Abstract 2531: The mechanism of HPV oncogenes in the regulation of upstream microRNA pathway in cervical cancer

Abstract

Abstract High risk Human Papillomavirus (HPVs) is a very important etiological agent in cervical cancer. HPV types have been subdivided into low-risk types and high-risk types, which are frequently associated with invasive cervical cancer. HPV16 and HPV18 count for 70% of cervical cancer. The E6, E7 genes in the early region of HPV genome are proved to have a significant impact on progression of cervical cancer. miRNA is a kind of short non-coding RNA which regulates the gene expression on post-transcriptional and translational level, and it has been proved to have a significant impact on tumor development. Our group previously investigated the correlation of miRNAs and HPV oncogenes, and identified several differentially expressed miRNAs in cervical cancer cell lines and clinical specimens. The expression level of miR-145, miR-195 and miR-142-3p were down-regulated in cervical cancer patients. However, whether the HPV oncogenes regulate miRNAs is still unknown. In order to determine the relationship between HPV oncogenes and miRNAs. We did several experiments. We found that up/down-regulate HPV 16/18 E6 and E7 caused an decrease/increase of BRCA1, miR-145 and miR-195, and BRCA1 could increase the expression of miR-145 and miR-195 in different cell lines transfected with HPV 16/18 E6 and E7 by using qRT-PCR and Western-blot. We also found the binding activity of E2F1 and MYC to the promoter region of BRCA1, which validated by ChIP-PCR and Luciferase assay. These pathways were also validated in tumor xenograft nude mice. We also tried to find the target genes of miR-145 and miR-195, and investigated how they affect tumorigenesis in cervical cancer. These findings provided a solid foundation that HPV 16/18 E6 and E7 regulated miR-145 and miR-195 via BRCA1 in cervical cancer. It can be an important pathway for the pathogenesis of cervical cancer induced by high risk HPV. These findings could provide new ways in diagnosis and treatment for cervical cancer. They also give a new insight to investigate molecular pathways for HPV-associated cancers. We believe that further investigation will be done for the mechanisms in the future. Citation Format: Yi Song, Yan Deng, Tao Tang, Chi Chiu Wang. The mechanism of HPV oncogenes in the regulation of upstream microRNA pathway in cervical cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2531.