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Cigarette Smoke Affects Apoptosis in Rat Tongue Mucosa: Role of bcl-2 Gene Family

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Abstract

While it has been clearly demonstrated that smoking is the most significant exogenous factor involved in oral carcinogenesis, little is known about the global molecular and cellular changes that occur prior to the appearance of clinically detectable symptoms. Thus, the aim of this study was to investigate the expressivity of bcl-2, bax and PCNA in the rat tongue mucosa exposed to cigarette smoke by means of immunohistochemistry. A total of twelve male Wistar rats were distributed into 2 groups: negative control and experimental group exposed to cigarette smoke during 75 days. After experimental period, no histopathological changes in the tongue mucosa were detected in the negative control and the experimental group. On the other hand, an overexpression of bcl-2 was detected (p < 0.01) throughout all layers of the epithelium, whereas bax did not show significant differences (p > 0.05). Also, the labeling index for bcl-2 and bax showed an increase 75 days after cigarette exposure (p < 0.01). PCNA-labeling index did not show remarkable changes between groups. Taken together, our results show that bcl-2 is overexpressed in the rat tongue keratinocytes after cigarette smoke exposure.

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References

  • Armstrong JS (2006) Mitochondria: a target for cancer therapy. Br J Pharmacol 147:239–248

    Article  PubMed  CAS  Google Scholar 

  • Asao Y, Otsuki Y, Kataoka S, Yto Y, Kataoka S, Ito Y, Tsujimoto Y (1994) Multiple subcellular localization of bcl-2: detection in nuclear outer membrane, endoplasmic reticulum membrane, and mitochondrial membranes. Cancer Res 54:2468–2471

    Google Scholar 

  • Arends MJ, Wyllie AH (1991) Apoptosis: mechanisms and roles in pathology. Int Rev Exp Pathol 32:223–254

    PubMed  CAS  Google Scholar 

  • Arredondo J, Chernyavsky AI, Marubio LM, Beaudet al, Jolkovsky DL, Pinkerton KE, Grando SA (2005) Receptor-mediated tobacco toxicity: regulation of gene expression through alpha3beta2 nicotinic receptor in oral epithelial cells. Am J Pathol 166:597–613

    PubMed  CAS  Google Scholar 

  • Argentim G, Cicchetti R (2004) Genotoxic and antiapoptotic effect of nicotine on human gingival fibroblasts. Toxicol Sci 79:75–81

    Article  CAS  Google Scholar 

  • Bagchi M, Balmoori J, Bagchi D, Ray SD, Kuszynski C, Stohs SJ (1999) Smokeless tobacco, oxidative stress, apoptosis, and antioxidants in human oral keratinocytes. Free Rad Biol Med 26:992–1000

    Article  PubMed  CAS  Google Scholar 

  • Bloching M, Hofmann A, Lautenschlager CH, Berghaus A, Grummt T (2000) Exfoliative cytology of normal buccal mucosa to predict the relative risk of cancer in the upper aerodigestive tract using the MN-assay. Oral Oncol 36:550–555

    Article  PubMed  CAS  Google Scholar 

  • Cendon SP (1997) Pulmonary emphysema induced by passive smoking: an experimental study in rats. Braz J Biol Med Res 30:1241–1247

    CAS  Google Scholar 

  • Cleary ML, Smith SD, Sklar J (1986) Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47:19–28

    Article  PubMed  CAS  Google Scholar 

  • D’Agostini F, Balansky RM, Izzotti A, Lubet RA, Kelloff GJ, De Flora S (2001) Modulation of apoptosis by cigarette smoke and cancer chemopreventive agents in the respiratory tract of rats. Carcinogenesis 22:375–380

    Article  PubMed  CAS  Google Scholar 

  • Hahn M, Hagedorn G, Kuhlisch E, Schackert HK, Eckelt U (2002) Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to oral cavity cancer. Oral Oncol 38:486–490

    Article  PubMed  CAS  Google Scholar 

  • Harada H, Mitsuyasu T, Seta Y, Maruoka Y, Toyoshima K, Yasumoto S (1998) Overexpression of bcl-2 protein inhibits terminal differentiation of oral keratinocytes in vitro. J Oral Pathol Med 27:11–17

    Article  PubMed  CAS  Google Scholar 

  • Jordan RCK, Catzavelos GC, Barrett AW, Speight PM (1996) Differential expression of bcl-2 and bax in squamous cell carcinomas of the oral cavity. Oral Oncol 32B:394–400

    CAS  Google Scholar 

  • Kao SY, Wu CH, Lin SC, Yap SK, Chang CS, Wong YK, Chi LY, Liu TY (2002) Genetic polymorphism of cytochrome P4501A1 and susceptibility to oral squamous cell carcinoma and oral precancer lesions associated with smoking/betel use. J Oral Pathol Med 31:505–511

    Article  PubMed  CAS  Google Scholar 

  • Kerr JR, Wyllie AH, Currie AR (1972) Apoptosis: a basic phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    PubMed  CAS  Google Scholar 

  • Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN (1993) Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Sem Cancer Biol 4:327–332

    CAS  Google Scholar 

  • Krajewski S, Krajewska M, Shabaik A, Miyashita T, Wang HG, Reed JC (1994) Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am J Pathol 145:1323–1336

    PubMed  CAS  Google Scholar 

  • Kulkarni V, Saranath D (2004) Concurrent hypermethylation of multiple regulatory genes in chewing tobacco associated oral squamous cell carcinomas and adjacent normal tissues. Oral Oncol 40:145–153

    Article  PubMed  CAS  Google Scholar 

  • Lee HJ, Guo HY, Lee SK, Jeon BH, Jun CD, Lee SK, Park MH, Kim EC (2005) Effects of nicotine on proliferation, cell cycle, and differentiation in immortalized and malignant oral keratinocytes. J Oral Pathol Med 34:436–443

    Article  PubMed  CAS  Google Scholar 

  • Linden MD, Torres FX, Kubus J, Zarbo RJ (1992) Clinical application of morphologic and imunocytochemical assessments of cell proliferation [editorial]. Am J Clin Pathol 97:S4–13

    PubMed  CAS  Google Scholar 

  • Liu W, Bulgaru A, Haigentz M (2003) The bcl-2 family of protein ligants as cancer drugs: next generation of therapeutics. Curr Med Chem Anti-Canc Agents 3:217–223

    Article  CAS  Google Scholar 

  • Loro LL, Vintermyr OK, Johannessen AC (2003) Cell death regulation in oral squamous cell carcinoma: methodological considerations and clinical significance. J Oral Pathol Med 32:125–138

    Article  PubMed  CAS  Google Scholar 

  • Loro L, Vintermyr OK, Johannessen AC (2005) Apoptosis in normal and diseased oral tissues. Oral Dis 11:274–287

    Article  PubMed  Google Scholar 

  • Lu QL, Abel P, Foster CS, Lalani EN (1996) Bcl-2: role in epithelial differentiation and oncogenesis. Human Pathol 27:102–110

    Article  CAS  Google Scholar 

  • Magrath I, Litvak J (1993) Cancer in developing countries: opportunity and challenge. J Natl Cancer Inst 85:862–874

    Article  PubMed  CAS  Google Scholar 

  • Miquel C, Borrini F, Grandjouan S, Auperin A, Viguier J, Velasco V, Duvillard P, Praz F, Sabourin JC (2005) Role of bax mutations in apoptosis in colorectal cancers with microsatellite instability. Am J Clin Pathol 123:562–570

    Article  PubMed  CAS  Google Scholar 

  • Nikitakis NG, Sauk JJ, Papanicolaou SI (2004) The role of apoptosis in oral disease: mechanisms; aberrations in neoplastic, autoimmune, infectious, hematologic, and developmental diseases; and therapeutic opportunities. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 97:476–490

    Article  PubMed  Google Scholar 

  • Nishimura A (1999) Changes in Bcl-2 and Bax expression in rat tongue during 4-nitroquinoline 1-oxide-induced carcinogenesis. J Dent Res 78:1264–1269

    PubMed  CAS  Google Scholar 

  • Niwa S, Ueno S, Shirasu R (2001) Alteration of pRB expression in the development of rat tongue carcinoma induced by 4-nitroquinoline 1-oxide. Oral Oncol 37:579–585

    Article  PubMed  CAS  Google Scholar 

  • Okazaki Y, Tanaka Y, Tonogi M, Yamane G (2002) Investigation of environmental factors for diagnosing malignant potential in oral epithelial dysplasia. Oral Oncol 38:562–573

    Article  PubMed  CAS  Google Scholar 

  • Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74:609–619

    Article  PubMed  CAS  Google Scholar 

  • Polverini PJ, Nor JE (1999) Apoptosis and predisposition to oral cancer. Critical Rev Oral Biol Med 10:139–52

    Article  CAS  Google Scholar 

  • Reed JC (1994) Bcl-2 and the regulation of programmed cell death. J Cell Biol 124:1–6

    Article  PubMed  CAS  Google Scholar 

  • Ribeiro DA, Salvadori DMF, Marques MEA (2005) Abnormal expression of bcl-2 and bax in rat tongue mucosa during the development of squamous cell carcinoma induced by 4-nitroquinoline 1-oxide. Int J Exp Pathol 86:375–381

    Article  PubMed  CAS  Google Scholar 

  • Simani AS, Inoue S, Hogg JC (1974) Penetration of the respiratory epithelium of guinea pigs following exposure to cigarette smoke. Lab Invest 31:75–81

    PubMed  CAS  Google Scholar 

  • Schwartz JL, Muscat JE, Baker V, Larios E, Stephenson GD, Guo W, Xie T, Gu X, Chung FL (2003) Oral cytology assessment by flow cytometry of DNA adducts, aneuploidy, proliferation and apoptosis shows differences between smokers and non-smokers. Oral Oncol 39:842–854

    Article  PubMed  CAS  Google Scholar 

  • Strasser A, Huang DC, Vaux DL (1997) The role of the bcl-2/ced-9 gene family in cancer and general implications of defects in cell death control for tumourigenesis and resistance to chemotherapy. Biochim Biophys Acta 24:F151–178

    Google Scholar 

  • Suzuki N, Wakisaka S, Takeba Y, Mihara S, Sakane T (1999) Effects of cigarette smoking on Fas/Fas ligand expression of human lymphocytes. Cell Immunol 192:48–53

    Article  PubMed  CAS  Google Scholar 

  • Tsujimoto Y, Cossman J, Jaffe E, Croce CM (1985) Involvement of the bcl-2 gene in human follicular lymphoma. Science 228:1440–1443

    Article  PubMed  CAS  Google Scholar 

  • Wang XD, Liu C, Bronson RT, Smith DE, Krinsky NI, Russell M (1999) Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke. J Natl Cancer Inst 91:60–66

    Article  PubMed  CAS  Google Scholar 

  • Wright SC, Zhong J, Zheng H, Larrick JW (1993) Nicotine inhibition of apoptosis suggests a role in tumor promotion. FASEB J 7:1045–1051

    PubMed  CAS  Google Scholar 

  • Xi S, Grandis JR (2003) Gene therapy for the treatment of oral squamous cell carcinoma. J Dent Res 82:11–16

    Article  PubMed  CAS  Google Scholar 

  • Zhang D, Tao Y, Gao J, Zhang C, Wan S, Chen Y, Huang X, Sun X, Duan S, Schonlau F, Rohdewald P, Zhao B (2002) Pycnogenol in cigarette filters scavenges free radicals and reduces mutagenicity and toxicity of tobacco smoke in vivo. Toxicol Ind Health 18:215–224

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Tania Mary Cestari for her technical assistance. This work was supported by CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant number: 141501/2002-2) and FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo, Grant number: 02/09454-0).

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Correspondence to Daniel A Ribeiro.

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Assis, G.F., Ceolin, D.S., Marques, M.E.A. et al. Cigarette Smoke Affects Apoptosis in Rat Tongue Mucosa: Role of bcl-2 Gene Family. J Mol Hist 36, 483–489 (2005). https://doi.org/10.1007/s10735-006-9023-z

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  • DOI: https://doi.org/10.1007/s10735-006-9023-z

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