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KISS1 Suppresses Apoptosis and Stimulates the Synthesis of E2 in Porcine Ovarian Granulosa Cells.

ABSTRACT: Previous studies have strongly recommended that KISS-1 metastasis suppressor (KISS1) plays an essential gatekeeper of the initiation of reproductive maturation in mammals. However, KISS1 has been recently reported to highly express in ovarian granulosa cells (GCs). But the biological functionalities of KISS1 on cell apoptosis, cell cycle, and synthesis of estradiol-17? (E2) have not been explored in GCs. In this study, using porcine GCs as a cellular model, the overexpression plasmid of KISS1 was built to explore the biological effects of KISS1 on the PI3K signaling pathway, estrogen signaling pathway, cell apoptosis, cell cycle, and E2 secretion. We found that mRNA of KISS1 highly expressed in the ovary and significantly increased from immature to mature follicles in gilts. Overexpression of KISS1 could significantly increase the mRNA expression of PIK3CG, PIK3C1, and PDK1, and significantly decreased the mRNA levels of FOXO3, TSC2, and BAD of PI3K signaling pathway. Furthermore, results of the flow cytometry showed that overexpression of KISS1 significantly inhibited the apoptosis of GCs and decreased the percentage of GCs at G0/G1 phase of the cell cycle. Additionally, overexpression of KISS1 could increase the mRNA levels of Star, CYP17, 3B-HSD, 17B-HSD of estrogen synthesis signaling pathway, significantly increase the concentration of E2 in the supernatant of the cultured GCs, and up-regulate the mRNA expression levels of ESR1 and ESR2. These results suggested that KISS1 might suppress cell apoptosis through activating the PI3K signaling pathway and stimulate synthesis of E2 via boosting the estrogen synthesis signaling pathway. This study would be of great interests for exploring the biological functionalities of KISS1 in the folliculogenesis and sex steroid production of the ovaries in mammals.

SUBMITTER: Xin X

PROVIDER: S-EPMC6406274 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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KISS1 Suppresses Apoptosis and Stimulates the Synthesis of E2 in Porcine Ovarian Granulosa Cells.

Xin Xiaoping X Li Zhonghui Z Zhong Yuyi Y Li Qingqing Q Wang Jiaying J Zhang Hao H Yuan Xiaolong X Li Jiaqi J Zhang Zhe Z

Animals : an open access journal from MDPI 20190212 2

Previous studies have strongly recommended that KISS-1 metastasis suppressor (KISS1) plays an essential gatekeeper of the initiation of reproductive maturation in mammals. However, KISS1 has been recently reported to highly express in ovarian granulosa cells (GCs). But the biological functionalities of KISS1 on cell apoptosis, cell cycle, and synthesis of estradiol-17β (E2) have not been explored in GCs. In this study, using porcine GCs as a cellular model, the overexpressio ...[more]

PMID: 30759773

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Project description:BackgroundIn mammals, it is known that the estradiol-17β (E2) is mainly synthetized in ovarian granulosa cells (GCs), and the excessive apoptosis of GCs induces the follicular atresia. Many studies have implicated the essential role of KISS1, with the pro-synthetic effect of E2 and the anti-apoptotic effect on GCs, in the mammalian folliculogenesis, and several STAT4 potential binding sites were previously predicted on the promoter of KISS1 in pigs. However, the biological effects of STAT4 on GCs and the molecular regulation between STAT4 and KISS1 remained largely unknown.MethodsUsing the porcine GCs as the cellular model, the overexpression plasmid, small interfering RNA, 5'-deletion and luciferase assay were applied to investigate the molecular mechanisms for STAT4 regulating the expression of KISS1.ResultsIn this study, the STAT4 negatively regulated the mRNA and protein levels of KISS1 in porcine GCs, and the mRNA level of STAT4 was observed to significantly decrease from immature to mature follicles, which was inversed with that of KISS1. The relative luciferase activity of KISS1 promoter was significantly increased with deletion of the fourth potential binding site (- 305/- 295), and ChIP further confirmed that the STAT4 bound at - 305/- 295 region of KISS1. Besides, the STAT4 significantly regulated the mRNA levels of PDK1, FOXO3 and TSC2 of PI3K signaling pathway to promote the cell apoptosis and the percentage of cells at G0/G1 phase of cell cycle in GCs. Alternatively, the STAT4 significantly decreased the mRNA levels of CYP17, 3B-HSD, 17B-33 HSD, ESR1, and ESR2, as well as the concentration of E2 in GCs. Furthermore, interfering with the expression of STAT4 was observed to significantly stimulate the pro-synthetic effect of E2 and anti-apoptotic effect of KISS1 in GCs.ConclusionsCollectively, the STAT4 might directly target at - 305/- 295 region of KISS1 to negatively regulate the transcription of KISS1, promote the cell apoptosis via PI3K signaling pathway, suppress the synthesis of E2 through the estrogen signaling pathway in porcine GCs. These proposed works could provide useful insight in further investigations on the molecular functionalities of STAT4 and KISS1 in the folliculogenesis of mammals.

Dataset Information

KISS1 Suppresses Apoptosis and Stimulates the Synthesis of E2 in Porcine Ovarian Granulosa Cells.

Publications

KISS1 Suppresses Apoptosis and Stimulates the Synthesis of E2 in Porcine Ovarian Granulosa Cells.

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