Abstract
The importance of the Piwi-interacting RNA (piRNA) pathway for germ cell maintenance, genome integrity, DNA methylation and retrotransposon control raises possible roles of this pathway in cancer. Indeed aberrant expression of human PIWI orthologs and Maelstrom has been observed in various cancers. In this study we explored the expression and function of piRNA pathway genes in human ovarian cancer, based on our recent work, which showed widespread expression of piRNA pathway genes in the mammalian. Our work shows that PIWIL1 and MAEL expression is significantly increased in malignant EOC (n = 25) compared to benign tumor tissues (n = 19) and normal ovarian tissue (n = 8). The expression of PIWIL3 is lower in malignant and benign tissues when compared to normal ovary. Sequencing of PIWIL1 transcript revealed that in many tumors deletion of exon 17 leads to the introduction of a premature stop codon in the PIWI domain, likely due to a splicing error. In situ hybridization on tumor sections revealed that L1, PIWIL1, 2 and MAEL are specifically expressed in epithelial cells (cancerous cells) of EOC. Furthermore, PIWIL2 and MAEL are co-expressed in the stromal cells adjacent to tumor cells. Since PIWIL1 and MAEL are up regulated in malignant EOC and expressed in the epithelial cells, we investigated if these two genes affect invasiveness of ovarian cancer cell lines that do not normally express these genes. PIWIL1 and MAEL were transiently over expressed in the ovarian cancer cell line SKOV3, followed by real-time measurements of cell invasiveness. Surprisingly both PIWIL1 and MAEL over expression decreased the invasiveness of SKOV3 cells. Our findings support a growing body of evidence that shows that genes in this pathway are upregulated in cancer. In ovarian cancer we show for the first time that Piwil1 transcript may often be abnormal result in non functional product. In contrast to what has been observed in other cell types, we found that PIWIL1 and MAEL have a repressive effect on cell invasiveness.
Highlights
Ovarian cancer is the most lethal gynaecological cancer, and the fifth leading cause of cancer-related death among women in the Western World [1]
Expression of Piwi-interacting RNA (piRNA) pathway genes is increased in malignant EOC compared to benign tumors or normal ovarian tissues piRNA pathway genes are consistently expressed in the mammalian ovary [11]
In order to investigate a possible role of this pathway in EOC, we performed semi-quantitative RT-PCR to investigate the expression of PIWIL1, PIWIL2, PIWIL3, PIWIL4 and MAEL in advanced stage serous EOC (n = 25), benign ovarian tumors (n = 19) and normal ovarian tissue (n = 8) (Table 1, Table S3 and Fig. 1A, B)
Summary
Ovarian cancer is the most lethal gynaecological cancer, and the fifth leading cause of cancer-related death among women in the Western World [1]. The five-year relative survival rate for women with ovarian cancer is only around 40% [1]. Ovarian cancers are heterogeneous tumors which exhibit distinct morphological characteristics, genetic mutations and origins. There are three major types of ovarian cancer - epithelial, germ cell and sex cord stromal tumors. Ovarian germ cell tumors and sex cord stromal tumors comprise 10% of ovarian cancers, and are derived from primitive ovarian germ cells or mesenchymal cells in the sexcord derived tissue of the ovary, respectively [2]. EOCs account for more than 90% of ovarian malignancies. Based on histology EOCs are classified into four main subtypes (serous, mucinous, endometroid and clear cell carcinomas) with over 70% of the cases diagnosed as serous carcinomas (SCs) [3]
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