; Xu, X.; Jin, H.; et al. Nicotine may Promote Tongue Squamous Cell Carcinoma Progression by Activating The Wnt/β-Catenin and Wnt/PCP Signaling Pathways. Oncol. Lett. 2017. 13(5), 3479–3486.
  74. Chien, C.Y.; Chen, Y.C.; Hsu, C.C.; et al. YAP-Dependent BiP Induction is Involved in Nicotine-Mediated Oral Cancer Malignancy. Cells 2021, 10(8), 2080.
  75. Nishioka, T.; Kim, H.S.; Luo, L.Y.; et al. Sensitization of Epithelial Growth Factor Receptors by Nicotine Exposure to Promote Breast Cancer Cell Growth. Breast Cancer Res. 2011. 13(6), R113.
  76. Chernyavsky, A.I.; Arredondo, J.; Vetter, D.E.; et al. Central Role of Alpha9 Acetylcholine Receptor in Coordinating Keratinocyte Adhesion and Motility at the Initiation of Epithelialization. Exp. Cell Res. 2007, 313(16), 3542–3555.
  77. Laag, E.; Majidi, M.; Cekanova, M.; et al. NNK activates ERK1/2 and CREB/ATF-1 via Beta-1-AR and EGFR Signaling in Human Lung Adenocarcinoma and Small Airway Epithelial Cells. Int. J. Cancer 2006, 119(7), 1547–1552.
  78. Sabbah, D.A.; Hajjo, R.; Sweidan, K. Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Curr. Top. Med. Chem. 2020, 20(10), 815–834.
  79. Nishioka, T.; Tada, H.; Ibaragi, S.; et al. Nicotine Exposure Induces the Proliferation of Oral Cancer Cells through the α7 Subunit of the Nicotinic Acetylcholine Receptor. Biochem. Biophys. Res. Commun. 2019, 509(2), 514–520.
  80. Wisniewski, D.J.; Ma, T.; Schneider, A. Nicotine Induces Oral Dysplastic Keratinocyte Migration via Fatty Acid Synthase-Dependent Epidermal Growth Factor Receptor Activation. Exp. Cell Res. 2018, 370(2), 343–352.
  81. Shimizu, R.; Ibaragi, S.; Eguchi, T.; et al. Nicotine Promotes Lymph Node Metastasis and Cetuximab Resistance in Head And Neck Squamous Cell Carcinoma. Int. J. Oncol. 2019, 54(1), 283–294.
  82. Verhoeven, Y.; Tilborghs, S.; Jacobs, J.; et al. The Potential and Controversy of Targeting STAT Family Members in Cancer. Semin. Cancer Biol. 2020, 60, 41–56.
  83. Owen, K.L.; Brockwell, N.K.; Parker, B.S. JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression. Cancers (Basel) 2019, 11(12), page range.
  84. Arredondo, J.; Chernyavsky, A.I.; Grando, S.A. The Nicotinic Receptor Antagonists Abolish Pathobiologic Effects of Tobacco-Derived Nitrosamines on BEP2D Cells. J. Cancer Res. Clin. Oncol. 2006, 132(10), 653–663.
  85. Arredondo, J.; Chernyavsky, A.I.; Grando, S.A. Nicotinic Receptors Mediate Tumorigenic Action of Tobacco-Derived Nitrosamines on Immortalized Oral Epithelial Cells. Cancer Biol. Ther. 2006, 5(5), 511–517.
  86. Peng, H.Y.; Hsiao, J.R.; Chou, S.T.; et al. MiR-944/CISH Mediated Inflammation via STAT3 is Involved in Oral Cancer Malignance by Cigarette Smoking. Neoplasia 2020, 22(11), 554–565.
  87. Mishra, R.; Das, B.R. Activation of STAT 5-Cyclin D1 Pathway in Chewing Tobacco Mediated Oral Squamous Cell Carcinoma. Mol. Biol. Rep. 2005, 32(3), 159–166.
  88. Nagpal, J.K.; Mishra, R.; Das, B.R. Activation of Stat-3 as One of the Early Events in Tobacco Chewing-Mediated Oral Carcinogenesis. Cancer 2002, 94(9), 2393–2400.
  89. Xia, F.; Xu, J.C.; Zhang, P.; et al. Glucose-Regulated Protein 78 and Heparanase Expression in Oral Squamous Cell Carcinoma: Correlations and Prognostic Significance. World J. Surg. Oncol. 2014, 12, 121.
  90. Dauer, P.; Sharma, N.S.; Gupta, V.K.; et al. ER Stress Sensor, Glucose Regulatory Protein 78 (GRP78) Regulates Redox Status in Pancreatic Cancer Thereby Maintaining “Stemness”. Cell Death Dis. 2019, 10(2), 132.
  91. Li, Z.W.; Li, Z.Y. Glucose Regulated Protein 78: A Critical Link between Tumor Microenvironment and Cancer Hallmarks. Biochim. Biophys. Acta 2012, 1826(1), 13–22.
  92. Lin, C.Y.; Chen, W.H.; Liao, C.T.; et al. Positive Association of Glucose-Regulated Protein 78 During Oral Cancer Progression and the Prognostic Value in Oral Precancerous Lesions. Head Neck 2010, 32(8), 1028–1039.
  93. Sarkar, R.; Das, A.; Paul, R.R.; et al. Cigarette Smoking Promotes Cancer-Related Transformation of Oral Epithelial Cells through Activation of Wnt and MAPK Pathway. Future Oncol. 2019, 3619–3631.
  94. Shin, V.Y.; Jin, H.C.; Ng, E.K.; et al. Nicotine and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone Induce Cyclooxygenase-2 Activity in Human Gastric Cancer Cells: Involvement of Nicotinic Acetylcholine Receptor (nAChR) and Beta-Adrenergic Receptor Signaling Pathways. Toxicol. Appl. Pharmacol. 2008, 233(2), 254–261.
  95. Schuller, H.M.; Tithof, P.K.; Williams, M.; et al. The Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone is a Beta-Adrenergic Agonist and Stimulates DNA synthesis in Lung Adenocarcinoma via Beta-Adrenergic Receptor-Mediated Release of Arachidonic Acid. Cancer Res. 1999. 59(18), 4510–4515.
  96. Khammanivong, A.; Anandharaj, A.; Qian, X.; et al. Transcriptome Profiling in Oral Cavity and Esophagus Tissues from (S)-N’-Nitrosonornicotine-Treated Rats Reveals Candidate Genes Involved in Human Oral Cavity and Esophageal Carcinogenesis. Mol. Carcinog. 2016, 55(12), 2168–2182.
  97. Nieh, S.; Jao, S.W.; Yang, C.Y.; et al. Regulation of Tumor Progression via the Snail-RKIP Signaling Pathway by Nicotine Exposure in Head and Neck Squamous Cell Carcinoma. Head Neck 2015, 37(12), 1712–1721.
  98. Peng, Q.; Deng, Z.; Pan, H.; et al. Mitogen-Activated Protein Kinase Signaling Pathway in Oral Cancer. Oncol. Lett. 2018, 15(2), 1379–1388.
  99. Rajagopalan, P.; Patel, K.; Jain, A.P.; et al. Molecular Alterations Associated with Chronic Exposure to Cigarette Smoke and Chewing Tobacco in Normal Oral Keratinocytes. Cancer Biol. Ther. 2018, 19(9), 773–785.
  100. Patil, S.; Patel, K.; Advani, J.; et al. Multiomic Analysis of Oral Keratinocytes Chronically Exposed to Shisha. J. Oral Pathol. Med. 2019, 48(4), 284–289.
  101. Vander Broek, R.; Mohan, S.; Eytan, D.F.; et al. The PI3K/Akt/mTOR Axis in Head and Neck Cancer: Functions, Aberrations, Cross-Talk, and Therapies. Oral Dis. 2015, 21(7), 815–825.
  102. Garg, R.; Kapoor, V.; Mittal, M.; et al. Abnormal Expression of PI3K Isoforms in Patients with Tobacco-Related Oral Squamous Cell Carcinoma. Clin. Chim. Acta 2013, 416, 100–106.
  103. Shikata, M.; Toyooka, T.; Komaki, Y.; et al. 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone-Induced Histone Acetylation via α7nAChR-Mediated PI3K/Akt Activation and Its Impact on γ-H2AX Generation. Chem. Res. Toxicol. 2021. 34(12), 2512–2521.
  104. Roy, N.K.; Monisha, J.; Padmavathi, G.; et al. Isoform-Specific Role of Akt in Oral Squamous Cell Carcinoma. Biomolecules 2019, 9(7), 253.
  105. Nishioka, T.; Guo, J.; Yamamoto, D.; et al. Nicotine, through Upregulating Pro-Survival Signaling, Cooperates with NNK to Promote Transformation. J. Cell Biochem. 2010, 109(1), 152–161.
  106. Padmavathi, G.; Monisha, J.; Bordoloi, D.; et al. Tumor Necrosis Factor-α Induced Protein 8 (TNFAIP8/TIPE) Family is Differentially Expressed in Oral Cancer and Regulates Tumorigenesis through Akt/mTOR/STAT3 Signaling Cascade. Life Sci. 2021, 287, 120118.
  107. Monisha, J.; Roy, N.K.; Padmavathi, G.; et al. NGAL is Downregulated in Oral Squamous Cell Carcinoma and Leads to Increased Survival, Proliferation, Migration and Chemoresistance. Cancers 2018,10(7), 228.
  108. Monteiro, L.S.; Delgado, M.L.; Ricardo, S.; et al. Phosphorylated Mammalian Target of Rapamycin is Associated with an Adverse Outcome in Oral Squamous Cell Carcinoma. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2013, 115(5), 638–645.
  109. Yu, C.C.; Chang, Y.C. Enhancement of Cancer Stem-Like and Epithelial-Mesenchymal Transdifferentiation Property in Oral Epithelial Cells with Long-Term Nicotine Exposure: Reversal by Targeting SNAIL. Toxicol. Appl. Pharmacol. 2013, 266(3), 459–469.
  110. Nakanishi, C.; Toi, M. Nuclear Factor-KappaB Inhibitors as Sensitizers to Anticancer Drugs. Nat. Rev. Cancer 2005, 5(4), 297–309.
  111. Shishodia, S.; Aggarwal, B.B. Nuclear Factor-kappaB: A Friend or a Foe in cancer?. Biochem. Pharmacol. 2004, 68(6), 1071–1080.
  112. Ho, Y.S.; Chen, C.H.; Wang, Y.J.; et al. Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone (NNK) Induces Cell Proliferation in normal Human Bronchial Epithelial Cells Through NFkappaB Activation and Cyclin D1 Up-Regulation. Toxicol. Appl. Pharmacol. 2005, 205(2), 133–148.
  113. Tsurutani, J.; Castillo, S.S.; Brognard, J.; et al. Tobacco Components Stimulate Akt-Dependent Proliferation and NFkappaB-Dependent Survival in Lung Cancer Cells. Carcinogenesis 2005, 26(7), 1182–1195.
  114. Ye, Y.N.; Liu, E.S.; Shin, V.Y.; et al. The Modulating Role of Nuclear Factor-KappaB in the Action Of Alpha7-Nicotinic Acetylcholine Receptor And Cross-Talk between 5-Lipoxygenase and Cyclooxygenase-2 in Colon Cancer Growth induced by 4-(N-Methyl-N-Nitrosamino)-1-(3-Pyridyl)-1-Butanone. J. Pharmacol. Exp. Ther. 2004, 311(1), 123–130.
  115. Sawhney, M.; Rohatgi, N.; Kaur, J.; et al. Expression of NF-KappaB Parallels COX-2 Expression in Oral Precancer and Cancer: Association with Smokeless Tobacco. Int. J. Cancer 2007, 120(12), 2545–2556.
  116. Moazeni-Roodi, A.; Allameh, A.; Harirchi, I.; et al. Studies on the Contribution of Cox-2 Expression in the Progression of Oral Squamous Cell Carcinoma and H-Ras Activation. Pathol. Oncol. Res. 2017, 23(2), 355–360.
  117. Salimi, M.; Esfahani, M.; Habibzadeh, N.; et al. Change in Nicotine-Induced VEGF, PGE2 AND COX-2 Expression Following COX Inhibition in Human Oral Squamous Cancer. J. Environ. Pathol. Toxicol. Oncol. 2012, 31(4), 349–356.
  118. Lee, C.H.; Chang, J.S.; Syu, S.H.; et al. IL-1β Promotes Malignant Transformation and Tumor Aggressiveness in Oral Cancer. J. Cell Physiol. 2015, 230(4), 875–884.
  119. Urbaniak, S.K.; Boguszewska, K.; Szewczuk, M.; et al. 8-Oxo-7,8-Dihydro-2’-Deoxyguanosine (8-oxodG) and 8-Hydroxy-2’-Deoxyguanosine (8-OHdG) as a Potential Biomarker for Gestational Diabetes Mellitus (GDM) Development. Molecules 2020, 25(1), 202.
  120. Sanchez, M.; Roussel, R.; Hadjadj, S.; et al. Plasma Concentrations of 8-Hydroxy-2’-Deoxyguanosine and Risk of Kidney Disease and Death in Individuals with Type 1 Diabetes. Diabetologia 2018, 61(4), 977–984.
  121. Wu, H.J.; Chi, C.W.; Liu, T.Y. Effects of pH on Nicotine-Induced DNA Damage and Oxidative Stress. J. Toxicol. Environ. Health. A 2005, 68(17–18), 1511–1523.
  122. Kaur, J.; Politis, C.; Jacobs, R. Salivary 8-Hydroxy-2-Deoxyguanosine, Malondialdehyde, Vitamin C, and Vitamin E in Oral Pre-Cancer and Cancer: Diagnostic Value and Free Radical Mechanism of Action. Clin. Oral. Investig. 2016, 20(2), 315–319.
  123. Murugaiyan, S.B.; Ramasamy, R.; Nakkeeran, M.; et al. Urinary 8-Hydroxydeoxyguanosine as a Marker of Oxidative Stress Induced Genetic Toxicity in Oral Cancer Patients. Indian J. Dent. Res. 2015, 26(3), 226–230.
  124. Nandakumar, A.; Nataraj, P.; James, A.; et al. Estimation of Salivary 8-Hydroxydeoxyguanosine (8-OHdG) as a Potential Biomarker in Assessing Progression towards Malignancy: A Case-Control Study. Asian Pac. J. Cancer Prev. 2020, 21(8), 2325–2329.
  125. Don, K.R.; Ramani, P.; Ramshankar, V.; et al. Promoter Hypermethylation Patterns of P16, DAPK and MGMT in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. Indian J. Dent. Res. 2014, 25(6), 797–805.
  126. Shridhar, K.; Walia, G.K.; Aggarwal, A.; et al. DNA Methylation Markers for Oral Pre-Cancer Progression: A Critical Review. Oral Oncol. 2016, 53, 1–9.
  127. Pulling, L.C.; Klinge, D.M.; Belinsky,S.A. p16INK4a and Beta-Catenin Alterations in Rat Liver Tumors Induced by NNK. Carcinogenesis 2001, 22(3), 461–466.
  128. Pegg, A.E. Mammalian O6-Alkylguanine-DNA Alkyltransferase: Regulation and Importance in Response to Alkylating Carcinogenic and Therapeutic Agents. Cancer Res. 1990, 50(19), 6119–6129.
  129. Sawhney, M.; Rohatgi, N.; Kaur, J.; et al. MGMT Expression in Oral Precancerous and Cancerous Lesions: Correlation with Progression, Nodal Metastasis and Poor Prognosis. Oral Oncol. 2007, 43(5), 515–522.