Frontiers in Endocrinology (Feb 2021)
TOX3 Promotes Ovarian Estrogen Synthesis: An RNA-Sequencing and Network Study
- Yuanyuan Man,
- Yuanyuan Man,
- Yuanyuan Man,
- Yuanyuan Man,
- Yuanyuan Man,
- Rusong Zhao,
- Rusong Zhao,
- Rusong Zhao,
- Rusong Zhao,
- Rusong Zhao,
- Xueying Gao,
- Xueying Gao,
- Xueying Gao,
- Xueying Gao,
- Xueying Gao,
- Yue Liu,
- Yue Liu,
- Yue Liu,
- Yue Liu,
- Yue Liu,
- Shigang Zhao,
- Shigang Zhao,
- Shigang Zhao,
- Shigang Zhao,
- Shigang Zhao,
- Gang Lu,
- Wai-Yee Chan,
- Peter C. K. Leung,
- Yuehong Bian,
- Yuehong Bian,
- Yuehong Bian,
- Yuehong Bian,
- Yuehong Bian
Affiliations
- Yuanyuan Man
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Yuanyuan Man
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Yuanyuan Man
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Yuanyuan Man
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Yuanyuan Man
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
- Rusong Zhao
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Rusong Zhao
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Rusong Zhao
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Rusong Zhao
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Rusong Zhao
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
- Xueying Gao
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Xueying Gao
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Xueying Gao
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Xueying Gao
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Xueying Gao
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
- Yue Liu
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Yue Liu
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Yue Liu
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Yue Liu
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Yue Liu
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
- Shigang Zhao
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shigang Zhao
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Shigang Zhao
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shigang Zhao
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Shigang Zhao
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
- Gang Lu
- CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Wai-Yee Chan
- CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Peter C. K. Leung
- Department of Obstetrics and Gynaecology, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
- Yuehong Bian
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Yuehong Bian
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
- Yuehong Bian
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Yuehong Bian
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- Yuehong Bian
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
- DOI
- https://doi.org/10.3389/fendo.2020.615846
- Journal volume & issue
-
Vol. 11
Abstract
BackgroundWomen who undergo chronic exposure to excessive estrogen are at a high risk of developing breast cancer. TOX3 has been reported to be highly expressed in breast tumors and is closely related to estrogen receptors. However, the effect of TOX3 on estrogen synthesis remains poorly understood.MethodsUsing lentiviruses as a vector, we stably overexpressed TOX3 in the ovarian granulosa cell line KGN, the cells where estradiol is primarily produced, to investigate its role in estrogen production as well as cell viability and apoptosis. RNA-Sequencing was applied to uncover the global gene expression upon TOX3 overexpression.ResultsWe observed an increased level of cell viability and a reduced cell apoptosis rate after TOX3 overexpression, and the level of estradiol in the cell culture supernatant also increased significantly. Gene set enrichment analysis of the transcriptome showed that the ovarian steroidogenesis pathway was significantly enriched. Similarly, pathway mapping using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses also showed that TOX3 overexpression affects the ovarian steroidogenesis pathway. Further experiments showed that upregulated FSHR, CYP19A1, and BMP6 accounted for the enhanced estrogen synthesis.ConclusionOur study demonstrated that TOX3 quantitatively and qualitatively stimulates estrogen synthesis by enhancing estrogen signaling pathway–related gene expression in ovarian granulosa cells. These findings suggest that TOX3 may play a vital role in the pathogenesis of breast cancer.
Keywords
