Effects of acetaldehyde on C-Jun/AP-1 expression in oral keratinocytes.

摘要

Oral cancer is a significant health problem, particularly among individuals that ingest alcohol in combination with the use of tobacco products. The enhanced development of tobacco-initiated oral cancers by ethanol suggests that ethanol or one of its metabolites may act as a type of tumor promoter. Nevertheless, the mechanisms underlying the ability of ethanol to enhance oral carcinogenesis remain unclear. We hypothesize that acetaldehyde, the first metabolite of ethanol, may activate the expression and/or activity of Jun/AP-1 in oral keratinocytes analogous to the phorbol ester TPA and other tumor promoters in epidermal keratinocytes. We also hypothesize that acetaldehyde, and indirectly ethanol, may play a role during the progression stage of oral carcinogenesis by activating Jun/AP-1 expression and/or activity in transformed cells for the facilitation and/or maintenance of the malignant phenotype. To test this hypothesis, we treated HPV immortalized, non-tumorigenic human oral keratinocytes as well as transformed human oral keratinocytes, SCC-25, with acetaldehyde at various concentrations (10 μM–5 mM) and for various times (2–24h) and measured several parameters of Jun/AP-1 expression and function. Our results indicated that c-Jun mRNA and protein levels increased in the acetaldehyde treated cells compared to untreated control cells in both the non-tumorigenic and transformed cell lines. Moreover, Jun/AP-1 DNA binding activity was rapidly activated in the HPV-immortalized and transformed cells by acetaldehyde in a dose-dependent fashion. The increases in Jun protein and AP-1 DNA binding activity were accompanied by increased transactivation of an AP-1 responsive reporter construct transfected into the HPV-immortalized oral keratinocytes. The levels of acetaldehyde employed were minimally toxic to the HPV-immortalized cells as determined by MTT assays. Thus, acetaldehyde was found to activate the expression and activity of an oncogenic transcription factor in HPV-initiated cells as well as transformed malignant cells. Taken together, these results suggest that acetaldehyde may participate, at least in part, during both the promotion and progression stages of oral carcinogenesis.