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.

Tumour microbiota structure predicts hypopharyngeal carcinoma recurrence and metastasis

“…In addition, few studies have investigated the relationship between HPV and microbial communities in the hypopharynx. In our study, the HPV-positive cohort was proven to have an increased abundance of specific microbes, particularly Streptococcus , consistent with other studies [ 25 , 26 ]. Streptococcus promotes HPV infection by expressing furin-like peptidases and is involved in ethanol metabolism, resulting in carcinogenesis [ 25 , 26 ].…”

“…In our study, the HPV-positive cohort was proven to have an increased abundance of specific microbes, particularly Streptococcus , consistent with other studies [ 25 , 26 ]. Streptococcus promotes HPV infection by expressing furin-like peptidases and is involved in ethanol metabolism, resulting in carcinogenesis [ 25 , 26 ]. According to our results, patients with different abundances of key taxa presented different prognoses, indicating that the abundances of the two screened genera enable better prediction of recurrence in HPSCC patients than clinical variables, leading to the conclusion that microbiota examination may be an encouraging approach for clinical application.…”

Streptococcus endopeptidases promote HPV infection in vitro

“…In our previous publications, we reported that Streptococcus promotes HPV16 entry into oral keratinocytes and oral squamous cell carcinoma cells. These suggest a possible interplay for Streptococcus and other similar bacteria to contribute to HPV16 entry (Schwartz et al., ; Tao, Pavlova, Gasparovich, Jin, & Schwartz, ). It is, therefore, reasonable to investigate how these microorganisms could play a role in determining HPV tissue tropism, and subsequently, how they might contribute to the development of tissue‐specific neoplasia.…”

The environmental pollutant and tobacco smoke constituent dibenzo[def,p]chrysene is a co-factor for malignant progression of mouse oral papillomavirus infections

“…Other co-factors that have been implicated thus far include UV-exposure [11] and HCV infections [12]. Furthermore, in vitro cell culture studies using oral keratinocytes showed co-operation between HPV and tobacco carcinogens [13][14][15], alcohol metabolism by streptococci [16], and EBV-co-infections [17,18]. Early diagnosis of HPV-HNSCC in patients is challenging due to patients often first presenting at the clinic with a neck mass representing an advanced stage of disease [19].…”