Downregulation of LHCGR Attenuates COX-2 Expression and Induces Luteinized Unruptured Follicle Syndrome in Endometriosis

Abstract

An association between endometriosis and luteinized unruptured follicle syndrome (LUFs) has long been identified. Although inactivating mutation of luteinizing hormone/choriogonadotropin receptor (LHGCR) results in LUFs, whether LHCGR contributes to promoting LUFs in endometriosis remains elusive. To investigate the effect of LHCGR signaling in the development of endometriosis-associated LUFs and dissect the underlying mechanism in vivo mouse endometriosis model was established to measure the effect on ovarian folliculogenesis. In vitro cultures of primary human GCs collected from patients undergoing in vitro fertilization were performed and treated with human chorionic gonadotropin (hCG), dibutyryl cyclic-AMP (db-cAMP), LHCGR or CCAAT/enhancer binding protein-α (C/EBPα) small interfering RNA to identify the potential mechanisms. KGN cell line was used to investigate the mechanistic features of transcriptional regulation. Results showed an increased incidence of LUFs was observed in mice with endometriosis. The expression of LHCGR was decreased in the GCs of endometriosis mice. In in vitro cell models, LHCGR signaling increased the expression of C/EBPα and cyclooxygenase-2(COX-2), while inhibiting C/EBPα mitigated the induced COX-2 expression. Mechanically, C/EBPα bounded to the promoter region of COX-2 and increased the transcriptional activity under the stimulation of hCG or db-cAMP. Taken together, this study demonstrated that the LHCGR signaling was reduced in GCs of endometriosis and resulted in a decrease in gonadotropin-induced COX-2 expression. Our study might provide new insights into the dysfunction of GCs in endometriosis.

Screening and identification of key biomarkers associated with endometriosis using bioinformatics and next generation sequencing data analysis

“…Signaling pathways include extracellular matrix organization [101], nervous system development [102], signal transduction [103], hemostasis [104], muscle contraction [105], signaling by retinoic acid [106] and diseases of glycosylation [107] were responsible for advancement of endometriosis. Altered expression of L1CAM [108], HSD17B2 [109], VCAM1 [110], SOX6 [111], FGF10 [112], MMP12 [113], CCR1 [114], PROK1 [115], PRL (prolactin) [116], TIMP3 [117], ADAMTS9 [118], NDNF (neuron derived neurotrophic factor) [119], LHCGR (luteinizing hormone/choriogonadotropin receptor) [120], PDGFB (platelet derived growth factor subunit B) [121], LDLR (low density lipoprotein receptor) [122], CD4 [123], FOXL2 [124], TRPA1 [125], ADRB2 [126], PLAU (plasminogen activator, urokinase) [127], EPCAM (epithelial cell adhesion molecule) [128], UCN2 [129], CYP1A1 [130], NTN1 [131], IL15 [132], BMP2 [133], APOE (apolipoprotein E) [134], CASP1 [135], ABCG2 [136], ACE (angiotensin I converting enzyme) [137], PGR (progesterone receptor) [138], ALPP (alkaline phosphatase, placental) [139], LPAR4 [140], ATRNL1 [141], HLA-C [142], MMP3 [143], PDLIM3 [144], NFASC (neurofascin) [145], IL33 [146], NGF (nerve growth factor) [147], COMP (cartilage oligomeric matrix protein) [148], FST (follistatin) [149], EFEMP1 [150], GATA6 [151], TCF21 [152], PTGS2 [153], HOXC8 [154], AKR1C3 [155], BDNF (brain derived neurotrophic factor) [119], EPHA3 [156], INHBA (inhibin subunit beta A) [157], RAP1GAP [158], TLR3 [159], NOX4 [160], TGFBI (transforming growth factor beta induced) [161], IGF2BP1 [162], DLX5 [163], VDR (vitamin D receptor) [164], F...…”

Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats

“…LH and hCG enhance Cox-2 gene expression by activating the transcription factor CCAAT/enhancer binding protein-α (C/EBPα), which interacts with the Cox-2 gene promoter. Of decisive importance in this effect of gonadotropins is their stimulating effect on the LH/hCG receptor-G s protein-adenylate cyclase-cAMP-protein kinase A signaling pathway, especially since the effect of LH and hCG is reproduced using non-hydrolyzable cAMP analogs [81]. A significant increase in the expression of the LH/hCG receptor in granulosa cells during the the preovulatory period plays an important role in the control of the expression of the Cox-2 gene since the weakening of Lhcgr gene expression during this period or inactivation of mutations in this gene suppress the gonadotropin-induced peak of COX-2 expression and reduce the level of prostaglandin E2, which interferes with the normal course of ovulation.…”

“…A significant increase in the expression of the LH/hCG receptor in granulosa cells during the the preovulatory period plays an important role in the control of the expression of the Cox-2 gene since the weakening of Lhcgr gene expression during this period or inactivation of mutations in this gene suppress the gonadotropin-induced peak of COX-2 expression and reduce the level of prostaglandin E2, which interferes with the normal course of ovulation. This is characteristic of endometriosis and the closely associated luteinized unruptured follicle (LUF) syndrome [81]. Suppression of COX-2 expression by knocking out the gene encoding this enzyme, as well as pharmacological antagonists of COX-2, have similar effects, and the administration of exogenous prostaglandin E2 significantly normalizes the ovulation process [82][83][84].…”