Abstract
Hyperplastic candidiasis is characterized by thickening of the mucosal epithelia with Candida albicans infection with occasional progression to squamous cell carcinoma (SCC). C. albicans is a critical factor in tumor development; however, the oncogenic mechanism is unclear. We have previously produced an animal model for hyperplastic candidiasis in the rat forestomach. In the present study, we investigate whether impaired DNA methylation and associated protein expression of tumor suppressor and DNA repair genes are involved in the SCC carcinogenesis process using this hyperplastic candidiasis model. Promoter methylation and protein expression were analyzed by methylation specific PCR and immunohistochemical staining, respectively, of 5 areas in the forestomachs of alloxan-induced diabetic rats with hyperplastic candidiasis: normal squamous epithelia, squamous hyperplasia, squamous hyperplasia adjacent to SCC, squamous hyperplasia transitioning to SCC, and SCC. We observed nuclear p16 overexpression despite increases in p16 gene promoter methylation during the carcinogenic process. TIMP3 and RAR-β2 promoter methylation progressed until the precancerous stage but disappeared upon malignant transformation. In comparison, TIMP3 protein expression was suppressed during carcinogenesis and RAR-β2 expression was attenuated in the cytoplasm but enhanced in nuclei. ERCC1 and BRCA1 promoters were not methylated at any stage; however, their protein expression disappeared beginning at hyperplasia and nuclear protein re-expression in SCC was observed only for ERCC1. These results suggest that aberrant p16, RAR-β2, TIMP3, ERCC1, and BRCA1 expression might occur that is inconsistent with the respective gene promoter methylation status, and that this overexpression might serve to promote the inflammatory carcinogenesis caused by C. albicans infection.
Highlights
Candida albicans (C. albicans) is known to induce oral, esophageal, and vaginal candidiasis [1]
We investigated the association of aberrant DNA methylation and protein expression of tumor suppressor and DNA repair genes with the process of multistep carcinogenesis using our animal model for hyperplastic candidiasis and determined the potential role such changes might play in the mechanism underlying squamous cell carcinoma (SCC)
We demonstrated that altered expression of p16, RAR-β2, TIMP3, BRCA1 and ERCC1 was associated with the carcinogenic process of SCC subsequent to chronic inflammation and C. albicans infection
Summary
Candida albicans (C. albicans) is known to induce oral, esophageal, and vaginal candidiasis [1]. We have reported that alloxan-induced diabetic rats frequently developed severe mucosal proliferative lesions with C. albicans and bacterial infection in the forestomach and that these lesions progressed to squamous cell carcinoma (SCC) [6, 7]. The basal cells of the hyperplastic mucosa infiltrate beyond the muscularis mucosa to its submucosa in the carcinogenesis process; this invasive carcinoma represents a well-differentiated SCC with desmoplasia As this progression is similar to that observed in oral and/or esophageal hyperplastic candidiasis in humans, we were convinced that our model might be suitable to analyze the mechanism of multistep carcinogenesis in C. albicans-induced SCC.
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