Amphiregulin mediates hCG-induced StAR expression and progesterone production in human granulosa cells

Fang, Lanlan; Yu, Yiping; Zhang, Ruizhe; He, Jiehua; Sun, Yingpu

doi:10.1038/srep24917

Cited by 34 publications

(28 citation statements)

References 39 publications

(59 reference statements)

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“…AREG has been shown to bind exclusively to EGFR 32 . Our recent study shows that AREG treatment induces EGFR down-regulation in human granulosa cells 33 . In the present study, AREG-induced activation of ERK1/2 signaling was significantly attenuated by knockdown of SPRY2.…”

Section: Discussionmentioning

confidence: 90%

hCG-induced Sprouty2 mediates amphiregulin-stimulated COX-2/PGE2 up-regulation in human granulosa cells: a potential mechanism for the OHSS

Cheng

Fang

Chang

et al. 2016

Sci Rep

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Sprouty2 (SPRY2) is an important intracellular regulator for epidermal growth factor receptor (EGFR)-mediated ERK1/2 signaling. In human granulosa cells, although SPRY2 is expressed, its regulation and function remains complete unknown and must be defined. Our previous study has shown that human chorionic gonadotropin (hCG)/luteinizing hormone (LH) up-regulates the expression levels of EGF-like growth factor, amphiregulin (AREG), which subsequently contributes to the hCG/LH-induced COX-2 expression and PGE2 production. The aim of the present study was to investigate the effect of hCG on SPRY2 expression and the role of hCG-induced SPRY2 in AREG-stimulated COX-2 expression and PGE2 production in human granulosa cells. Our results demonstrated that the expression of SPRY2 was up-regulated by hCG treatment. Using pharmacological inhibitors and siRNA knockdown, we showed that activation of ERK1/2 signaling was required for hCG-induced up-regulation of SPRY2 expression. Further, SPRY2 knockdown attenuated the AREG-induced COX-2 expression and PGE2 production by inhibiting AREG-activated ERK1/2 signaling. Interestingly, we showed that SPRY2 expression levels were significantly increased in granulosa cells of ovarian hyperstimulation syndrome (OHSS) patients. These results for the first time elucidate the physiological roles of SPRY2 in human granulosa cells and suggest that aberrant expression of SPRY2 may contribute to the pathogenesis of OHSS.

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Section: Discussionmentioning

confidence: 90%

hCG-induced Sprouty2 mediates amphiregulin-stimulated COX-2/PGE2 up-regulation in human granulosa cells: a potential mechanism for the OHSS

Cheng

Fang

Chang

et al. 2016

Sci Rep

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“…Under the regulation of gonadotropic hormones and cytokines, a series of changes, including proliferation, differentiation, and apoptosis, occurs in granulosa cells (18,22). At the same time, granulosa cells also synthesize steroid hormones, such as estradiol (E 2 ) and progesterone (P 4 ) (12,46). The existing evidence indicates that paracrine, juxtacrine, and gap junction signaling plays important roles in the interaction between granulosa cells and oocytes (38,43).…”

mentioning

confidence: 99%

ATF6 knockdown decreases apoptosis, arrests the S phase of the cell cycle, and increases steroid hormone production in mouse granulosa cells

Xiong

Chen

Lin

et al. 2017

American Journal of Physiology-Cell Physiology

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Activating transcription factor 6 (ATF6), a sensor protein located in the endoplasmic reticulum (ER) membrane, is an important factor in the ER stress signaling pathway. ER stress is known to be involved in folliculogenesis, follicular growth, and ovulation; however, the physiological function of ATF6 in mouse granulosa cells remains largely unknown. The aim of this study was to assess the role of ATF6 in mouse granulosa cells with respect to apoptosis, the cell cycle, and steroid hormone production, as well as several key genes related to follicular development, via RNA interference, immunohistochemical staining, real-time quantitative PCR, Western blotting, flow cytometry, terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling (TUNEL) assay, and ELISA. Immunohistochemical staining revealed that ATF6 was extensively distributed in the granulosa cells of various ovarian follicles and oocytes in adult female mice. FSH or LH treatment significantly increased ATF6 protein levels in mouse granulosa cells. In the meantime, a recombinant plasmid was used to deplete ATF6 successfully using short hairpin RNA-mediated interference technology, which was verified at both the mRNA and protein levels. Flow cytometry and TUNEL assay analysis indicated that ATF6 depletion decreased apoptosis and arrested the S phase of the cell cycle in mouse granulosa cells. Consistent with these results, ,, ,, ,, and mRNA expression decreased, whereas and mRNA expression increased. Interestingly, ATF6 knockdown obviously increased progesterone and estradiol production in mouse granulosa cells. () mRNA levels were downregulated, whereas ,, and mRNA levels were upregulated, in keeping with the changes in steroid hormones. Furthermore, ATF6 disruption remarkably increased () expression and decreased (), (), and () expression in mouse granulosa cells, which are proteins crucial for follicular development. But, after treating with tunicamycin, the levels of ,, and increased relatively, whereas expression decreased. Collectively, these results imply that ATF6, as a key player in ER stress signaling, may regulate apoptosis, the cell cycle, steroid hormone synthesis, and other modulators related to folliculogenesis in mouse granulosa cells, which may indirectly be involved in the development, ovulation, and atresia of ovarian follicles by affecting the physiological function of granulosa cells. The present study extends our understanding and provides new insights into the physiological significance of ATF6, a key signal transducer of ER stress, in ovarian granulosa cells.

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“…On the contrary, immortalized steroidogenic granulosa cells and primary rat and human granulosa cells show an increase in STAR expression and progesterone production when cells were subjected to ERK1/2 inhibition 15 , 16 . Nonetheless, another study has shown that ERK1/2 inhibition attenuated STAR expression and progesterone synthesis in primary cell cultures of human granulosa cells 68 . In our in vivo bovine model, the LH-induced increase in STAR mRNA granulosa cells was not abolished by ERK1/2 inhibition.…”

Section: Discussionmentioning

confidence: 98%

ERK1/2-dependent gene expression in the bovine ovulating follicle

Schuermann

Rovani

Gasperin

et al. 2018

Sci Rep

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Ovulation is triggered by gonadotropin surge-induced signaling cascades. To study the role of extracellular signal-regulated kinase 1/2 (ERK1/2) in bovine ovulation, we administered the pharmacological inhibitor, PD0325901, into the preovulatory dominant follicle by intrafollicular injection. Four of five cows treated with 50 µM PD0325901 failed to ovulate. To uncover the molecular basis of anovulation in ERK1/2-inhibited cows, we collected granulosa and theca cells from Vehicle and PD0325901 treated follicles. Next-generation sequencing of granulosa cell RNA revealed 285 differentially expressed genes between Vehicle and PD0325901-treated granulosa cells at 6 h post-GnRH. Multiple inflammation-related pathways were enriched among the differentially expressed genes. The ERK1/2 dependent LH-induced genes in granulosa cells included EGR1, ADAMTS1, STAT3 and TNFAIP6. Surprisingly, PD0325901 treatment did not affect STAR expression in granulosa cells at 6 h post-GnRH. Granulosa cells had higher STAR protein and theca cells had higher levels of STAR mRNA in ERK1/2-inhibited follicles. Further, both granulosa and theca cells of ERK1/2-inhibited follicles had higher expression of SLC16A1, a monocarboxylate transporter, transporting substances including β-hydroxybutyrate across the plasma membrane. Taken together, ERK1/2 plays a significant role in mediating LH surge-induced gene expression in granulosa and theca cells of the ovulating follicle in cattle.

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Amphiregulin mediates hCG-induced StAR expression and progesterone production in human granulosa cells

Cited by 34 publications

References 39 publications

hCG-induced Sprouty2 mediates amphiregulin-stimulated COX-2/PGE2 up-regulation in human granulosa cells: a potential mechanism for the OHSS

hCG-induced Sprouty2 mediates amphiregulin-stimulated COX-2/PGE2 up-regulation in human granulosa cells: a potential mechanism for the OHSS

ATF6 knockdown decreases apoptosis, arrests the S phase of the cell cycle, and increases steroid hormone production in mouse granulosa cells

ERK1/2-dependent gene expression in the bovine ovulating follicle

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