CC BY-NC-ND 4.0 · J Lab Physicians
DOI: 10.1055/s-0043-1772680
Original Article

Evaluation of Cyclooxygenase-2, P53, Vascular Endothelial Growth Factor, and Nitric Oxide Synthase-2 in Angiogenesis and Growth of Tobacco-Related Malignancies

Shruti Gautam
1   Department of Histopathology, National Institute of Pathology, Indian Council of Medical Research (ICMR), New Delhi, India
,
Manisha Sangma
1   Department of Histopathology, National Institute of Pathology, Indian Council of Medical Research (ICMR), New Delhi, India
,
Safia Rana
2   Department of Pathology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India
,
Shaan Khetrapal
2   Department of Pathology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India
,
Sujala Kapur
1   Department of Histopathology, National Institute of Pathology, Indian Council of Medical Research (ICMR), New Delhi, India
,
Zeeba S. Jairajpuri
2   Department of Pathology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India
› Author Affiliations

Abstract

Introduction In India, tobacco consumption is responsible for half of all the cancers in men and a quarter in women. The present study focuses on the expression of cyclooxygenase-2 (COX-2), P53, vascular endothelial growth factor (VEGF), and nitric oxide synthase (NOS) and their relationship with the growth and angiogenesis of tobacco-related malignancies of the oral cavity, esophagus, lungs, and stomach. It further evaluates the carcinogenic action of nicotine and examines whether COX-2 and NOS-2 overexpression is responsible for tumor growth and associated angiogenic VEGF expression via its receptor.

Material and Methods A cross-sectional study on 140 biopsies, resected specimens of cancer of oral cavity, esophagus, stomach, and lungs, was done. Immunohistochemical evaluation for p53, COX-2, VEGF, and inducible NOS was done. Relevant statistical analysis was applied for the significance of the findings.

Results Immunohistochemical evaluation of pattern of expression of COX-2, NOS-2, VEGF, and p53 was done in both tobacco- and nontobacco-associated cases. The results of the present study revealed an upregulation of COX-2, NOS-2, VEGF, and p53 in all the malignancies.

Conclusion The present results indicated that p53 protein accumulation and increased expression of COX-2, NOS-2, and VEGF might be responsible for carcinogenesis and tumor aggressiveness by enhancing angiogenesis. A possible significant effect of nicotine on COX-2 and P53 expression in tumorigenesis is revealed. These data might have important implications for the therapeutic use of COX-2, NOS-2, and VEGF inhibitors as well as of p53 gene therapy in future anticancer therapeutic strategies in tobacco-related malignancies.



Publication History

Received: 14 June 2023

Accepted: 20 July 2023

Article published online:
22 September 2023

© 2023. The Indian Association of Laboratory Physicians. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Nooshinfar E, Bashash D, Abbasalizadeh MS. et al. The molecular mechanisms of tobacco in cancer pathogenesis. Int J Cancer Manag 2017; 10 (01) e7902
  • 2 Asthana S, Patil RS, Labani S. Tobacco-related cancers in India: a review of incidence reported from population-based cancer registries. Indian J Med Paediatr Oncol 2016; 37 (03) 152-157
  • 3 Pu X, Lippman SM, Yang H, Lee JJ, Wu X. Cyclooxygenase-2 gene polymorphisms reduce the risk of oral premalignant lesions. Cancer 2009; 115 (07) 1498-1506
  • 4 Jeng JH, Ho YS, Chan CP. et al. Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mRNA and protein expression of human oral keratinocytes. Carcinogenesis 2000; 21 (07) 1365-1370
  • 5 Pandey M, Prakash O, Santhi WS, Soumithran CS, Pillai RM. Overexpression of COX-2 gene in oral cancer is independent of stage of disease and degree of differentiation. Int J Oral Maxillofac Surg 2008; 37 (04) 379-383
  • 6 Kaur J, Srivastava A, Ralhan R. Overexpression of p53 protein in betel- and tobacco-related human oral dysplasia and squamous-cell carcinoma in India. Int J Cancer 1994; 58 (03) 340-345
  • 7 Surget S, Khoury MP, Bourdon JC. Uncovering the role of p53 splice variants in human malignancy: a clinical perspective. OncoTargets Ther 2013; 7: 57-68
  • 8 Cox G, Jones JL, Walker RA, Steward WP, O'Byrne KJ. Angiogenesis and non-small cell lung cancer. Lung Cancer 2000; 27 (02) 81-100
  • 9 Mattern J, Koomägi R, Volm M. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumour cell proliferation in human epidermoid lung carcinoma. Br J Cancer 1996; 73 (07) 931-934
  • 10 Volm M, Rittgen W, Drings P. Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas. Br J Cancer 1998; 77 (04) 663-669
  • 11 Mollace V, Muscoli C, Masini E, Cuzzocrea S, Salvemini D. Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol Rev 2005; 57 (02) 217-252
  • 12 Brennan JA, Boyle JO, Koch WM. et al. Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N Engl J Med 1995; 332 (11) 712-717
  • 13 National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention (US);; 2014
  • 14 Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 2002; 21 (48) 7435-7451
  • 15 Pannone G, Bufo P, Caiaffa MF. et al. Cyclooxygenase-2 expression in oral squamous cell carcinoma. Int J Immunopathol Pharmacol 2004; 17 (03) 273-282
  • 16 Mohammad S, Ram H, Gupta PN, Husain N, Bhatt ML. Overexpression of COX-2 in oral squamous cell carcinoma patients undergoing chemoradiotherapy. Natl J Maxillofac Surg 2011; 2 (01) 17-21
  • 17 Zafar S, Kehar Si. Cyclooxygenase-2 and cancer: a silent link with fatal ending. Int J Pathol 2013; 11: 32-38
  • 18 Banerjee AG, Gopalakrishnan VK, Bhattacharya I, Vishwanatha JK. Deregulated cyclooxygenase-2 expression in oral premalignant tissues. Mol Cancer Ther 2002; 1 (14) 1265-1271
  • 19 Gallo O, Schiavone N, Papucci L. et al. Down-regulation of nitric oxide synthase-2 and cyclooxygenase-2 pathways by p53 in squamous cell carcinoma. Am J Pathol 2003; 163 (02) 723-732
  • 20 Chen KM, Guttenplan JB, Zhang SM. 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 (06) 1300-1309
  • 21 Le Calvez F, Mukeria A, Hunt JD. et al. TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res 2005; 65 (12) 5076-5083
  • 22 Marrogi AJ, Travis WD, Welsh JA. et al. Nitric oxide synthase, cyclooxygenase 2, and vascular endothelial growth factor in the angiogenesis of non-small cell lung carcinoma. Clin Cancer Res 2000; 6 (12) 4739-4744
  • 23 Yao L, Liu F, Hong L. et al. The function and mechanism of COX-2 in angiogenesis of gastric cancer cells. J Exp Clin Cancer Res 2011; 30 (01) 13
  • 24 Taghavi N, Biramijamal F, Sotoudeh M. et al. Association of p53/p21 expression with cigarette smoking and prognosis in esophageal squamous cell carcinoma patients. World J Gastroenterol 2010; 16 (39) 4958-4967
  • 25 Shetty SS, Krishnapillai R, Prabhu S. Assessment and comparison of p53 and p63 expression in oral epithelial dysplasia and squamous cell carcinoma. SRM J Res Dent Sci 2014; 5: 149-154
  • 26 Gibbons DL, Byers LA, Kurie JM. Smoking, p53 mutation, and lung cancer. Mol Cancer Res 2014; 12 (01) 3-13
  • 27 Padma Malini K, Srivani O, Kumar Shravan. Study of expression of P53 in gastric carcinoma – as a prognostic indicator. Int Arch Int Med 2016; 3: 54-60
  • 28 Yildirim M, Kaya V, Demirpence O, Gunduz S, Bozcuk H. Prognostic significance of p53 in gastric cancer: a meta- analysis. Asian Pac J Cancer Prev 2015; 16 (01) 327-332
  • 29 Kruszyna Ł, Murawa D, Jagodziński PP, Oszkinis G, Krasiński Z. The expression and prognostic significance of VEGF and CXCR4 in gastric cancer: correlation with angiogenesis, lymphangiogenesis and progression. Curr Issues Mol Biol 2022; 44 (07) 3075-3088
  • 30 Rapone B, Ferrara E. Vascular Endothelial Growth Factor Expression in the Pathological Angiogenesis in Oral Squamous Cell Carcinoma [Internet]. Oral Diseases. IntechOpen; 2020. Accessed August 6, 2023 at: http://dx.doi.org/10.5772/intechopen.90924
  • 31 Cui Y, Dong C, Wu BQ. et al. Expression of cyclooxygenase-2, vascular endothelial growth factor, and epidermal growth factor receptor in Chinese patients with esophageal squamous cell carcinoma. J Cancer Res Ther 2015; 11 (Suppl. 01) C44-C48
  • 32 Frezzetti D, Gallo M, Maiello MR. et al. VEGF as a potential target in lung cancer. Expert Opin Ther Targets 2017; 21 (10) 959-966
  • 33 de Oliveira GA, Cheng RYS, Ridnour LA. et al. Inducible nitric oxide synthase in the carcinogenesis of gastrointestinal cancers. Antioxid Redox Signal 2017; 26 (18) 1059-1077