Abstract
DNA methyltransferases (DNMTs) are key regulators of DNA methylation and have crucial roles in carcinogenesis, embryogenesis and epigenetic modification. In general, DNMT1 has enzymatic activity affecting maintenance of DNA methylation, whereas DNMT3A and DNMT3B are involved in de novo methylation events. Although DNMT genes are well known in mammals including humans and mice, they are not well studied in avian species, especially the laying hen which is recognized as an excellent animal model for research on human ovarian carcinogenesis. Results of the present study demonstrated that expression of DNMT1, DNMT3A and DNMT3B genes was significantly increased, particularly in the glandular epithelia (GE) of cancerous ovaries, but not normal ovaries. Consistent with this result, immunoreactive 5-methylcytosine protein was predominantly abundant in nuclei of stromal and GE cells of cancerous ovaries, but it was also found that, to a lesser extent, in nuclei of stromal cells of normal ovaries. Methylation-specific PCR analysis detected hypermethylation of the promoter regions of the tumor suppressor genes in the initiation and development of chicken ovarian cancer. Further, several microRNAs, specifically miR-1741, miR-16c, and miR-222, and miR-1632 were discovered to influence expression of DNMT3A and DNMT3B, respectively, via their 3′-UTR which suggests post-transcriptional regulation of their expression in laying hens. Collectively, results of the present study demonstrated increased expression of DNMT genes in cancerous ovaries of laying hens and post-transcriptional regulation of those genes by specific microRNAs, as well as control of hypermethylation of the promoters of tumor suppressor genes.
Highlights
Ovarian cancer is the most common malignancy in the female genital tract in the United States, and the fifth leading cause of cancer-related deaths among women
Key findings of the present study were that expression of the DNMT1, DNMT3A and DNMT3B genes are abundantly expressed only in glandular epithelia (GE) of cancerous ovaries as compared to normal ovaries of laying hens, and that expression of DNMT3A and DNMT3B genes are post-transcriptionally regulated by miR-1741, miR-16c, miR222, or miR-1632, respectively
We mainly focused on multiple epigenetic mechanisms involved in the regulation of DNA methyltransferases (DNMTs) genes in normal and cancerous ovaries of laying hens, which are the most relevant animal model to identify biomarkers of human ovarian cancer such as CA125, cytokeratin, EGFR, Lewis Y, and erbB-2 and expressed in carcinoma cells, but not normal cells in ovaries of laying hens [15,16,17,18]
Summary
Ovarian cancer is the most common malignancy in the female genital tract in the United States, and the fifth leading cause of cancer-related deaths among women. The early diagnosis of epithelial ovarian cancer and prediction of prognosis for patient survival using specific biomarkers is increasingly recognized as a better approach to identify this disease. To overcome these limitations and obstacles and to elucidate the etiology and pathogenesis of epithelial ovarian cancer, various genetically engineered rodent models have been developed and they are very useful; the artificial nature of the induced tumors in rodents limits their clinical relevance [4,5,6]. The laying hen is the only established animal model that spontaneously develops ovarian surface epithelium-derived tumors. Laying hen animal model shares a number of common pathological features and histological subtypes with human ovarian cancer. [4,5,7]
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