Skip to main content
SpringerLink
Log in

Alcohol Metabolism by Oral Streptococci and Interaction with Human Papillomavirus Leads to Malignant Transformation of Oral Keratinocytes

  • Conference paper
  • First Online:
Biological Basis of Alcohol-Induced Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 815))

Abstract

Poor oral hygiene, ethanol consumption, and human papillomavirus (HPV) are associated with oral and esophageal cancers. However, the mechanism is not fully known. This study examines alcohol metabolism in Streptococcus and its interaction with HPV-16 in the malignant transformation of oral keratinocytes. The acetaldehyde-producing strain Streptococcus gordonii V2016 was analyzed for adh genes and activities of alcohol and aldehyde dehydrogenases. Streptococcus attachment to immortalized HPV-16 infected human oral keratinocytes, HOK (HPV/HOK-16B), human oral buccal keratinocytes, and foreskin keratinocytes was studied. Acetaldehyde, malondialdehyde, DNA damage, and abnormal proliferation among keratinocytes were also quantified. We found that S. gordonii V2016 expressed three primary alcohol dehydrogenases, AdhA, AdhB, and AdhE, which all oxidize ethanol to acetaldehyde, but their preferred substrates were 1-propanol, 1-butanol, and ethanol, respectively. S. gordonii V2016 did not show a detectable aldehyde dehydrogenase. AdhE is the major alcohol dehydrogenase in S. gordonii. Acetaldehyde and malondialdehyde production from permissible Streptococcus species significantly increased the bacterial attachment to keratinocytes, which was associated with an enhanced expression of furin to facilitate HPV infection and several malignant phenotypes including acetaldehyde adduct formation, abnormal proliferation, and enhanced migration through integrin-coated basement membrane by HPV-infected oral keratinocytes. Therefore, expression of multiple alcohol dehydrogenases with no functional aldehyde dehydrogenase contributes to excessive production of acetaldehyde from ethanol by oral streptococci. Oral Streptococcus species and HPV may cooperate to transform oral keratinocytes after ethanol exposure. These results suggest a significant clinical interaction, but further validation is warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bagnardi V, Blangiardo M, La Vecchia C et al (2001) Alcohol consumption and the risk of cancer: a meta-analysis. Alcohol Res Health 25:263–270

    CAS  PubMed  Google Scholar 

  2. Abnet CC, Kamangar F, Islami F et al (2008) Tooth loss and lack of regular oral hygiene are associated with higher risk of esophageal squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 17:3062–3068

    Article  PubMed Central  PubMed  Google Scholar 

  3. Homann N (2001) Alcohol and upper gastrointestinal tract cancer: the role of local acetaldehyde production. Addict Biol 6:309–323

    Article  CAS  PubMed  Google Scholar 

  4. Homann N, Tillonen J, Rintamäki H et al (2001) Poor dental status increases acetaldehyde production from ethanol in saliva: a possible link to increased oral cancer risk among heavy drinkers. Oral Oncol 37:153–158

    Article  CAS  PubMed  Google Scholar 

  5. Brown LM, Check DP, Devesa SS (2011) Oropharyngeal cancer incidence trends: diminishing racial disparities. Cancer Causes Control 22:753–763

    Article  PubMed  Google Scholar 

  6. Brown SD, Guss AM, Karpinets TV et al (2011) Mutant alcohol dehydrogenase leads to improved ethanol tolerance in Clostridium thermocellum. Proc Natl Acad Sci U S A 108:13752–13757

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Meurman JH, Uittamo J (2008) Oral micro-organisms in the etiology of cancer. Acta Odontol Scand 66:321–326

    Article  PubMed  Google Scholar 

  8. Bassi DE, Fu J, Lopez de Cicco R et al (2005) Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol Carcinog 44:151–161

    Article  CAS  PubMed  Google Scholar 

  9. Thomas G (2002) Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 3:753–766

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Homann N, Jousimies-Somer H, Jokelainen K et al (1997) High acetaldehyde levels in saliva after ethanol consumption: methodological aspects and pathogenetic implications. Carcinogenesis 18:1739–1743

    Article  CAS  PubMed  Google Scholar 

  11. Muto M, Hitomi Y, Ohtsu A et al (2000) Acetaldehyde production by non-pathogenic Neisseria in human oral microflora: implications for carcinogenesis in upper aerodigestive tract. Int J Cancer 88:342–350

    Article  CAS  PubMed  Google Scholar 

  12. Nobbs AH, Lamont RJ, Jenkinson HF (2009) Streptococcus adherence and colonization. Microbiol Mol Biol Rev 73:407–450

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Kurkivuori J, Salaspuro V, Kaihovaara P et al (2007) Acetaldehyde production from ethanol by oral streptococci. Oral Oncol 43:181–186

    Article  CAS  PubMed  Google Scholar 

  14. Väkeväinen S, Tillonen J, Blom M et al (2001) Acetaldehyde production and other ADH-related characteristics of aerobic bacteria isolated from hypochlorhydric human stomach. Alcohol Clin Exp Res 25:421–426

    Article  PubMed  Google Scholar 

  15. Woutersen RA, Appelman LM, Van Garderen-Hoetmer A et al (1986) Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. Toxicology 41:213–231

    Article  CAS  PubMed  Google Scholar 

  16. Obe G, Anderson D (1987) International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 15/1. Genetic effects of ethanol. Mutat Res 186:177–200

    Article  CAS  PubMed  Google Scholar 

  17. Vaca CE, Fang JL, Schweda EK (1995) Studies of the reaction of acetaldehyde with deoxynucleosides. Chem Biol Interact 98:51–67

    Article  CAS  PubMed  Google Scholar 

  18. Espina N, Lima V, Lieber CS et al (1988) In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O 6-methylguanine transferase. Carcinogenesis 9:761–766

    Article  CAS  PubMed  Google Scholar 

  19. Secretan B, Straif K, Baan R et al (2009) A review of human carcinogens. Part E. Tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 10:1033–1034

    Article  PubMed  Google Scholar 

  20. Rehm J, Kanteres F, Lachenmeier DW (2010) Unrecorded consumption, quality of alcohol and health consequences. Drug Alcohol Rev 29:426–436

    Article  PubMed  Google Scholar 

  21. Druesne-Pecollo N, Tehard B, Mallet Y et al (2009) Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. Lancet Oncol 10:173–180

    Article  CAS  PubMed  Google Scholar 

  22. Marttila E, Bowyer P, Sanglard D et al (2013) Fermentative 2-carbon metabolism produces carcinogenic levels of acetaldehyde in Candida albicans. Mol Oral Microbiol 28:281–291

    Article  CAS  PubMed  Google Scholar 

  23. Uittamo J, Siikala E, Kaihovaara P et al (2009) Chronic candidosis and oral cancer in APECED-patients: production of carcinogenic acetaldehyde from glucose and ethanol by Candida albicans. Int J Cancer 124:754–756

    Article  CAS  PubMed  Google Scholar 

  24. Dewhirst FE, Chen T, Izard J et al (2010) The human oral microbiome. J Bacteriol 192:5002–5017

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Turnbaugh PJ, Ley RE, Hamady M (2007) The human microbiome project. Nature 449:804–810

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. O’Hara AM, Shanahan F (2006) The gut flora as a forgotten organ. EMBO Rep 7:688–693

    Article  PubMed Central  PubMed  Google Scholar 

  27. Salaspuro MP (2003) Acetaldehyde, microbes, and cancer of the digestive tract. Crit Rev Clin Lab Sci 40:183–208

    Article  CAS  PubMed  Google Scholar 

  28. Väkeväinen S, Tillonen J, Agarwal DP et al (2000) High salivary acetaldehyde after a moderate dose of alcohol in ALDH2-deficient subjects: strong evidence for the local carcinogenic action of acetaldehyde. Alcohol Clin Exp Res 24:873–877

    Article  PubMed  Google Scholar 

  29. Väkeväinen S, Tillonen J, Salaspuro M (2001) 4-Methylpyrazole decreases salivary acetaldehyde levels in ALDH2-deficient subjects but not in subjects with normal ALDH2. Alcohol Clin Exp Res 25:829–834

    Article  PubMed  Google Scholar 

  30. Pavlova SI, Jin L, Gasparovich SR et al (2013) Multiple alcohol dehydrogenases but no functional acetaldehyde dehydrogenase causing excessive acetaldehyde production from ethanol by oral streptococci. Microbiology 159:1437–1446

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Vickerman MM, Iobst S, Jesionowski AM et al (2007) Genome-wide transcriptional changes in Streptococcus gordonii in response to competence signaling peptide. J Bacteriol 189:7799–7807

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Lau PC, Sung CK, Lee JH et al (2002) PCR ligation mutagenesis in transformable streptococci: application and efficiency. J Microbiol Methods 49:193–205

    Article  CAS  PubMed  Google Scholar 

  33. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory, Cold Spring Harbor

    Google Scholar 

  34. Gabriel O (1971) Locating enzymes on gels. Methods Enzymol 22:578–604

    Article  Google Scholar 

  35. Grell EH, Jacobson KB, Murphy JB (1968) Alterations of genetics material for analysis of alcohol dehydrogenase isozymes of Drosophila melanogaster. Ann N Y Acad Sci 151:441–455

    Article  CAS  PubMed  Google Scholar 

  36. Koo OK, Jeong DW, Lee JM et al (2005) Cloning and characterization of the bifunctional alcohol/acetaldehyde dehydrogenase gene (adhE) in Leuconostoc mesenteroides isolated from Kimchi. Biotechnol Lett 27:505–510

    Article  CAS  PubMed  Google Scholar 

  37. Hiyama T, Yoshihara M, Tanaka S et al (2007) Genetic polymorphisms and esophageal cancer risk. Int J Cancer 121:1643–1658

    Article  CAS  PubMed  Google Scholar 

  38. Lewis SJ, Smith GD (2005) Alcohol, ALDH2, and esophageal cancer: a meta-analysis which illustrates the potentials and limitations of a Mendelian randomization approach. Cancer Epidemiol Biomarkers Prev 14:1967–1971

    Article  CAS  PubMed  Google Scholar 

  39. Yokoyama A, Muramatsu T, Ohmori T et al (1998) Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics. Carcinogenesis 19:1383–1387

    Article  CAS  PubMed  Google Scholar 

  40. Martincorena I, Seshasayee AS, Luscombe NM (2012) Evidence of non-random mutation rates suggests an evolutionary risk management strategy. Nature 485:95–98

    Article  CAS  PubMed  Google Scholar 

  41. Reinke LA, Rau JM, McCay PB (1994) Characteristics of an oxidant formed during iron (II) autoxidation. Free Radic Biol Med 16:485–492

    Article  CAS  PubMed  Google Scholar 

  42. Welch KD, Davis TZ, Aust SD (2002) Iron autoxidation and free radical generation: effects of buffers, ligands, and chelators. Arch Biochem Biophys 397:360–369

    Article  CAS  PubMed  Google Scholar 

  43. Nnyepi MR, Peng Y, Broderick JB (2007) Inactivation of E. coli pyruvate formate-lyase: role of AdhE and small molecules. Arch Biochem Biophys 459:1–9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Asanuma N, Yoshii T, Hino T (2004) Molecular characteristics and transcription of the gene encoding a multifunctional alcohol dehydrogenase in relation to the deactivation of pyruvate formate-lyase in the ruminal bacterium Streptococcus bovis. Arch Microbiol 181:122–128

    Article  CAS  PubMed  Google Scholar 

  45. Jagadeesan B, Koo OK, Kim KP et al (2010) LAP, an alcohol acetaldehyde dehydrogenase enzyme in Listeria, promotes bacterial adhesion to enterocyte-like Caco-2 cells only in pathogenic species. Microbiology 156:2782–2795

    Article  CAS  PubMed  Google Scholar 

  46. Yao S, Mikkelsen MJ (2010) Identification and overexpression of a bifunctional aldehyde/alcohol dehydrogenase responsible for ethanol production in Thermoanaerobacter mathranii. J Mol Microbiol Biotechnol 19:123–133

    Article  CAS  PubMed  Google Scholar 

  47. Brendel M, Marisco G, Ganda I et al (2010) DNA repair mutant pso2 of Saccharomyces cerevisiae is sensitive to intracellular acetaldehyde accumulated by disulfiram-mediated inhibition of acetaldehyde dehydrogenase. Genet Mol Res 9:48–57

    Article  CAS  PubMed  Google Scholar 

  48. Schwartz J, Pavlova S, Kolokythas A et al (2013) Streptococci-human papilloma virus interaction with ethanol exposure leads to keratinocyte damage. J Oral Maxillofac Surg 70:1867–1879

    Article  Google Scholar 

  49. Knobloch JK, Horstkotte MA, Rohde H et al (2002) Alcoholic ingredients in skin disinfectants increase biofilm expression of Staphylococcus epidermidis. J Antimicrob Chemother 49:683–687

    Article  CAS  PubMed  Google Scholar 

  50. Buck CB, Thompson CD (2007) Production of papillomavirus-based gene transfer vectors. Curr Protoc Cell Biol, Chapter 26 (Unit 26 21)

    Google Scholar 

  51. Richards RM, Lowry DR, Schiller JT et al (2006) Cleavage of the papillomavirus minor capsid protein, L2 at a furin consensus site is necessary for infection. Proc Natl Acad Sci U S A 103:1522–1527

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. AbeY OM, Inagaki F et al (1998) Disulfide bond structure of human epidermal growth factor receptor. J Biol Chem 273:11150–11157

    Article  Google Scholar 

  53. Gschwind A, Zwick E, Prenzel N et al (2001) Cell communication networks: epidermal growth factor receptor transactivation as the paradigm for intereceptor signal transmission. Oncogene 30:1594–1600

    Article  Google Scholar 

  54. Poling JS, Ma XJ, Bui S et al (2014) Human papillomavirus (HPV) status of non-tobacco related squamous cell carcinoma of the lateral tongue. Oral Oncol 50:306–310

    Article  CAS  PubMed  Google Scholar 

  55. Pytynia KB, Dahlstrom KR, Sturgis EM (2014) Epidemiology of HPV-associated oropharynx cancer. Oral Oncol 50:380–386

    Article  PubMed  Google Scholar 

  56. Termine N, Panzarella V, Falaschini S et al (2008) HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988-2007). Ann Oncol 19:1681–1690

    Article  CAS  PubMed  Google Scholar 

  57. Smith EM, Rubenstein LM, Haugen TH et al (2010) Tobacco and alcohol use increases the risk of both HPV-associated and HPV-independent head and neck cancers. Cancer Causes Control 21:1369–1378

    Article  PubMed  Google Scholar 

  58. Smith EM, Rubenstein LM, Haugen TH et al (2012) Complex etiology underlies risk and survival in head and neck cancer human papillomavirus, tobacco, and alcohol: a case for multifactor disease. J Oncol 2012:571862. doi:10.1155/2012/571862

    Article  PubMed Central  PubMed  Google Scholar 

  59. Salaspuro V, Nyfors S, Heine R et al (1999) Ethanol oxidation and acetaldehyde production in vitro by human intestinal strains of Escherichia coli under aerobic, microaerobic, and anaerobic conditions. Scand J Gastroenterol 34:967–973

    Article  CAS  PubMed  Google Scholar 

  60. Park NH, Min BM, Li SL et al (1991) Immortalization of normal human oral keratinocytes with type 16 human papillomavirus. Carcinogenesis 12:1627–1631

    Article  CAS  PubMed  Google Scholar 

  61. Ranhand JM (1974) Simple, inexpensive procedure for the disruption of bacteria. J Appl Microbiol 28:66–69

    CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from NIH National Cancer Institute (CA162537). We thank Dr. Mark Herzberg for sending us 14 oral Streptococcus laboratory strains. We thank Drs. Antonia Kolokythas, Mulokozi Lugakingira, and Michael Miloro for collecting human oral buccal keratinocytes and other technical assistance.

Author information

Authors and Affiliations

  1. Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Lin Tao, Sylvia I. Pavlova & Ling Jin

  2. 81st Dental Squadron, Keesler Air Force Base, Biloxi, MS, USA

    Stephen R. Gasparovich

  3. Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Joel Schwartz

Authors
  1. Lin Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sylvia I. Pavlova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen R. Gasparovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ling Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joel Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lin Tao .

Editor information

Editors and Affiliations

  1. Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA

    Vasilis Vasiliou

  2. Distilled Spirits Council of the United States, Washington, District of Columbia, USA

    Samir Zakhari

  3. Centre of Alcohol Research, University of Heidelberg, Germany and Salem Medical Centre, Heidelberg, Germany

    Helmut K. Seitz

  4. Department of Pathology, Anatomy, & Cell, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Jan B. Hoek

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this paper

Cite this paper

Tao, L., Pavlova, S.I., Gasparovich, S.R., Jin, L., Schwartz, J. (2015). Alcohol Metabolism by Oral Streptococci and Interaction with Human Papillomavirus Leads to Malignant Transformation of Oral Keratinocytes. In: Vasiliou, V., Zakhari, S., Seitz, H., Hoek, J. (eds) Biological Basis of Alcohol-Induced Cancer. Advances in Experimental Medicine and Biology, vol 815. Springer, Cham. https://doi.org/10.1007/978-3-319-09614-8_14

Download citation

Publish with us

Policies and ethics

Search

Navigation