title: Alcohol metabolism by oral streptococci and interaction with human papillomavirus leads to malignant transformation of oral keratinocytes.
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.
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL, 60612, USA, ltao@uic.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Tao
authors.forename: Sylvia I
authors.initials: SI
authors.lastname: Pavlova
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Gasparovich
authors.forename: Ling
authors.initials: L
authors.lastname: Jin
authors.forename: Joel
authors.initials: J
authors.lastname: Schwartz
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism; D001422:Bacterial Adhesion; D002471:Cell Transformation, Neoplastic; D000431:Ethanol / Q000378:metabolism* / Q000633:toxicity; D052162:Human papillomavirus 16 / Q000472:pathogenicity*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology*; D009062:Mouth Neoplasms / Q000209:etiology*; D054773:Streptococcus gordonii / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D000431:Ethanol; D000079:Acetaldehyde