Epigenetic and Post-transcriptional Regulation of Cancer-associated Genes in the Avian Ovarian Carcinomas

Abstract

Ovarian Cancer is the most lethal gynecological disease among women due to difficult to diagnose at early stage and lack of molecular biomarkers. To overcome this limitations and obstacles, research is required to gain a better understanding of ovarian carcinogenesis mechanisms both genetics and epigenetics in avian species, especially laying hens which are the best animal model for research on human ovarian carcinogenesis. The aims of this study with laying hens were to determine: 1) the expression of DNA methyltransferases (DNMTs), cyclins, cyclin dependent kinases and their inhibitors, and pleiotrophin (PTN) gene in normal and cancerous ovaries

2) whether these genes are regulated by post-transcriptional actions of specific microRNAs

and 3) methylation patterns of several specific genes.

DNMTs are key regulators of DNA methylation and have crucial roles in carcinogenesis, embryogenesis and epigenetic modification. 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.

The cell cycle system is controlled in a timely manner by three groups of cyclins, cyclin dependent kinases and their inhibitors. Abnormal alterations of cell cycle regulatory mechanisms are a common feature of many diseases including numerous tumor types such as ovarian cancer. Results of the present study demonstrated increased expression of cell cycle-related genes in cancerous ovaries of laying hens and indicate that expression of these genes is post-transcriptionally regulated by specific microRNAs.

PTN is a developmentally-regulated growth factor which is widely distributed in various tissues and also detected in many kinds of carcinomas. Our results indicated that PTN is most abundant in the GE of adenocarcinoma of cancerous, but not normal ovaries of hens. Bisulfite sequencing revealed that 30- and 40% of -1311 and -1339 CpG sites are demethylated in ovarian cancer cells, respectively. Further, several microRNAs, specifically miR-499 and miR-1709 were discovered to influence PTN expression via its 3′-UTR which suggests that post-transcriptional regulation influences PTN expression in chickens.

Collectively, this present study provides new insights into epigenetic regulation and functional roles in ovarian carcinogenesis in laying hens that are highly relevant to the development of therapies for treatment of ovarian cancers in humans. As well as, it absolutely provides better approach to identify epithelial derived human ovarian cancer.