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Chandras, C., T. E. Harris, A. López Bernal, D. R. E. Abayasekara, and A. E. Michael. "PTGER1 and PTGER2 receptors mediate regulation of progesterone synthesis and type 1 11β-hydroxysteroid dehydrogenase activity by prostaglandin E2 in human granulosa–lutein cells." Journal of Endocrinology 194, no. 3 (September 2007): 595–602. http://dx.doi.org/10.1677/joe-07-0128.
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In luteinizing granulosa cells, prostaglandin E2 (PGE2) can exert luteotrophic actions, apparently via the cAMP signalling pathway. In addition to stimulating progesterone synthesis, PGE2 can also stimulate oxidation of the physiological glucocorticoid, cortisol, to its inactive metabolite, cortisone, by the type 1 11β-hydroxysteroid dehydrogenase (11βHSD1) enzyme in human granulosa–lutein cells. Having previously shown these human ovarian cells to express functional G-protein coupled, E-series prostaglandin (PTGER)1, PTGER2 and PTGER4 receptors, the aim of this study was to delineate the roles of PTGER1 and PTGER2 receptors in mediating the effects of PGE2 on steroidogenesis and cortisol metabolism in human granulosa–lutein cells. PGE2-stimulated concentration-dependent increases in both progesterone production and cAMP accumulation (by 1.9 ± 0.1- and 18.7 ± 6.8-fold respectively at 3000 nM PGE2). While a selective PTGER1 antagonist, SC19220, could partially inhibit the steroidogenic response to PGE2 (by 55.9 ± 4.1% at 1000 nM PGE2), co-treatment with AH6809, a mixed PTGER1/PTGER2 receptor antagonist, completely abolished the stimulation of progesterone synthesis at all tested concentrations of PGE2 and suppressed the stimulation of cAMP accumulation. Both PGE2 and butaprost (a preferential PTGER2 receptor agonist) stimulated concentration-dependent increases in cortisol oxidation by 11βHSD1 (by 42.5 ± 3.1 and 40.0 ± 3.0% respectively, at PGE2 and butaprost concentrations of 1000 nM). Co-treatment with SC19220 enhanced the ability of both PGE2 and butaprost to stimulate 11βHSD1 activity (by 30.2 ± 0.2 and 30.5 ± 0.6% respectively), whereas co-treatment with AH6809 completely abolished the 11βHSD1 responses to PGE2 and butaprost. These findings implicate the PTGER2 receptor–cAMP signalling pathway in the stimulation of progesterone production and 11βHSD1 activity by PGE2 in human granulosa–lutein cells.
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Miyoshi, Moe, Masayuki Sato, Kenji Saito, Lila Otani, Katsuhiko Shirahige, Fumihito Miura, Takashi Ito, Huijuan Jia, and Hisanori Kato. "Maternal Protein Restriction Alters the Renal Ptger1 DNA Methylation State in SHRSP Offspring." Nutrients 10, no. 10 (October 5, 2018): 1436. http://dx.doi.org/10.3390/nu10101436.
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We previously reported that maternal protein restriction (LP) during pregnancy increases salt sensitivity in offspring using the Stroke-Prone Spontaneously Hypertensive Rat (SHRSP). In the present study, we focus on DNA methylation profiles of prostaglandin E receptor 1 gene (ptger1), which is known to be associated with hypertension. We evaluated the ptger1 DNA methylation status via bisulfite sequencing, and analyzed the expression of ptger1-related genes. The results of these analyses showed that, compared to controls, the LP-S offspring exhibited both marked ptger1 hypermethylation, and significantly increased ptger1 expression. Moreover, they also exhibited significantly decreased expression of the downstream gene epithelial Na+ channel alpha (enacα). Interestingly, LP offspring that were provided with a standard water drinking supply (W) also exhibited increased ptger1 methylation and expression. Together, these results suggest that maternal protein restriction during pregnancy modulates the renal ptger1 DNA methylation state in SHRSP offspring, and thereby likely mediates ptger1 and enacα gene expression to induce salt sensitivity.
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González, Luz María, Nicolás Roberto Robles, Sonia Mota-Zamorano, José Manuel Valdivielso, Juan López-Gómez, and Guillermo Gervasini. "Genetic Variants in PGE2 Receptors Modulate the Risk of Nephrosclerosis and Clinical Outcomes in These Patients." Journal of Personalized Medicine 11, no. 8 (August 6, 2021): 772. http://dx.doi.org/10.3390/jpm11080772.
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Prostaglandin E2 (PGE2) is a major actor mediating renal injury. We aimed to determine genetic variability in the genes coding for its receptors (PTGER1-4) and study associations with nephrosclerosis risk and clinical outcomes. We identified 96 tag-SNPs capturing global variability in PTGER1-4 and screened 1209 nephrosclerosis patients and controls. The effect of these variants was evaluated by multivariate regression analyses. Two PTGER3 SNPs, rs11209730 and rs10399704, remained significant in a backward elimination regression model with other non-genetic variables (OR = 1.45 (1.07–1.95), p = 0.016 and OR = 0.71 (0.51–0.99), p = 0.041, respectively). In the nephrosclerosis patients, a proximal region of PTGER3 was tagged as relevant for eGFR (p values for identified SNPs ranged from 0.0003 to 0.038). Two consecutive PTGER3 SNPs, rs2284362 and rs2284363, significantly decreased systolic (p = 0.005 and p = 0.0005), diastolic (p = 0.039 and p = 0.005), and pulse pressure values (p = 0.038 and 0.014). Patients were followed for a median of 47 months (7–54) to evaluate cardiovascular (CV) risk. Cox regression analysis showed that carriers of the PTGER1rs2241360 T variant had better CV event-free survival than wild-type individuals (p = 0.029). In addition, PTGER3rs7533733 GG carriers had lower event-free survival than AA/AG patients (p = 0.011). Our results indicate that genetic variability in PGE2 receptors, particularly EP3, may be clinically relevant for nephrosclerosis and its associated CV risk.
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Kowalewski, Mariusz Pawel, Hakki Bülent Beceriklisoy, Christiane Pfarrer, Selim Aslan, Hans Kindahl, Ibrahim Kücükaslan, and Bernd Hoffmann. "Canine placenta: a source of prepartal prostaglandins during normal and antiprogestin-induced parturition." REPRODUCTION 139, no. 3 (March 2010): 655–64. http://dx.doi.org/10.1530/rep-09-0140.
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Expression of cyclooxygenase 2 (COX2, now known as PTGS2), prostaglandin E2 synthase (PTGES, PGES), and prostaglandin F2α synthase (PGFS), of the respective receptors PTGFR (FP), PTGER2 (EP2), and PTGER4 (EP4) and of the progesterone receptor (PGR, PR) was assessed by real-time PCR, immunohistochemistry (IHC), or in situ hybridization (ISH) in utero/placental tissue samples collected from three to five bitches on days 8–12 (pre-implantation), 18–25 (post-implantation), and 35–40 (mid-gestation) of pregnancy and during the prepartal luteolysis. Additionally, ten mid-pregnant bitches were treated with the antiprogestin aglepristone (10 mg/kg bw (2×/24 h)); ovariohysterectomy was 24 and 72 h after the second treatment. Plasma progesterone and 15-ketodihydro-PGF2α (PGFM) concentrations were determined by RIA. Expression of the PGR was highest before implantation and primarily located to the endometrium; expression in the placenta was restricted to the decidual cells. PTGS2 was constantly low expressed until mid-gestation; a strong upregulation occurred at prepartal luteolysis concomitant with an increase in PGFM. PGFS was upregulated after implantation and significantly elevated through early and mid-gestation. PTGES showed a gradual increase and a strong prepartal upregulation. PTGFR, PTGER2, and PTGER4 were downregulated after implantation; a gradual upregulation of PTGFR and PTGER2 occurred towards parturition. ISH and IHC co-localized PGFS, PTGFR, PTGES, and PTGS2 in the trophoblast and endometrium. The changes following application of aglepristone were in the same direction as those observed from mid-gestation to prepartal luteolysis. These data suggest that the prepartal increase of PGF2α results from a strong upregulation of PTGS2 in the fetal trophoblast with the withdrawal of progesterone having a signalling function and the decidual cells playing a key role in the underlying cell-to-cell crosstalk.
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Zschockelt, Lina, Olga Amelkina, Marta J. Siemieniuch, Mariusz P. Kowalewski, Martin Dehnhard, Katarina Jewgenow, and Beate C. Braun. "Synthesis and reception of prostaglandins in corpora lutea of domestic cat and lynx." Reproduction 152, no. 2 (August 2016): 111–26. http://dx.doi.org/10.1530/rep-16-0180.
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Felids show different reproductive strategies related to the luteal phase. Domestic cats exhibit a seasonal polyoestrus and ovulation is followed by formation ofcorpora lutea(CL). Pregnant and non-pregnant cycles are reflected by diverging plasma progesterone (P4) profiles. Eurasian and Iberian lynxes show a seasonal monooestrus, in which physiologically persistent CL (perCL) support constantly elevated plasma P4 levels. Prostaglandins (PGs) represent key regulators of reproduction, and we aimed to characterise PG synthesis in feline CL to identify their contribution to the luteal lifespan. We assessed mRNA and protein expression of PG synthases (PTGS2/COX2, PTGES, PGFS/AKR1C3) and PG receptors (PTGER2, PTGER4, PTGFR), and intra-luteal levels of PGE2and PGF2α. Therefore, CL of pregnant (pre-implantation, post-implantation, regression stages) and non-pregnant (formation, development/maintenance, early regression, late regression stages) domestic cats, and prooestrous Eurasian (perCL, pre-mating) and metoestrous Iberian (perCL, freshCL, post-mating) lynxes were investigated. Expression ofPTGS2/COX2, PTGES and PTGER4 was independent of the luteal stage in the investigated species. High levels of luteotrophic PGE2in perCL might be associated with persistence of luteal function in lynxes. Signals for PGFS/AKR1C3 expression were weak in mid and late luteal stages of cats but were absent in lynxes, concomitant with low PGF2αlevels in these species. Thus, regulation of CL regression by luteal PGF2αseems negligible. In contrast, expression of PTGFR was evident in nearly all investigated CL of cat and lynxes, implying that luteal regression, e.g. at the end of pregnancy, is triggered by extra-luteal PGF2α.
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Thibodeau, Jean-François, Rania Nasrallah, Anthony Carter, Ying He, Rhian Touyz, Richard L. Hébert, and Christopher R. J. Kennedy. "PTGER1 Deletion Attenuates Renal Injury in Diabetic Mouse Models." American Journal of Pathology 183, no. 6 (December 2013): 1789–802. http://dx.doi.org/10.1016/j.ajpath.2013.08.022.
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Nuttinck, Fabienne, Brigitte Marquant-Le Guienne, Laetitia Clément, Pierrette Reinaud, Gilles Charpigny, and Bénédicte Grimard. "Expression of genes involved in prostaglandin E2 and progesterone production in bovine cumulus–oocyte complexes during in vitro maturation and fertilization." REPRODUCTION 135, no. 5 (May 2008): 593–603. http://dx.doi.org/10.1530/rep-07-0453.
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Prostaglandin E2(PGE2) and progesterone appear to be critical mediators of cumulus expansion and the resumption of oocyte meiosis. The aim of this study was to identify the types of prostaglandin E synthase (PTGES) expressed in the bovine cumulus–oocyte complex (COC), to characterize their temporal expression during the periconceptional interval using anin vitromodel of maturation (IVM) and fertilization (IVF), and to compare their expression with the level of steroidogenic gene expression. Real-time RT-PCR analysis revealed that enzymes related to the PGE2biosynthesis pathway were mainly expressed during IVM. Transcripts encoding PTGES1–3 were detected in bovine COCs. Only the expression of PTGES1 significantly increased during IVM whereas that of PTGES2 and PTGES3 remained unchanged. The induction of PTGES1 expression paralleled the induction of prostaglandin G/H synthase-2 (PTGS2) expression and the amounts of PGE2secreted by maturing COCs. Concomitantly, cholesterol side chain cleavage cytochrome P450 expression was significantly upregulated in maturing COCs and the high level of expression persisted in fertilized COCs. The expression of the StAR protein remained constant during IVM and then decreased significantly during IVF. Expression of the progesterone catabolic-related enzyme, 20α-hydroxysteroid dehydrogenase significantly decreased throughout the periconceptional interval. This was associated with a rising level of progesterone released by COCs in the culture media. In conclusion, our results suggest that the periconceptional differentiation of the bovine COC includes the transient induction of PGE2biosynthetic activity via the PTGS2/PTGES1 pathway during the maturation period and the increasing ability to produce progesterone from the immature to the fertilized stages.
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Waclawik, Agnieszka, Piotr Kaczynski, and Henry N. Jabbour. "Autocrine and Paracrine Mechanisms of Prostaglandin E2 Action on Trophoblast/Conceptus Cells through the Prostaglandin E2 Receptor (PTGER2) during Implantation." Endocrinology 154, no. 10 (October 1, 2013): 3864–76. http://dx.doi.org/10.1210/en.2012-2271.
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The conceptus and endometrium secrete large amounts of prostaglandin E2 (PGE2) into the porcine uterine lumen during the periimplantation period. We hypothesized that PGE2 acts on conceptus/trophoblast cells through auto- and paracrine mechanisms. Real-time RT-PCR analysis revealed that PGE2 receptor (PTGER)2 mRNA was 14-fold greater in conceptuses/trophoblasts on days 14–25 (implantation and early placentation period) vs preimplantation day 10–13 conceptuses (P < .05). Similarly, expression of PTGER2 protein increased during implantation. Conceptus expression of PTGER4 mRNA and protein did not differ on days 10–19. PGE2 stimulated PTGER2 mRNA expression in day 15 trophoblast cells through PTGER2 receptor signaling. PGE2 elevated aromatase expression and estradiol-17β secretion by trophoblast cells. Moreover, PGE2 and the PTGER2 agonist, butaprost, increased the adhesive capacity of both human HTR-8/SVneo trophoblast and primary porcine trophoblast cells to extracellular matrix. This PGE2-induced alteration in trophoblast cell adhesion to extracellular matrix was abolished by incubation of these cells with AH6809 (PTGER2 antagonist), ITGAVB3-directed tetrapeptide arg-gly-asp-ser or integrin ITGAVB3 antibody. PGE2 stimulated adhesion of porcine trophoblast cells via the estrogen receptor and MEK/MAPK signaling pathway. PGE2 induced phosphorylation of MAPK1/MAPK3 through PTGER2 and up-regulated expression of cell adhesion proteins such as focal adhesion kinase and intercellular adhesion molecule-1. Our study indicates that elevated PGE2 in the periimplantation uterine lumen stimulates conceptus PTGER2 expression, which in turn promotes trophoblast adhesion via integrins, and synthesis and secretion of the porcine embryonic signal estradiol-17β. Moreover, the mechanism through which PGE2 increases trophoblast adhesion is not species specific because it is PTGER2- and integrin-dependent in both porcine and human trophoblast cells.
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Jamshed, Laiba, Genevieve A. Perono, Shanza Jamshed, Kim Ann Cheung, Philippe J. Thomas, and Alison Holloway. "The Effects of Naphthenic Acids on Tryptophan Metabolism and Peripheral Serotonin Signalling." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A493. http://dx.doi.org/10.1210/jendso/bvab048.1008.
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Abstract Introduction: Serotonin produced in the periphery has been shown to affect glucose and lipid homeostasis. The availability of the amino acid tryptophan, the precursor of serotonin, affects serotonin availability. In addition, the metabolism of tryptophan via the kynurenine pathway produces physiologically active metabolites which have been shown to be altered under conditions of increased adiposity and dysglycemia. There is now evidence demonstrating some environmental xenobiotics, known to affect glucose and lipid homeostasis, can also alter serotonin production and key components of the kynurenine pathway. Recent evidence suggests that exposure to compounds present in petroleum and wastewaters from oil and gas extraction sites can impact endocrine signaling and result in aberrant lipid accumulation and altered glycemic control. However, whether any of these changes can be causally ascribed to altered serotonin synthesis/signaling or tryptophan metabolism remains unknown. The goal of this study was to determine the effects of exposure to naphthenic acid (NA), a key toxicant found in wastewater from bitumen (thick crude oil present in oil sands deposits) extraction on the enzymes involved in tryptophan metabolism and serotonin production. Methods: McA-RH7777 rat hepatoma cells, were exposed to a technical NA mixture for 48 hours at concentrations within the reported range of NA found in wastewaters from oil extraction. We assessed mRNA expression for key rate-limiting enzymes involved in tryptophan metabolism that lead to either serotonin [Tph1] and/or kynurenine [Ido2 and Tdo2] production, as well as downstream enzymes in the kynurenine pathway [Afmid, Kyat1, Aadat, Kyat3, Kmo, Haao, Acmsd, Qprt]. We also examined the effects of NA on prostaglandin synthesis [Ptgs1, Ptgs2, Ptges] and signalling [Ptger2, Ptger4] as prostaglandins have been shown to be induced by serotonin and are linked to hepatic fat accumulation. Results: NA treatment significantly increased Tph1 and Ido2 expression; this occurred in association with a significant increase in the expression of the inducible prostaglandin synthase Ptgs2 (COX-2), prostaglandin E synthase Ptges, and prostaglandin receptors Ptger2 and Ptger4. Acmsd was the only downstream enzyme in the kynurenine pathway that was significantly altered by NA treatment. Conclusion: These results provide proof-of-concept that compounds associated with oil sands extraction have the potential to perturb key components of serotonin synthesis (Tph1) and tryptophan metabolism (Ido2, Acmsd). Furthermore, we found that the increase in Tph1 expression paralleled expression of Ptgs2. As increased prostaglandin production has been reported in association with nonalcoholic steatohepatitis, these data provide a potential mechanism by which exposure to NA and other petroleum-based compounds may increase the risk of metabolic disease.
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Zhao, Xin-mei, Yuan-Bin Li, Peng Sun, Ya-di Pu, Meng-jie shan, and Yuan-meng Zhang. "Bioinformatics analysis of key biomarkers for retinoblastoma." Journal of International Medical Research 49, no. 6 (June 2021): 030006052110222. http://dx.doi.org/10.1177/03000605211022210.
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Objective To identify key genes involved in occurrence and development of retinoblastoma. Methods The microarray dataset, GSE5222, was downloaded from the gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) between unilateral and bilateral retinoblastoma were identified and functional enrichment analysis performed. The protein–protein interaction (PPI) network was constructed and analysed by STRING and Cytoscape. Results DEGs were mainly associated with activation of cysteine-type endopeptidase activity involved in apoptotic process and small molecule catabolic process. Seven genes (WAS, GNB3, PTGER1, TACR1, GPR143, NPFF and CDKN2A) were identified as HUB genes. Conclusion Our research provides more understanding of the mechanisms of the disease at a molecular level and may help in the identification of novel biomarkers for retinoblastoma.
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Plaza-Serón, María del Carmen, Pedro Ayuso, Natalia Pérez-Sánchez, Inmaculada Doña, Natalia Blanca-Lopez, Carlos Flores, Luisa Galindo, et al. "Copy number variation in ALOX5 and PTGER1 is associated with NSAIDs-induced urticaria and/or angioedema." Pharmacogenetics and Genomics 26, no. 6 (June 2016): 280–87. http://dx.doi.org/10.1097/fpc.0000000000000216.
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Seron, Maria Del Carmen Plaza, Pedro Ayuso Parejo, Natalia Blanca-López, Inmaculada Doña, Jose A. Cornejo-Garcia, María José Torres, Javier Fernández, et al. "Copy Number Variations In ALOX5 and PTGER1 Genes Are Associated With Susceptibility To AERD and Mnsaid-UA." Journal of Allergy and Clinical Immunology 133, no. 2 (February 2014): AB264. http://dx.doi.org/10.1016/j.jaci.2013.12.936.
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Waclawik, Agnieszka, Agnieszka Blitek, and Adam J. Ziecik. "Oxytocin and tumor necrosis factor α stimulate expression of prostaglandin E2 synthase and secretion of prostaglandin E2 by luminal epithelial cells of the porcine endometrium during early pregnancy." REPRODUCTION 140, no. 4 (October 2010): 613–22. http://dx.doi.org/10.1530/rep-10-0092.
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Oxytocin (OXT) and tumor necrosis factor α (TNF) have been implicated in the control of luteolysis by stimulating endometrial secretion of luteolytic prostaglandin F2α(PGF2α). Nevertheless, OXT concentration in porcine uterine lumen increases markedly on days 11–12 of pregnancy, and TNF is expressed in endometrium during pregnancy. The objective of the study was to determine the effect of OXT and TNF on expression of the enzymes involved in PG synthesis: PG-endoperoxide synthase 2 (PTGS2), PGE2synthase (mPGES-1) and PGF synthase, and PGE2receptor (PTGER2), as well as on PG secretion by endometrial luminal epithelial cells (LECs) on days 11–12 of the estrous cycle and pregnancy. LECs isolated from gilts on days 11–12 of the estrous cycle (n=8) and pregnancy (n=7) were treated with OXT (100 nmol/l) and TNF (0.6 nmol/l) for 24 h. OXT increasedPTGS2mRNA and mPGES-1 protein contents, as well as PGE2secretion but only on days 11–12 of pregnancy. TNF stimulatedPTGS2andmPGES-1mRNA, as well as mPGES-1 protein expression and PGE2release on days 11–12 of pregnancy and the estrous cycle. In addition, expressions of PTGER2 and PTGER4 were determined in corpus luteum (CL). Abundance ofPTGER2mRNA and PTGER4 protein in CL was upregulated on day 14 of pregnancy versus day 14 of the estrous cycle. This study indicates that TNF and OXT regulate PGE2synthesis in LECs during early pregnancy. PGE2secreted by LECs, after reaching ovaries, could have a luteoprotective effect through luteal PTGER2 and PTGER4, or may directly promote uterine function and conceptus development.
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Karaky, Mohamad, Gabrielle Boucher, Saraï Mola, Sylvain Foisy, Claudine Beauchamp, Marie-Eve Rivard, Melanie Burnette, et al. "Prostaglandins and calprotectin are genetically and functionally linked to the Inflammatory Bowel Diseases." PLOS Genetics 18, no. 9 (September 26, 2022): e1010189. http://dx.doi.org/10.1371/journal.pgen.1010189.
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Background Genome wide association studies (GWAS) have identified and validated more than 200 genomic loci associated with the inflammatory bowel disease (IBD), although for most the causal gene remains unknown. Given the importance of myeloid cells in IBD pathogenesis, the current study aimed to uncover the role of genes within IBD genetic loci that are endogenously expressed in this cell lineage. Methods The open reading frames (ORF) of 42 genes from IBD-associated loci were expressed via lentiviral transfer in the THP-1 model of human monocytes and the impact of each of these on the cell’s transcriptome was analyzed using a RNA sequencing-based approach. We used a combination of genetic and pharmacologic approaches to validate our findings in the THP-1 line with further validation in human induced pluripotent stem cell (hiPSC)-derived-monocytes. Results This functional genomics screen provided evidence that genes in four IBD GWAS loci (PTGIR, ZBTB40, SLC39A11 and NFKB1) are involved in controlling S100A8 and S100A9 genes expression, which encode the two subunits of calprotectin (CP). We demonstrated that increasing PTGIR expression and/or stimulating PTGIR signaling resulted in increased CP expression in THP-1. This was further validated in hiPSC-derived monocytes. Conversely, knocking-down PTGIR endogenous expression and/or inhibiting PTGIR signaling led to decreased CP expression. These analyses were extended to the known IBD gene PTGER4, whereby its specific agonist also led to increased CP expression. Furthermore, we demonstrated that the PTGIR and PTGER4 mediated control of CP expression was dependent on signaling via adenylate cyclase and STAT3. Finally, we demonstrated that LPS-mediated increases in CP expression could be potentiated by agonists of PTGIR and PTGER4, and diminished by their antagonists. Conclusion Our results support a causal role for the PTGIR, PTGER4, ZBTB40, SLC39A11 and NFKB1 genes in IBD, with all five genes regulating the expression of CP in myeloid cells, as well as potential roles for the prostacyclin/prostaglandin biogenesis and signaling pathways in IBD susceptibility and pathogenesis.
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Przygrodzka, E., M. M. Kaczmarek, P. Kaczynski, and A. J. Ziecik. "Steroid hormones, prostanoids, and angiogenic systems during rescue of the corpus luteum in pigs." REPRODUCTION 151, no. 2 (February 2016): 135–47. http://dx.doi.org/10.1530/rep-15-0332.
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In order to characterize the transition of the corpora lutea (CL) from acquisition of luteolytic sensitivity to rescue of luteal function: i) the expression of 38 factors associated with steroids, prostanoids, and angiogenic systems and ii) concentrations of the main hormones responsible for maintenance of CL function in cyclic and pregnant pigs were examined. Additionally, the effect of prostaglandin (PG) E2 and F2α on luteal function during the estrous cycle and pregnancy was evaluated in vitro. Significantly up-regulated gene expression was revealed in CL collected on day 14 of the estrous cycle (CYP19A1, ESR2, PTGS2, HIF1A, and EDN1) and on days 12–14 of pregnancy (SCARB1, PGRMC1, STAR, HSD3B1, NR5A1, PTGFR, PTGER4, and VEGFA). Elevated concentrations of estradiol-17β and PGE2 occurred in CL on days 12 and 14 of pregnancy respectively, while an increased intraluteal PGF2α content was noted on day 14 of the estrous cycle. Both PGs increased the synthesis of progesterone by cultured luteal slices obtained on day 14 of pregnancy, in contrast to the action of PGF2α on the corresponding day of the estrous cycle. PGE2 stimulated cAMP production via PTGER2 and PTGER4, while PGF2α elevated the content of CREB in cultured luteal slices from CL of pregnant pigs. In silico analysis showed that infiltration of lymphocytes and apoptosis of microvascular endothelium were activated in CL on day 12 of the estrous cycle vs pregnancy. Summarizing, an abundance of E2 and PGE2 during pregnancy regulates specific pathways responsible for steroidogenesis, the prostanoid signaling system and angiogenesis during rescue from luteolysis in porcine CL.
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Gillio-Meina, Carolina, Sen Han Phang, James P. Mather, Brian S. Knight, and Thomas G. Kennedy. "Expression patterns and role of prostaglandin-endoperoxide synthases, prostaglandin E synthases, prostacyclin synthase, prostacyclin receptor, peroxisome proliferator-activated receptor delta and retinoid x receptor alpha in rat endometrium during artificially-induced decidualization." REPRODUCTION 137, no. 3 (March 2009): 537–52. http://dx.doi.org/10.1530/rep-08-0294.
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To determine if changes in endometrial expression of the enzymes and receptors involved in prostaglandin (PG) synthesis and action might provide insights into the PGs involved in the initiation of decidualization, ovariectomized steroid-treated rats at the equivalent of day 5 of pseudopregnancy were given a deciduogenic stimulus and killed at various times up to 32 h thereafter. The expression of PG-endoperoxide synthases (PTGS1 and PTGS2), microsomal PGE synthases (PTGES and PTGES2), cytosolic PGE synthase (PTGES3), prostacyclin synthase (PTGIS), prostacyclin receptor, peroxisome proliferator-activated receptor δ (PPARD) and retinoid x receptor α (RXRA) in endometrium was assessed by semiquantitative RT-PCR, western blot analyses and immunohistochemistry. In addition, to determine which PG is involved in mediating decidualization, we compared the ability of PGE2, stable analogues of PGI2, L165041 (an agonist of PPARD), and docasahexanoic acid (an agonist of RXRA) to increase endometrial vascular permeability (EVP, an early event in decidualization), and decidualization when infused into the uterine horns of rats sensitized for the decidual cell reaction (DCR). EVP was assessed by uterine concentrations of Evans blue 10 h after initiation of infusions. DCR was assessed by the uterine mass 5 days after the initiation of the infusions. Because enzymes associated with the synthesis of PGE2, including PTGS2, are up-regulated in response to a deciduogenic stimulus and because PGE2 was more effective than the PGI2 analogues and PPARD and RXRA agonists in increasing EVP and inducing decidualization, we suggest that PGE2 is most likely the PG involved in the initiation of decidualization in the rat.
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Mangelsen, Eva, Michael Rothe, Angela Schulz, Aikaterini Kourpa, Daniela Panáková, Reinhold Kreutz, and Juliane Bolbrinker. "Concerted EP2 and EP4 Receptor Signaling Stimulates Autocrine Prostaglandin E2 Activation in Human Podocytes." Cells 9, no. 5 (May 19, 2020): 1256. http://dx.doi.org/10.3390/cells9051256.
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Glomerular hyperfiltration is an important mechanism in the development of albuminuria. During hyperfiltration, podocytes are exposed to increased fluid flow shear stress (FFSS) in Bowman’s space. Elevated Prostaglandin E2 (PGE2) synthesis and upregulated cyclooxygenase 2 (Cox2) are associated with podocyte injury by FFSS. We aimed to elucidate a PGE2 autocrine/paracrine pathway in human podocytes (hPC). We developed a modified liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) protocol to quantify cellular PGE2, 15-keto-PGE2, and 13,14-dihydro-15-keto-PGE2 levels. hPC were treated with PGE2 with or without separate or combined blockade of prostaglandin E receptors (EP), EP2, and EP4. Furthermore, the effect of FFSS on COX2, PTGER2, and PTGER4 expression in hPC was quantified. In hPC, stimulation with PGE2 led to an EP2- and EP4-dependent increase in cyclic adenosine monophosphate (cAMP) and COX2, and induced cellular PGE2. PTGER4 was downregulated after PGE2 stimulation in hPC. In the corresponding LC/ESI-MS/MS in vivo analysis at the tissue level, increased PGE2 and 15-keto-PGE2 levels were observed in isolated glomeruli obtained from a well-established rat model with glomerular hyperfiltration, the Munich Wistar Frömter rat. COX2 and PTGER2 were upregulated by FFSS. Our data thus support an autocrine/paracrine COX2/PGE2 pathway in hPC linked to concerted EP2 and EP4 signaling.
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Nelis, H. M., K. Goossens, B. Leemans, L. Peelman, and A. Van Soom. "220 STEROID-REGULATED mRNA EXPRESSION IN OVIDUCT EPITHELIAL CELLS IN THE MARE." Reproduction, Fertility and Development 25, no. 1 (2013): 258. http://dx.doi.org/10.1071/rdv25n1ab220.
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It is well known that oviducal physiology undergoes cyclical changes under the influence of steroid hormones associated with the establishment of an optimal microenvironment for fertilization and early embryonic development. Genes associated with the preovulatory phase are likely to be involved in modulation of gamete function and sperm storage, whereas those in the post-ovulatory phase are involved in embryonic development. So far, in the horse, no genes that change activity during the oestrous cycle, which may be important in fertilization, gamete and embryo passage, and early embryonic development, have been identified. Therefore, to identify steroid-regulated genes, we compared the mRNA expression of PAI-1, uPA, TGFA, TIMP-1, MMP-1, CSF, PTGER2, and PTGER4 in oviducal explants from mares in the pre- and the post-ovulatory early luteal stages. The cycle stage of healthy warmblood mares was determined in the slaughterhouse by assessment of ovarian morphology and uterine oedema. Oviducal explants were isolated by scraping the epithelium of oviducts ipsilateral to a preovulatory follicle or a recent corpus luteum and frozen in lysis buffer at –80°C until RNA extraction. The genes were quantified by RT-qPCR and normalized against the geometric mean of 6 validated reference genes (UBB, SDHA, 18S, TUB, ACTB, HPRT) according to the MIQE-guidelines (Bustin et al., 2009). Data were analysed using the independent samples t-test or the Mann–Whitney U-test. The mRNA expression of PAI-1, MMP-1, TGFA (0.01 < P < 0.05), and uPA (P = 0.007) was downregulated in the post-ovulatory phase, whereas no significant change in TIMP-1, CSF, PTGER2, and PTGER4 expression was observed. The results show that mRNA of components of the extracellular matrix turnover, such as PAI-1, uPA, MMP-1, and TIMP-1 as well as growth factors, such as TFGA and CSF and prostaglandin E2 receptors (PTGER2 and PTGER4), are produced. Moreover, down-regulation of PAI-1, MMP-1, TGFA, and uPA in the early luteal stage indicates that mRNA expression of these genes is steroid regulated. In other species, all these components are likely to protect gametes and the early embryo against proteolytic degradation and to stimulate embryonic development. Further transcriptome and proteome analyses are necessary to unravel changes in the oviducal epithelium during the oestrous cycle and early pregnancy in the mare.
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Hartney, John M., Kenneth G. Coggins, Stephen L. Tilley, Leigh A. Jania, Alysia Kern Lovgren, Laurent P. Audoly, and Beverly H. Koller. "Prostaglandin E2 protects lower airways against bronchoconstriction." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 1 (January 2006): L105—L113. http://dx.doi.org/10.1152/ajplung.00221.2005.
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Prostaglandin E2 (PGE2), similar to β-adrenergic receptor agonists, can protect airways from bronchoconstriction and resulting increase in airway resistance induced by a number of agents, including cholinergic receptor agonists and antigen. We examined the impact of sustained alterations in PGE2 pathways on changes in airway resistance. Genetic methods were utilized to alter PGE2 metabolism and signal transduction in the murine lung. PGE2 levels were elevated by generating mice lacking 15-hydroxyprostaglandin ( Hpgd−/−), the major catabolic enzyme of PGE2, and by generating a transgenic line in which mouse PGE2 synthase ( Ptges) expression is driven by a human lung-specific promoter, hSP-C. Conversely, to determine the impact of loss of PGE2 on airway reactivity, we examined mice lacking this synthase ( Ptges−/−) and receptors that mediate the actions of PGE2, particularly the PGE2 EP2 receptor ( Ptger2). Diminished capacity to produce and respond to PGE2 did not alter the response of mice to cholinergic stimuli. In contrast, the responsiveness to cholinergic stimulation was dramatically altered in animals with elevated PGE2 levels. The Hpgd−/− and hSP- C- Ptges transgenic lines both showed attenuated airway responsiveness to methacholine as measured by lung resistance. Thus, whereas compromise of the Ptges/PGE2/ Ptger2 pathway does not alter airway responsiveness, genetic modulation that elevates PGE2 levels in the lung attenuates airway responsiveness.
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Kim, Soon Ok, Nune Markosyan, Gerald J. Pepe, and Diane M. Duffy. "Estrogen promotes luteolysis by redistributing prostaglandin F2α receptors within primate luteal cells." REPRODUCTION 149, no. 5 (May 2015): 453–64. http://dx.doi.org/10.1530/rep-14-0412.
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Prostaglandin F2α (PGF2α) has been proposed as a functional luteolysin in primates. However, administration of PGF2α or prostaglandin synthesis inhibitors in vivo both initiate luteolysis. These contradictory findings may reflect changes in PGF2α receptors (PTGFRs) or responsiveness to PGF2α at a critical point during the life span of the corpus luteum. The current study addressed this question using ovarian cells and tissues from female cynomolgus monkeys and luteinizing granulosa cells from healthy women undergoing follicle aspiration. PTGFRs were present in the cytoplasm of monkey granulosa cells, while PTGFRs were localized in the perinuclear region of large, granulosa-derived monkey luteal cells by mid-late luteal phase. A PTGFR agonist decreased progesterone production in luteal cells obtained at mid-late and late luteal phases, but did not decrease progesterone production by granulosa cells or luteal cells from younger corpora lutea. These findings are consistent with a role for perinuclear PTGFRs in functional luteolysis. This concept was explored using human luteinizing granulosa cells maintained in vitro as a model for luteal cell differentiation. In these cells, PTGFRs relocated from the cytoplasm to the perinuclear area in an estrogen- and estrogen receptor-dependent manner. Similar to our findings with monkey luteal cells, human luteinizing granulosa cells with perinuclear PTGFRs responded to a PTGFR agonist with decreased progesterone production. These data support the concept that PTGFR stimulation promotes functional luteolysis only when PTGFRs are located in the perinuclear region. Estrogen receptor-mediated relocation of PTGFRs within luteal cells may be a necessary step in the initiation of luteolysis in primates.
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Misawa, Kiyoshi, Atsushi Imai, Takeharu Kanazawa, Masato Mima, Satoshi Yamada, Daiki Mochizuki, Taiki Yamada, et al. "G Protein-Coupled Receptor Genes, PTGDR1, PTGDR2, and PTGIR, Are Candidate Epigenetic Biomarkers and Predictors for Treated Patients with HPV-Associated Oropharyngeal Cancer." Microorganisms 8, no. 10 (September 29, 2020): 1504. http://dx.doi.org/10.3390/microorganisms8101504.
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Differences in the biology of human papillomavirus (HPV)-associated oropharyngeal cancers (OPCs) and HPV-negative OPCs may have implications in patient management. Early detection is imperative to reduce HPV-associated OPC mortality. Circulating tumor DNA (ctDNA) can potentially serve as a biomarker for monitoring clinically relevant cancer-related genetic and epigenetic modifications. We analyzed the methylation status of 24 G protein-coupled receptor (GPCR) genes in verification (85 OPC primary samples) and validation (8 OPC ctDNA samples) studies using quantitative methylation-specific polymerase chain reaction (Q-MSP). The Q-MSP-based verification study with 85 OPC primary samples revealed the GPCR genes that were significantly associated with recurrence in high methylation groups (≥14 methylated genes) with OPC and HPV-associated OPC (p < 0.001). In the Kaplan–Meier estimate and multivariate Cox proportional hazard analyses, 13 GPCR genes were significantly related to increased recurrence in the methylation group. Furthermore, the validation study on ctDNA showed that three of these genes (Prostaglandin D2 receptor 1: PTGDR1, Prostaglandin D2 receptor 2: PTGDR2, and Prostaglandin I2 Receptor: PTGIR) had a prediction performance as emerging biomarkers. We characterized the relationship between the methylation status of GPCR genes and outcomes in HPV-associated OPC. Our results highlight the potential utility of ctDNA methylation-based detection for the clinical management of HPV-associated OPC.
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Kautz, E., A. Gram, S. Aslan, S. S. Ay, M. Selçuk, H. Kanca, E. Koldaş, et al. "Expression of genes involved in the embryo–maternal interaction in the early-pregnant canine uterus." REPRODUCTION 147, no. 5 (May 2014): 703–17. http://dx.doi.org/10.1530/rep-13-0648.
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Although there is no acute luteolytic mechanism in the absence of pregnancy in the bitch, a precise and well-timed embryo–maternal interaction seems to be required for the initiation and maintenance of gestation. As only limited information is available about these processes in dogs, in this study, the uterine expression of possible decidualization markers was investigated during the pre-implantation stage (days 10–12) of pregnancy and in the corresponding nonpregnant controls. In addition, the expression of selected genes associated with blastocyst development and/or implantation was investigated in embryos flushed from the uteri of bitches used for this study (unhatched and hatched blastocysts). There was an upregulated expression of prolactin receptor (PRLR) and IGF2 observed pre-implantation. The expression of PRL and of IGF1 was unaffected, and neither was the expression of progesterone- or estrogen receptor β (ESR2). In contrast, (ESR1) levels were elevated during early pregnancy. Prostaglandin (PG)-system revealed upregulated expression of PGE2-synthase and its receptors, PTGER2 and PTGER4, and of the PG-transporter. Elevated levels of AKR1C3 mRNA, but not the protein itself, were noted. Expression of prostaglandin-endoperoxide synthase 2 (PTGS2) remained unaffected. Most of the transcripts were predominantly localized to the uterine epithelial cells, myometrium and, to a lesser extent, to the uterine stroma. PGES (PTGES) mRNA was abundantly expressed in both groups of embryos and appeared higher in the hatched ones. The expression level of IGF2 mRNA appeared higher than that of IGF1 mRNA in hatched embryos. In unhatched embryos IGF1, IGF2, and PTGS2 mRNA levels were below the detection limit.
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Walusimbi, S. S., L. M. Wetzel, D. H. Townson, and J. L. Pate. "Isolation of luteal endothelial cells and functional interactions with T lymphocytes." Reproduction 153, no. 5 (May 2017): 519–33. http://dx.doi.org/10.1530/rep-16-0578.
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The objectives of this study were to optimize the isolation of luteal endothelial cells (LEC) and examine their functional interactions with autologous T lymphocytes. Analysis by flow cytometry showed that the purity of LEC isolated by filtration was nearly 90% as indicated byBandeiraea simplicifolia(BS)-1 lectin binding. LEC expressed mRNA for progesterone receptor (PGR), prostaglandin receptors (PTGFR, PTGER2 and 4, and PTGIR), tumor necrosis factor receptors (TNFRSF1A&B) and interleukin (IL) 1B receptors (IL1R1&2). LEC were pretreated with either vehicle, progesterone (P4; 0–20 µM), prostaglandin (PG) E2or PGF2α(0–0.2 µM), and further treated with or without TNF and IL1B (50 ng/mL each). LEC were then incubated with autologous T lymphocytes in an adhesion assay. Fewer lymphocytes adhered to LEC after exposure to high compared to low P4concentrations (cubic response;P < 0.05). In contrast, 0.2 µM PGE2and PGF2αeach increased T lymphocyte adhesion in the absence of cytokines (P < 0.05). LEC induced IL2 receptor alpha (CD25) expression and proliferation of T lymphocytes. In conclusion, filtration is an effective way of isolating large numbers of viable LEC. It is proposed that PGs and P4modulate the ability of endothelial cells to bind T lymphocytes, potentially regulating extravasation, and that LEC activate T lymphocytes migrating into or resident in the CL.
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Yang, Ling, Xu Han, Leying Zhang, Ning Li, Zimo Zhao, and Jiachen Bai. "Changes in expression of prostaglandin synthase in ovine liver during early pregnancy." Canadian Journal of Animal Science 100, no. 3 (September 1, 2020): 432–39. http://dx.doi.org/10.1139/cjas-2019-0171.
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Liver can function as part of the innate and adaptive immune systems. We hypothesize that prostaglandins participate in the regulation of hepatic immune function during early pregnancy in sheep. The objective of this study was to elucidate expression of prostaglandin synthase in ovine liver during early pregnancy. Ovine livers were sampled on day 16 of the estrous cycle, and days 13, 16, and 25 of pregnancy, and the expression of prostaglandin synthases, including prostaglandin-endoperoxide synthase 1 (PTGS1), PTGS2, prostaglandin E synthase (PTGES), and aldo-keto reductase family 1, member B1, a prostaglandin F synthase (PGFS), were detected by quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry analysis. There were increases in the expression of mRNA and the proteins of PTGS2, PTGES, and PGFS in the livers during early pregnancy, but PTGS1 was decreased in the pregnant ewes. The PGFS protein was limited to the hepatocytes and the endothelial cells of the proper hepatic arteries and hepatic portal veins. In summary, the upregulation of PTGS2, PTGES, and PGFS and downregulation of PTGS1 may be involved in the maternal hepatic immune adjustment during early pregnancy in sheep.
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Williams, Joseph H., and Paulo E. Oliveira. "For things to stay the same, things must change: polyploidy and pollen tube growth rates." Annals of Botany 125, no. 6 (January 20, 2020): 925–35. http://dx.doi.org/10.1093/aob/mcaa007.
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Abstract Background and Aims Pollen tube growth rate (PTGR) is an important single-cell performance trait that may evolve rapidly under haploid selection. Angiosperms have experienced repeated cycles of polyploidy (whole genome duplication), and polyploidy has cell-level phenotypic consequences arising from increased bulk DNA amount and numbers of genes and their interactions. We sought to understand potential effects of polyploidy on several underlying determinants of PTGR – pollen tube dimensions and construction rates – by comparing diploid–polyploid near-relatives in Betula (Betulaceae) and Handroanthus (Bignoniaceae). Methods We performed intraspecific, outcrossed hand-pollinations on pairs of flowers. In one flower, PTGR was calculated from the longest pollen tube per time of tube elongation. In the other, styles were embedded in glycol methacrylate, serial-sectioned in transverse orientation, stained and viewed at 1000× to measure tube wall thicknesses (W) and circumferences (C). Volumetric growth rate (VGR) and wall production rate (WPR) were then calculated for each tube by multiplying cross-sectional tube area (πr2) or wall area (W × C), by the mean PTGR of each maternal replicate respectively. Key Results In Betula and Handroanthus, the hexaploid species had significantly wider pollen tubes (13 and 25 %, respectively) and significantly higher WPRs (22 and 18 %, respectively) than their diploid congeners. PTGRs were not significantly different in both pairs, even though wider polyploid tubes were predicted to decrease PTGRs by 16 and 20 %, respectively. Conclusions The larger tube sizes of polyploids imposed a substantial materials cost on PTGR, but polyploids also exhibited higher VGRs and WPRs, probably reflecting the evolution of increased metabolic activity. Recurrent cycles of polyploidy followed by genome reorganization may have been important for the evolution of fast PTGRs in angiosperms, involving a complex interplay between correlated changes in ploidy level, genome size, cell size and pollen tube energetics.
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Vianello, Elena, Elena Dozio, Francesco Bandera, Marco Froldi, Emanuele Micaglio, John Lamont, Lorenza Tacchini, Gerd Schmitz, and Massimiliano Marco Corsi Romanelli. "Correlative Study on Impaired Prostaglandin E2 Regulation in Epicardial Adipose Tissue and Its Role in Maladaptive Cardiac Remodeling via EPAC2 and ST2 Signaling in Overweight Cardiovascular Disease Subjects." International Journal of Molecular Sciences 21, no. 2 (January 14, 2020): 520. http://dx.doi.org/10.3390/ijms21020520.
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There is recent evidence that the dysfunctional responses of a peculiar visceral fat deposit known as epicardial adipose tissue (EAT) can directly promote cardiac enlargement in the case of obesity. Here, we observed a newer molecular pattern associated with LV dysfunction mediated by prostaglandin E2 (PGE2) deregulation in EAT in a cardiovascular disease (CVD) population. A series of 33 overweight CVD males were enrolled and their EAT thickness, LV mass, and volumes were measured by echocardiography. Blood, plasma, EAT, and SAT biopsies were collected for molecular and proteomic assays. Our data show that PGE2 biosynthetic enzyme (PTGES-2) correlates with echocardiographic parameters of LV enlargement: LV diameters, LV end diastolic volume, and LV masses. Moreover, PTGES-2 is directly associated with EPAC2 gene (r = 0.70, p < 0.0001), known as a molecular inducer of ST2/IL-33 mediators involved in maladaptive heart remodelling. Furthermore, PGE2 receptor 3 (PTEGER3) results are downregulated and its expression is inversely associated with ST2/IL-33 expression. Contrarily, PGE2 receptor 4 (PTGER4) is upregulated in EAT and directly correlates with ST2 molecular expression. Our data suggest that excessive body fatness can shift the EAT transcriptome to a pro-tissue remodelling profile, may be driven by PGE2 deregulation, with consequent promotion of EPAC2 and ST2 signalling.
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Diel de Amorim, Mariana, Claudia Klein, Robert Foster, Lynn Dong, Maria Fernanda Lopez-Rodriguez, and Claire Card. "Expression of Oxytocin/Neurophysin I and Oxytocinase in the Equine Conceptus from Day 8 to Day 21 Post-Ovulation." Animals 12, no. 7 (March 22, 2022): 799. http://dx.doi.org/10.3390/ani12070799.
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Leucyl and cystinyl aminopeptidase (LNPEP/oxytocinase) is an enzyme that metabolizes oxytocin in serum and tissues. The presence of oxytocin/neurophysin I (OXT), oxytocin and LNPEP and their relationship to other genes is unknown in the equine conceptus. Our objective was to characterize gene expression of LNPEP and OXT on D8, 10, 12, 14, 15, 16 and 21 conceptuses in relationship to other genes. Immunohistochemistry, western blot and liquid chromatography with tandem mass spectrometry (LC-MS/MS) were used for identification of oxytocin and LNPEP in D15, 16 and 18 conceptuses. LNPEP was increased at D15 compared to D10, was immunolocalized in the equine trophectoderm and endoderm, and protein was confirmed by LC-MS/MS. Maximal abundance of OXT was at D21, and lowest on D12 and D14, but no protein was identified. OXTR abundance was highest on D14 and D21. LNPEP was correlated with PTGFR and PTGES on D12 and D14–D15, and high expression of PTGES, PTGS2 was found on D14, D15 and D21; PTGFR was found on D8 and D12–21. LNPEP may have a role in prostaglandin regulation and conceptus fixation by decreasing the availability of oxytocin. Further investigation on the role embryonic LNPEP during pregnancy is warranted.
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Wang, Yingzi, Andrei V. Krivtsov, Amit U. Sinha, Trista North, Wolfram Goessling, Leonard I. Zon, and Scott Armstrong. "β-Catenin Determines Developmental Stage Specific Transformation by Hox Genes." Blood 114, no. 22 (November 20, 2009): 385. http://dx.doi.org/10.1182/blood.v114.22.385.385.
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Abstract Abstract 385 Leukemia stem cells (LSC) possess extensive proliferative and self-renewal potential similar to normal hematopoietic stem cells (HSC). Therefore understanding the similarities and differences between HSC and LSC is critical if LSC specific therapies are to be developed. Hox genes represent a group of genes that can influence both normal HSC and LSC self-renewal, and are critical targets of leukemogenic MLL fusion proteins. Previous reports have described the ability of Hoxa9 and Meis1a (HoxA9/M) to induce leukemia when expressed in mouse bone marrow (BM). However, whether HoxA9/M can fully recapitulate the leukemogenic activity of MLL fusion proteins remains unclear. In this study, we show that HoxA9/M, unlike MLL-AF9, fails to induce leukemia from granulocyte-macrophage progenitors (GMP) but does so from HSC. Immunophenotypic analysis and in vivo limiting dilution transplantation of HSC-derived leukemias demonstrate heterogeneity with only a subset of cells possessing leukemia-propagating activity. The LSC in this model have an immunophenotype consistent with differentiating myeloid cells. Gene expression analysis of LSC induced by MLL-AF9 expression in GMP and HoxA9/M expression in HSC demonstrate an approximately 10-fold increase in prostaglandin-endoperoxide synthase 1 (PTGS1) (also known as Cycloxygenase-1 or Cox-1) and prostaglandin E receptor 1 (PTGER1) expression. As recent studies have highlighted a critical connection between prostaglandin synthesis and Wnt/ β-catenin signaling pathway, we hypothesized that β-catenin is aberrantly activated in LSC derived from either GMP expressing MLL-AF9 or HSC expressing HoxA9/M. Western blots and immunofluorescence using an antibody specific for dephosphorylated (activated) β-catenin identified active β-catenin in MLL-AF9-driven and HoxA9/M-driven LSC but not normal GMP. These data suggested that insufficient β-catenin activity might be a contributing factor to the inability of HoxA9/M to transform GMP and thus we sought to determine if activated β-catenin cooperated to induce leukemia from GMP. We found that co-expression of HoxA9/M and activated β-catenin efficiently induced leukemia from GMP whereas neither expressed alone had leukemogenic activity. Next, we assessed if β-catenin is required for HoxA9/M-mediated leukemogenesis initiated from HSC. Conditional β-catenin loss-of-function experiments demonstrated impaired in vivo expansion of cells derived from HoxA9/M transduced HSC, and β-cat-/- cells did not induce leukemia. This defect could be rescued by expression of a constitutively active form of β-catenin. Finally, we demonstrate that continued β-catenin activity is required for LSC maintenance by chemical suppression of the β-catenin pathway with indomethacin (a cox-1/cox-2 inhibitor), which shows remarkable selective elimination of the LSC fraction in mice transplanted with HoxA9/M transduced HSC. Our gain and loss-of-function studies demonstrate that β-catenin activity is required for leukemia initiation from HSC, and that constitutively active β-catenin can cooperate with HoxA9/M to efficiently transform GMP. Thus, Wnt/β-catenin activity makes cells permissive to transformation, which suggests that its restricted activation to stem cell populations in normal hematopoietic development limits the permissiveness of developmental cell types to transformation by specific oncogenes. These data have important implications for tumor development in other tissues/organs and for the development of β-catenin pathway antagonists in AML. Disclosures: No relevant conflicts of interest to declare.
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Gordeuk, Victor R., Xu Zhang, Wei Zhang, Shwu-Fan Ma, Craig Sable, Galina Miasniakova, Adelina Sergueeva, et al. "Novel Putative Polymorphism in SERPINC1 Encoding Antithrombin III Is Implicated in Elevated Estimated Systolic Pulmonary Pressure in Patients with Chuvash Polycythemia." Blood 120, no. 21 (November 16, 2012): 2869. http://dx.doi.org/10.1182/blood.v120.21.2869.2869.
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Abstract Abstract 2869 Chuvash polycythemia (CP) is characterized by homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL). This rare genetic disorder causes elevated levels of hypoxia inducible factor (HIF)-1 and HIF-2 that trigger constitutive hypoxia responses at normoxia. Hypoxia is a recognized cause of pulmonary hypertension. We recently reported that systolic pulmonary artery pressure (SPAP) estimated by echocardiography-determined tricuspid regurgitation velocity (TRV) was elevated in 120 CP patients compared to 31 Chuvash controls (P = 0.005), and that increasing age (P = 0.001), increasing systemic pulse pressure (P = 0.003) and lower serum ferritin concentration (P = 0.009) were independent predictors of higher estimated SPAP in CP patients [Sable et al., 2012]. In this study, we profiled gene expression for 16,642 genes in peripheral blood mononuclear cells (PBMCs) derived from a cohort of 43 CP patients, and measured the TRV for these individuals. Based on a prospectively chosen criterion of TRV ≥2.5 m/sec, 20 patients were classified as having elevated level of estimated SPAP and 23 were normal. Gene expression level between these two SPAP groups appeared to be homogenous. However, we identified 4777 genes at false discovery rate (FDR) <0.05 that exhibit pulse pressure by SPAP group interaction, suggesting a profound difference in pulse pressure regulation between the two SPAP groups. Further analysis of probe level data revealed a potential genetic polymorphism located within exon 7 of SERPINC1, encoding antithrombin III, at a site where a disease-associated SNP has not been reported. The minor allele of this polymorphism, which we designated “B”, was highly enriched in the elevated estimated SPAP group (P=0.0009), and classification based on the putative SERPINC1 genotypes strengthens the interaction effect with pulse pressure. Analysis of the gene expression data for the 43 CP patients with an additive genetic model of SERPINC1 identified 1902 differential genes at FDR <0.05. The 1120 genes up-regulated by the B allele were highly enriched in the Reactome G-protein coupled receptor pathway (Padjusted < 8×10−10). Several genes involved in smooth muscle contraction, regulation of blood pressure, and angiogenesis were up-regulated by the putative B allele, for example, HTR5A (serotonin receptor 5A), TAC3 (tachykinin 3), ADRA1D (adrenergic alpha-1D- receptor), BDKRB1 (bradykinin receptor B1), BDKRB2 (bradykinin receptor B1), EDN2 (endothelin 2), PTGER1 (prostaglandin E receptor 1), PTGIR (prostaglandin I2 receptor), APLNR (apelin receptor), RAMP2 (receptor activity modifying protein 2), MYH6 (myosin heavy chain 6), MYH7 (myosin heavy chain 7), MYL2 (myosin light chain 2), MYLK2 (myosin light chain kinase 2), MYLK3 (myosin light chain kinase 3), ACE (angiotensin I converting enzyme 1), ATP2A1 (ATPase cardiac muscle fast twitch 1), ADCY4 (adenylate cyclase 4), and PRKAA2 (protein kinase AMP-activated alpha 2 catalytic subunit). On the other hand, genes whose malfunction has been associated with familial pulmonary hypertension, including BMPR2 (bone morphogenetic protein receptor, type II), SMAD5 (SMAD family member 5), and ACVR2A (activin A receptor, type IIA), were among the 782 genes down regulated by the B allele. These results suggest that alterations in SERPINC1 may be implicated in the development of elevated SPAP in patients with CP. Antithrombin III deficiency is a potential factor in chronic thromboembolic pulmonary hypertension, but our results suggest that the putative B polymorphism may have effects beyond the coagulation cascade. Whether this is due to the SERPINC1 polymorphism itself or to another locus in linkage disequilibrium will require our future planned studies, beginning with sequencing of SERPINC1 exon 7 and identification of the polymorphism. Disclosures: No relevant conflicts of interest to declare.
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Lee, Jia Ming, Jemma R. Mayall, Anne Chevalier, Huw McCarthy, Dirk Van Helden, Philip M. Hansbro, Jay C. Horvat, and Phillip Jobling. "Chlamydia muridarum infection differentially alters smooth muscle function in mouse uterine horn and cervix." American Journal of Physiology-Endocrinology and Metabolism 318, no. 6 (June 1, 2020): E981—E994. http://dx.doi.org/10.1152/ajpendo.00513.2019.
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Chlamydia trachomatis infection is a primary cause of reproductive tract diseases including infertility. Previous studies showed that this infection alters physiological activities in mouse oviducts. Whether this occurs in the uterus and cervix has never been investigated. This study characterized the physiological activities of the uterine horn and the cervix in a Chlamydia muridarum ( Cmu)-infected mouse model at three infection time points of 7, 14, and 21 days postinfection (dpi). Cmu infection significantly decreased contractile force of spontaneous contraction in the cervix (7 and 14 dpi; P < 0.001 and P < 0.05, respectively), but this effect was not observed in the uterine horn. The responses of the uterine horn and cervix to oxytocin were significantly altered by Cmu infection at 7 dpi ( P < 0.0001), but such responses were attenuated at 14 and 21 dpi. Cmu infection increased contractile force to prostaglandin (PGF2α) by 53–83% in the uterine horn. This corresponded with the increased messenger ribonucleic acid (mRNA) expression of Ptgfr that encodes for its receptor. However, Cmu infection did not affect contractions of the uterine horn and cervix to PGE2 and histamine. The mRNA expression of Otr and Ptger4 was inversely correlated with the mRNA expression of Il1b, Il6 in the uterine horn of Cmu-inoculated mice ( P < 0.01 to P < 0.001), suggesting that the changes in the Otr and Ptger4 mRNA expression might be linked to the changes in inflammatory cytokines. Lastly, this study also showed a novel physiological finding of the differential response to PGE2 in mouse uterine horn and cervix.
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Robertson, Sarah A., Inge Christiaens, Camilla L. Dorian, Dean B. Zaragoza, Alison S. Care, Anke M. Banks, and David M. Olson. "Interleukin-6 Is an Essential Determinant of On-Time Parturition in the Mouse." Endocrinology 151, no. 8 (June 7, 2010): 3996–4006. http://dx.doi.org/10.1210/en.2010-0063.
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IL-6 abundance in amniotic fluid and uterine tissues increases in late gestation or with infection-associated preterm labor. A role in regulation of labor onset is suggested by observations that IL-6 increases expression of genes controlling prostaglandin synthesis and signaling in isolated uterine cells, but whether IL-6 is essential for normal parturition is unknown. To evaluate the physiological role of IL-6 in parturition in mice, we investigated the effect of Il6 null mutation on the timing of parturition and expression of genes associated with uterine activation. Il6 null mutant mice delivered 24 h later than wild-type mice, although circulating progesterone fell similarly in both genotypes during the prepartal period. Il6 null mutant mice were also refractory to low doses of lipopolysaccharide sufficient to induce preterm delivery in wild-type mice. The characteristic late-gestation elevation in uterine expression of Oxtr mRNA encoding oxytocin receptor, and peripartal increases in Ptgfr and Ptgs2 mRNAs regulating prostaglandin synthesis and signaling were delayed by 24 h in Il6 null mutant mice. Conversely, Ptger4 mRNA encoding the prostaglandin E receptor-4 was abnormally elevated in late-gestation in Il6 null mutant mice. Administration of recombinant IL-6 from d 11.5 postcoitum until term restored the normal timing of delivery and normalized Ptger4 mRNA expression in late gestation. We conclude that IL-6 has a key role in controlling the progression of events culminating in parturition and that it acts downstream of luteolysis in the uterus to regulate genes involved in the prostaglandin-mediated uterine activation cascade.
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Chen, Dongjiang, Son Le, Tarun Hutchinson, and David Tran. "DDRE-13. PROSTAGLANDIN E RECEPTOR 3 (PTGER3) REGULATES RESISTANCE TO TUMOR TREATING FIELDS (TTFields) IN GLIOBLASTOMA CELLS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi77. http://dx.doi.org/10.1093/neuonc/noab196.297.
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Abstract INTRODUCTION TTFields, a novel approved therapy for GBM, employ alternating intermediate-frequency electric fields to disrupt mitotic macromolecules leading to chromosome mis-segregation and apoptosis. The addition of TTFields significantly improves survival. However, most patients eventually develop resistance to TTFields through an unknown mechanism. METHODS Multiple human GBM cell lines were treated with TTFields continuously using Inovitro, an in vitro TTFields system, until cells with relative resistance to killing by TTFields emerged. Temporal gene expression profiles were analyzed using NETZEN, an innovative deep-learning and gene network-based ranking computational algorithm, to identify resistance pathways, followed by experimental validation. RESULTS PTGER3, a Gαi-protein-coupled cell surface receptor, is the top ranked master regulator in the predicted resistance program, which is upregulated in GBM cells within 24 hrs of exposure to TTFields and further reinforced as resistance sets in. Forced expression of PTGER3 in sensitive GBM cells confers relative resistance to TTFields, while PTGER3 depletion in resistant cells re-sensitizes them to TTFields. Most importantly, pharmacological inhibition of PTGER3 using either aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors effectively prevent resistance from developing. Mechanistically, PTGER3 is rapidly translocated from the plasma membrane to the nucleus after TTFields exposure, where it interacts with ZNF488, a stemness transcription factor tightly linked to PTGER3 in our predicted network to initiate and maintain the resistance program. Indeed, TTFields resistance is associated with a transition to glioma stem cells (GSCs) as determined by increased neurosphere formation and orthotopic tumorigenesis in immunocompromised mice, and PTGER3 inhibition alone reverses the GSC transition leading to improved tumor control and survival. CONCLUSIONS PTGER3 is at the apex of a novel pathway that indispensably regulates TTFields resistance through a unique mechanism involving the physical nuclear translocation of this 7-transmembrane receptor. PTGER3 and its pathway are thus potential therapeutic targets to enhance therapeutic efficacy of TTFields.
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Murn, Jernej, Olivier Alibert, Ning Wu, Simon Tendil, and Xavier Gidrol. "Prostaglandin E2 regulates B cell proliferation through a candidate tumor suppressor, Ptger4." Journal of Experimental Medicine 205, no. 13 (December 15, 2008): 3091–103. http://dx.doi.org/10.1084/jem.20081163.
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B cell receptor (BCR) signaling contributes to the pathogenesis of B cell malignancies, and most B cell lymphomas depend on BCR signals for survival. Identification of genes that restrain BCR-mediated proliferation is therefore an important goal toward improving the therapy of B cell lymphoma. Here, we identify Ptger4 as a negative feedback regulator of proliferation in response to BCR signals and show that its encoded EP4 receptor is a principal molecule conveying the growth-suppressive effect of prostaglandin E2 (PGE2). Stable knockdown of Ptger4 in B cell lymphoma markedly accelerated tumor spread in mice, whereas Ptger4 overexpression yielded significant protection. Mechanistically, we show that the intrinsic activity of Ptger4 and PGE2–EP4 signaling target a similar set of activating genes, and find Ptger4 to be significantly down-regulated in human B cell lymphoma. We postulate that Ptger4 functions in B cells as a candidate tumor suppressor whose activity is regulated by PGE2 in the microenvironment. These findings suggest that targeting EP4 receptor for prostaglandin may present a novel strategy for treatment of B cell malignancies.
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Kamyshna, Iryna, and Aleksandr Kamyshnyi. "Transcriptional Activity of Neurotrophins Genes and Their Receptors in the Peripheral Blood in Patients with Thyroid Diseases in Bukovinian Population of Ukraine." Open Access Macedonian Journal of Medical Sciences 9, A (May 2, 2021): 208–16. http://dx.doi.org/10.3889/oamjms.2021.6037.
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Objective. Thyroid hormone has an especially strong impact on central nervous system development, and thyroid hormone deficiency has been shown to result in severe mental retardation. It is crucial to identify compensatory mechanisms that can be involved in improving cognitive function and the quality of life of patients with hypothyroidism.
Methods: We used the pathway-specific PCR array (Neurotrophins and Receptors RT2 Profiler PCR Array, QIAGEN, Germany) to identify and validate neurotrophins genes and their receptor expression in patients with thyroid pathology and control group.
Results: The analysis of gene expression of neurotrophins and their receptors showed that CRHBP, FRS2, FRS3, GFRA1, GFRA2, GMFB, NGF, NRG2, NRG4, NTF4, TRO, and VGF significantly decreased their expression in Group 3, which includes the patients with postoperative hypothyroidism. The patients with primary hypothyroidism stemming from AIT had significantly reduced expression of CRHBP, GFRA1, GFRA2, GMFB, NGF, PTGER2, and VGF, while the expression of NRG4 and TRO increased. In Group 3, which includes the patients with AIT and elevated serum anti-Tg and anti-TPO autoantibodies, the mRNA levels of GFRA2, NGF, NRG2, NTF4, NGF, PTGER were reduced, and the expression of CRHBP, FRS2, FRS3 GFRA1, GMFB, NRG4, TRO, and VGF significantly increased.
Conclusion: These results indicate significant variability in the transcriptional activity of the genes of encoding neurotrophins and their receptors in the peripheral blood in people with thyroid diseases.
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Huang, Xianping, Weihe Zhou, Yuefeng Zhang, and Yong Liu. "High Expression of PTGR1 Promotes NSCLC Cell Growth via Positive Regulation of Cyclin-Dependent Protein Kinase Complex." BioMed Research International 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/5230642.
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Lung cancer has been the most common cancer and the main cause of cancer-related deaths worldwide for several decades. PTGR1 (prostaglandin reductase 1), as a bifunctional enzyme, has been involved in the occurrence and progression of cancer. However, its impact on human lung cancer is rarely reported. In this study, we found that PTGR1 was overexpressed in lung cancer based on the analyses of Oncomine. Moreover, lentivirus-mediated shRNA knockdown of PTGR1 reduced cell viability in human lung carcinoma cells 95D and A549 by MTT and colony formation assay. PTGR1 depletion led to G2/M phase cell cycle arrest and increased the proportion of apoptotic cells in 95D cells by flow cytometry. Furthermore, silencing PTGR1 in 95D cells resulted in decreased levels of cyclin-dependent protein kinase complex (CDK1, CDK2, cyclin A2, and cyclin B1) by western blotting and then PTGR1 is positively correlated with cyclin-dependent protein by using the data mining of the Oncomine database. Therefore, our findings suggest that PTGR1 may play a role in lung carcinogenesis through regulating cell proliferation and is a potential new therapeutic strategy for lung cancer.
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Yamazaki, Atsushi, Kazuya Edamura, Yuma Tomo, Mamiko Seki, and Kazushi Asano. "Variations in gene expression levels with severity of synovitis in dogs with naturally occurring stifle osteoarthritis." PLOS ONE 16, no. 1 (January 28, 2021): e0246188. http://dx.doi.org/10.1371/journal.pone.0246188.
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Osteoarthritis (OA) is one of the major causes of chronic pain in dogs. However, the pathogenesis of OA has not been fully understood in dogs. The objective of this study was to comprehensively investigate the mRNA expression levels of proinflammatory cytokines, inflammatory mediators, nerve growth factor and its receptor, and matrix metalloproteinases in the synovium of dogs with spontaneous OA as well as to elucidate their relationships with the severity of synovitis. Dogs that were diagnosed with stifle OA on the basis of radiographic findings were included, and the degree of synovitis was observed using stifle arthroscopy. The dogs were assigned to two different groups depending on their synovitis scores: the low-grade group (score of 1 or 2; n = 8) and high-grade group (score of 3 to 5; n = 18). The dogs showing no evidence of orthopedic disease were included in the control group (n = 6). Synovial tissue samples were collected from the sites at which synovitis scores were assessed using arthroscopy. Total RNA was extracted from the collected synovial tissue, and cDNA was synthesized. Subsequently, RT-qPCR were performed using canine-specific primer sets for IL1B, IL6, CXCL8, TNF, TGFB1, PTGS2, PTGES, MMP3, MMP13, NGF, NTRK1, and PTGER4. Expression levels of IL1B, IL6, CXCL8, and MMP13 were significantly higher in the high-grade group than in the control group. In addition, expression levels of IL1B, CXCL8, TNF, and PTGS2 were significantly higher in the high-grade group than in the low-grade group. Expression levels of IL1B, IL6, CXCL8, TNF, PTGS2, and PTGER4 showed significant positive correlation with synovitis score. In conclusion, all mRNA expression levels in the synovial membrane varied according to the degree of synovitis in dogs with spontaneous OA. Thus, this study may partially elucidate the pathogenesis of synovitis in dogs with spontaneous OA.
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Kobayashi, Yoshihiko, Kaori Wakamiya, Misa Kohka, Yuki Yamamoto, and Kiyoshi Okuda. "Summer heat stress affects prostaglandin synthesis in the bovine oviduct." REPRODUCTION 146, no. 2 (August 2013): 103–10. http://dx.doi.org/10.1530/rep-12-0479.
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Summer heat stress (HS) negatively affects reproductive functions, including prostaglandin (PG) F2α secretion in the endometrium, and decreases fertility in cattle. In the present study, we examined the effects of elevated temperatures on PG synthesis in oviductal epithelial cells. The epithelial cells obtained from the ampulla and isthmus of the oviduct were incubated at various temperatures (38.5, 39.5, 40.0, and 40.5 °C) for 24 h. In the ampulla, PGE2 concentration was higher at 40.5 °C than at 38.5 °C, while PGF2α production was not affected by the temperatures in this range. The expressions of microsomal PGE synthase 1 (PTGES (mPGES1)), cytosolic PGES (PTGES3 (cPGES)), and heat shock protein 90 (HSP90AA1 (HSP90)) mRNAs and proteins were higher at 40.5 °C than at 38.5 °C in the ampullary epithelial cells. Seasonal changes in the expressions of PGES and HSP90AA1 mRNAs in oviductal tissues were also investigated. The expressions of PTGES3 and HSP90AA1 mRNAs were higher in the ampullary tissues in summer than in winter. In summary, elevated temperatures stimulated PGE2 production in the ampullary oviduct by increasing the expressions of PGESs and HSP90AA1, which can activate cPGES. The overall results suggest that HS upsets PG secretions and reduces oviductal smooth muscle motility, which in turn could decrease gamete/embryo transport through the oviduct.
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Wu, Victoria H., Alexander Wenzel, Bryan Yung, Zhiyong Wang, Jill P. Mesirov, and J. Silvio Gutkind. "Illuminating the onco-GPCRome: targeting the prostaglandin receptor-Gαs signaling axis as a novel immune checkpoint in cancer." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 165.37. http://dx.doi.org/10.4049/jimmunol.204.supp.165.37.
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Abstract Recent advances in checkpoint blockade immunotherapy (CBI) have revolutionized cancer treatment, but the limited response rates in most cancers suggest that new approaches and targets are clearly needed to fully elucidate the underlying biology of dysfunctional CD8 T cells and achieve durable responses. G-protein coupled receptors (GPCRs) are the most intensively studied drug targets as they play key roles in many physiological processes, and they have remained longstanding favorable pharmacological targets. Using novel computational approaches integrating multiple single cell RNAseq databases, we first deconvoluted tumor-infiltrating T cell heterogeneity to generate a transcriptomic GPCR signature based on coupling specificity and receptor family. Preliminary data shows an upregulation of prostaglandin receptors, PTGER2 and PTGER4, on exhausted T cells, suggesting that these GPCRs, coupled to the Gαs G protein α subunit, may contribute to diminishing anti-tumor cytotoxicity. Expression and stimulation of EP2 and EP4 on highly activated CD8 T cells and subsequent Gαs signaling decreases cytokine secretion and CXCR3-mediated migration. Additionally, blockade of EP2 and EP4 significantly decreases tumor growth in multiple immune competent, syngeneic tumor models. Altogether, we hypothesize that activation of Gαs downstream signaling cascades may be dampening the anti-tumor cytotoxicity of CD8 T cells, thereby limiting the effectiveness of PD-1 and CTLA-4 blockade. EP2 and EP4 and Gαs signaling may represent promising candidates as immune checkpoints that can be targeted in combination with CBI as part of novel multimodality precision immunotherapy approaches to reactivate the immune system to destroy tumors.
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Ayiomamitis, Georgios D., George Notas, Thivi Vasilakaki, Aikaterini Tsavari, Styliani Vederaki, Theodosis Theodosopoulos, Elias Kouroumalis, and Apostolos Zaravinos. "Understanding the Interplay between COX-2 and hTERT in Colorectal Cancer Using a Multi-Omics Analysis." Cancers 11, no. 10 (October 11, 2019): 1536. http://dx.doi.org/10.3390/cancers11101536.
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Background: Cyclooxygenase 2 (COX-2) is involved in the initial steps of colorectal cancer (CRC) formation, playing a key role in the catalysis of arachidonic acid to prostaglandin E2 (PGE2). The human telomerase reverse transcriptase (hTERT or TERT) also plays an important role in colorectal cancer growth, conferring sustained cell proliferation and survival. Although hTERT induces COX-2 expression in gastric and cervical cancer, their interaction has not been investigated in the context of CRC. Methods: COX-2, PGE2 levels, and telomerase activity were evaluated by immunohistochemistry, ELISA, and TRAP assay in 49 colorectal cancer samples. PTGS1, PTGS2, PTGES3, TERT mRNA, and protein levels were investigated using RNA-seq and antibody-based protein profiling data from the TCGA and HPA projects. A multi-omics comparison was performed between PTGS2 and TERT, using RNAseq, DNA methylation, copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and insertions/deletions (Indels) data. Results: COX-2 expression was positive in 40/49 CRCs, bearing cytoplasmic and heterogeneous staining, from moderate to high intensity. COX-2 staining was mainly detected in the stroma of the tumor cells and the adjacent normal tissues. PGE2 expression was lower in CRC compared to the adjacent normal tissue, and inversely correlated to telomerase activity in right colon cancers. COX-1 and COX-2 were anticorrelated with TERT. Isoform structural analysis revealed the most prevalent transcripts driving the differential expression of PTGS1, PTGS2, PTGES3, and TERT in CRC. COX-2 expression was significantly higher among B-Raf proto-oncogene, serine/threonine kinase, mutant (BRAFmut) tumors. Kirsten ras oncogene (KRAS) mutations did not affect COX-2 or TERT expression. The promoter regions of COX-2 and TERT were reversely methylated. Conclusions: Our data support that COX-2 is involved in the early stages of colorectal cancer development, initially affecting the tumor’s stromal microenvironment, and, subsequently, the epithelial cells. They also highlight an inverse correlation between COX-2 expression and telomerase activity in CRC, as well as differentially methylated patterns within the promoter regions of COX-2 and TERT.
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Prager, Matthias, Janine Büttner, and Carsten Büning. "PTGER4 modulating variants in Crohn’s disease." International Journal of Colorectal Disease 29, no. 8 (May 3, 2014): 909–15. http://dx.doi.org/10.1007/s00384-014-1881-3.
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Michaud, Andréanne, Nicolas Lacroix-Pépin, Mélissa Pelletier, Marleen Daris, Laurent Biertho, Michel A. Fortier, and André Tchernof. "Expression of Genes Related to Prostaglandin Synthesis or Signaling in Human Subcutaneous and Omental Adipose Tissue: Depot Differences and Modulation by Adipogenesis." Mediators of Inflammation 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/451620.
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Objectives. (1) To examine depot-specific PGE2and PGF2αrelease and mRNA expression of enzymes or receptors involved in PG synthesis or signaling in human adipose tissues; (2) to identify changes in expression of these transcripts through preadipocyte differentiation; and (3) to examine associations between adipose tissue mRNA expression of these transcripts and adiposity measurements.Methods. Fat samples were obtained surgically in women. PGE2and PGF2αrelease by preadipocytes and adipose tissue explants was measured. Expression levels of mRNA coding for enzymes or receptors involved in PG synthesis or signaling were measured by RT-PCR.Results. Cultured preadipocytes and explants from omental fat released more PGE2and PGF2αthan those from the subcutaneous depot and the corresponding transcripts showed consistent depot differences. Following preadipocyte differentiation, expression of PLA2G16 and PTGER3 mRNA was significantly increased whereas COX-1, COX-2, PTGIS, and PTGES mRNA abundance were decreased in both compartments (P≤0.01for all). Transcripts that were stimulated during adipogenesis were those that correlated best with adiposity measurements.Conclusion. Cells from the omental fat compartment release more PGE2and PGF2αthan those from the subcutaneous depot. Obesity modulates expression of PG-synthesizing enzymes and PG receptors which likely occurs through adipogenesis-induced changes in expression of these transcripts.
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Chen, Dongjiang, Son Le, Tarun Hutchinson, and David Tran. "CSIG-15. INNOVATIVE COMPUTATIONAL PLATFORM ADDRESSES PROSTAGLANDIN E RECEPTOR 3 AS THE MASTER REGULATOR MEDIATING RESISTANCE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA CELLS." Neuro-Oncology 22, Supplement_2 (November 2020): ii30—ii31. http://dx.doi.org/10.1093/neuonc/noaa215.127.
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Abstract OBJECTIVES Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. The addition of TTFields resulted in a significant improvement in overall survival. However, most GBM patients eventually develop resistance to TTFields and the mechanism remains unexplored. METHODS Multiple GBM cell lines were treated continuously at clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally. RESULTS TTFields-induced chromosomal instability is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay, stemness markers such as CD44 and increased tumorigenesis when implanted into mouse brain. Using an innovative computational platform-NETZEN, we methodically dissected this stemness program in resistant cells. 3 networks were found disrupted and all play critical roles in GBM stemness. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked regulator responsible for resistance. PTGER3 is rapidly upregulated both in vitro and in vivo upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Immunofluorescence staining shows PTGER3’s nuclear translocation along with Lamin A/C disruption in response to TTFields. Pharmacological inhibition of PTGER3 using aspirin or PTGER3-specific inhibitors resensitized or prevent cells becoming resistance to TTFields. CONCLUSIONS We have identified a novel regulator PTGER3 at the apex that plays a critical role in TTFields resistance. This is a potential therapeutic target to reduce resistance to TTFields therapy in GBM.
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Kulkarni, Aditya, Diana Restifo, Igor A. Astsaturov, Umesh Kathad, Joseph McDermott, Kishor Bhatia, and Panna Sharma. "Synthetic lethality of LP-184, a next generation acylfulvene, in ex vivo PDX models with homologous recombination defects." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15064-e15064. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15064.
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e15064 Background: The clinical success of PARP inhibitors (PARPi) in homologous recombination (HR) deficient (HRD+) solid tumors has broadened the scope of identifying additional agents and vulnerabilities in cancers with DNA repair deficiencies. However, with more than 40% of BRCA1/2-deficient patients failing to respond to PARPi or acquiring resistance with prolonged PARPi administration, newer agents are also needed. LP-184, an acylfulvene, is a prodrug activated by PTGR1. Threshold expression levels of PTGR1 are higher in several tumors, providing a window of specificity for its cytotoxic action. DNA damage inflicted by acylfulvene (AF) agents is reliant upon HR pathway genes including BRCA1 for correction and removal. We hypothesized that tumors with high PTGR1 expression and HR deficiency will therefore be uniquely targeted and demonstrate synthetic lethality when exposed to LP-184. Methods: We evaluated ex vivo antitumor activity of LP-184 in selected PDX models representing lung, pancreatic and prostate cancers with high PTGR1 and known HR defects. Dissociated tumor fragments were treated with LP-184 across a concentration range of 5 nM to 36 uM for 5 days. Cell viability was quantified by CellTiter Glo. LP-184 IC50s were compared with PARPi efficacy. We further confirmed the dependency of PTGR1 in HR deficient tumor cells by comparing LP-184 sensitivity in the BRCA2 deficient cell line CAPAN-1 and the ATM mutant cell line PANC03.27, with and without PTGR1 suppression following an engineered CRISPR knockout of PTGR1. We also analyzed TCGA data to estimate the percentage of tumors with elevated PTGR1 and co-occurring damaging mutations in a panel of 60 HR genes. Results: The mean LP-184 IC50 across 15 HRD+ PDX models tested was 288 nM (range 31 - 2900 nM). LP-184 turned out to be 6 - 340X more potent ex vivo than the PARPi Olaparib in these models. 9 of 15 models were associated with no clinical response to or initial response followed by progression on approved standard of care (SOC) agents. 6 of 15 models showed < 10% tumor growth inhibition in vivo with SOC treatment. Regardless of cancer type, models with high-impact, loss-of-function mutations in ATM, ATR and BRCA1 showed exquisite sensitivity to LP-184 (mean IC50 ̃ 60 nM). CRISPRi-mediated stable suppression of PTGR1 in the pancreatic cancer cell lines CAPAN-1 and PANC03.27 entirely abrogated LP-184 sensitivity relative to isogenic parental cell lines. 17.6% of lung adenocarcinomas (n = 517), 4.5% of pancreatic adenocarcinomas (n = 179) and 9.6% of prostate adenocarcinomas (n = 498) displayed elevated PTGR1 along with damaging HR related mutations, and are likely to be responsive to LP-184 based on analysis of TCGA data. Conclusions: LP-184 is broadly effective in HRD+ tumors that may be less responsive to SOC including PARPi and could be useful clinically in a subset of tumors with high PTGR1 and HR defects.
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Rahman, M. Jubayer, Kameron Rodrigues, Yi Liu, Yongge Zhao, Juan A. Quiel, and Kristin V. Tarbell. "PTGER4 inhibition in non-obese diabetic mice restores impaired IFNAR signaling, decreases chronic inflammatory signals and inhibits autoimmunity." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 222.18. http://dx.doi.org/10.4049/jimmunol.198.supp.222.18.
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Abstract We recently demonstrated that dendritic cells (DCs) from autoimmune-prone non-obese diabetic (NOD) mice at prediabetic age (8–10 week) have a diminished IFN-alpha Receptor (IFNAR) response despite increased production of type 1 IFN. This impaired IFN response may result from chronic activation of inflammatory pathways that contribute to dysregulated innate activation. qPCR of innate targets showed that younger NOD mice (3 week old) did not yet display impaired IFNAR signaling, but already had higher IL-1. To understand the interplay between different innate signals, we compared gene expression of 5 key DC populations from prediabetic NOD mice and diabetes-resistant B6.g7 mice. Several inflammatory pathways including IL-1, Eicosanoids, and NFκB were higher in NOD DCs whereas type 1 IFN-response genes, especially those associated with tonic signal, were lower in prediabetic NOD mice. Analysis of potential upstream regulators of these changes identified increased PTGER4 signal and decreased IRF7. PTGER4 binds prostaglandin E2 (PGE2) and mediates specific aspects of both inflammatory and regulatory eicosanoid signaling. Interestingly, NOD mice treated with an inhibitor of PTGER4 displayed increased IFNAR signaling in DCs, but decreased IL-1, Nlrp3 and IFN-gamma production. These changes suggest restoration of cross-talk between key inflammatory mediators, namely that IFN-gamma and IL-1 can inhibit type 1 IFN and vice versa. Furthermore, mice treated with the PTGER4 antagonist display reduced autoimmune pathology, namely an increase in the number and percentage of healthy islets. These findings highlight PTGER4 as a potential target in type 1 diabetes, affecting several inflammatory pathways including IFNAR signaling.
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Huang, Wenhai, Hao Huang, Shuishen Zhang, Xueping Wang, Juan Ouyang, Zhichao Lin, and Peisong Chen. "A Novel Diagnosis Method Based on Methylation Analysis of SHOX2 and Serum Biomarker for Early Stage Lung Cancer." Cancer Control 27, no. 1 (January 1, 2020): 107327482096970. http://dx.doi.org/10.1177/1073274820969703.
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Objectives: Lung cancer (LC) is often accompanied by significant methylation abnormalities. This study aimed to develop a decision tree (DT) accompanied the stature homeobox 2 gene (SHOX2) / prostaglandin E receptor 4 (PTGER4) gene DNA methylation with traditional tumor marker in the differential diagnosis of benign and malignant lung nodule. Methods: We performed a study with 104 patients enrolled in the LC group and 36 patients in the benign lung diseases group. All the clinical data of these patients were collected through electronic medical record. Total Methylation (TM) status of both SHOX2 and PTGER4 was defined as methylation levels of SHOX2 plus methylation levels of PTGER4. One-way analysis was used to compare the concentrations of serum samples and t-test was used to compare pairwise mean values between groups. Receiver operating curve (ROC) was used to evaluate the diagnostic value. Furthermore, the strategy was validated in 19 LC patients and 11 patients with benign lung diseases. Results: There were significant differences between the concentration of neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA21 -1) and the methylation levels of SHOX2, PTGER4 and TM in lung benign diseases and cancer group. The AUCs of NSE, CEA, CYFRA21 -1, Methylation SHOX2, Methylation PTGER4 and TM were 0.721 (95% CI: 0.627–0.816), 0.753 (95% CI: 0.673–0.833) and 0.778(95% CI: 0.700–0.856), 0.851(0.786-0.916), 0.847(0.780-0.913) and 0.861(0.800-0.922) respectively. We developed a DT model with TM and CYFRA21 -1 used in this study, and the area under the curve (AUC) of DT was 0.921 and the sensitivity up to 0.856. In the validation cohort, the AUC of SHOX2, PTGER4 and TM was also much higher than traditional serum markers. Conclusions: Our results indicated that the DT model calculated from the TM and CYFRA21 -1 can accurately classify LC and benign diseases, which showed better diagnostic performance than traditional serum parameter.
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Chen, Dongjiang, Son Le, Nagheme Thomas, and David Tran. "DRES-06. PROSTAGLANDIN E RECEPTOR 3 MEDIATES RESISTANCE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA CELLS." Neuro-Oncology 21, Supplement_6 (November 2019): vi72. http://dx.doi.org/10.1093/neuonc/noz175.294.
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Abstract OBJECTIVES Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. However, most GBM patients eventually develop resistance to TTFields. The mechanism of TTFields resistance remains largely unexplored. Understanding how GBM cells circumvent the biophysical forces of TTFields and their downstream effects will improve therapeutic efficacy of this novel anti-cancer treatment modality. METHODS A panel of GBM cell lines were treated continuously with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally. RESULTS TTFields-induced chromosomal instability such as the formation of cytoplasmic micronuclei is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay. Using an innovative computational platform, we methodically dissected this stemness program in resistant cells. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked master regulator responsible for resistance. PTGER3 is rapidly upregulated in GBM cells upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Pharmacological inhibition of PTGER3 either using aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors resensitized cells to TTFields. CONCLUSIONS We have identified a novel pathway with PTGER3 at the apex that plays a critical role in TTFields resistance. This pathway is a potential therapeutic target to reduce resistance to TTFields therapy in GBM.
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Ozen, Gulsen, Rabia Deniz, Fatih Eren, Can Erzik, Ali Ugur Unal, Sule Yavuz, Sibel Zehra Aydin, Nevsun Inanc, Haner Direskeneli, and Pamir Atagunduz. "Association of ERAP1, IL23R and PTGER4 Polymorphisms with Radiographic Severity of Ankylosing Spondylitis." Open Rheumatology Journal 11, no. 1 (January 31, 2017): 1–9. http://dx.doi.org/10.2174/1874312901711010001.
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Background: Radiographic severity of ankylosing spondylitis (AS) shows such great variance that some patients never develop syndesmophytes throughout the entire disease span, whereas some develop bamboo spine relatively early. Objective: To study the association between ERAP1, IL23R and PTGER4 single nucleotide polymorphisms (SNPs) and radiographic severity in AS patients. Methods: rs27044 and rs30187 (ERAP1), rs11209032 (IL23R) and rs10440635 (PTGER4) SNPs were genotyped in 235 AS patients fulfilling the modified New York criteria. Patients were classified as mild- and severe-AS according to modified Stoke AS spinal score (mSASSS). Mild-AS is defined as having mSASSS of “0” following at least 10 years of disease duration. Severe-AS is defined as having mSASSS of >20 (patients with mild vertebral changes (i.e. squaring or erosions) were omitted for clear stratification) regardless of disease duration. Results: The genotype distributions and allele frequencies of ERAP1 rs27044 and rs30187, IL23R rs11209032 and PTGER4 rs10440635 SNPs were similar in mild- (n=171, mSASSS=0, 55.6% HLA-B27 positive) and severe-AS patients (n=64, mSASSS=48.5±17.8, 73.4% HLA-B27 positive). After adjustment for clinical differences between groups (gender, disease duration, HLA-B27 and smoking status) by logistic regression analysis, none of the alleles in the investigated SNPs were found to be associated with radiographic severity of AS. Conclusion: In radiographically well-categorized AS patients, ERAP1 rs27044 and rs30187, IL23R rs11209032 and PTGER4 rs10440635 SNPs are not found to be associated with radiographic severity of AS.
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Wu, Chien-Ting, Keren I. Hilgendorf, Romina J. Bevacqua, Yan Hang, Janos Demeter, Seung K. Kim, and Peter K. Jackson. "Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion." Genes & Development 35, no. 17-18 (August 12, 2021): 1243–55. http://dx.doi.org/10.1101/gad.348261.121.
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Multiple G protein-coupled receptors (GPCRs) are expressed in pancreatic islet cells, but the majority have unknown functions. We observed specific GPCRs localized to primary cilia, a prominent signaling organelle, in pancreatic α and β cells. Loss of cilia disrupts β-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet α and β cells, including FFAR4, PTGER4, ADRB2, KISS1R, and P2RY14. Free fatty acid receptor 4 (FFAR4) and prostaglandin E receptor 4 (PTGER4) agonists stimulate ciliary cAMP signaling and promote glucagon and insulin secretion by α- and β-cell lines and by mouse and human islets. Transport of GPCRs to primary cilia requires TULP3, whose knockdown in primary human and mouse islets relocalized ciliary FFAR4 and PTGER4 and impaired regulated glucagon or insulin secretion, without affecting ciliary structure. Our findings provide index evidence that regulated hormone secretion by islet α and β cells is controlled by ciliary GPCRs providing new targets for diabetes.
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Restifo, Diana, Aditya Kulkarni, Caleb Schimke, Joseph McDermott, Umesh Kathad, Kishor Bhatia, Panna Sharma, and Igor Astsaturov. "Abstract PO-036: LP184, a novel alkylating agent, is highly effective in pancreatic cancers with DNA damage repair defects." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—036—PO—036. http://dx.doi.org/10.1158/1538-7445.panca21-po-036.
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Abstract Biomarker-based chemotherapy with increased efficacy and prolonged disease-free survival are urgently needed in pancreatic cancer (PDAC). A 15-20% subset of PDAC tumors carry mutations in DNA repair pathway (BRCA1/BRCA2/PALB2/RAD51/ATM/FANCD2). Additionally, mutations in nucleotide excision repair (NER) genes (ERCC2/3/4/5/6) have been reported in ~5% of PDAC. LP184 is a novel synthetic small molecule acylfulvene analog. Using precise synthetic chemistry, we determined that only a negative enantiomer of LP184 is converted to an active alkylating agent in the strict dependency on oxidoreductase, prostaglandin reductase 1 (PTGR1). By computational analyses, we demonstrate a strong positive correlation of LP184 sensitivity with PTGR1 transcript levels (r=0.89, p<10−15) in a broad panel of cancer cell lines. Once activated by PTGR1, highly reactive LP-184 nucleophile creates covalent DNA adducts that are selectively repaired via Nucleotide Excision Repair (NER) mechanism coupled to transcription (TC-NER) and/or homologous recombination (HR). We reasoned that mutation or expression driven TC-NER and HR deficiency would predispose PDAC cells to increased sensitivity to LP184. To test the idea of LP184 activity in DNA repair-deficient tumors, we evaluated LP184 chemosensitivity in genetically defined PDAC models in vitro, ex vivo, and in xenografts. Testing in six different pancreatic cancer cell lines (Capan-1, CFPAC-1, Panc1, MiaPaCa2, Panc03.27 and BxPC-3) resulted in very potent inhibition with LP184 IC50 values ranging from 114 to 182 nM. In this cell line panel, LP184 sensitivity correlated negatively with transcript levels of an NER pathway gene ERCC8 (r = -0.94). In comparison to these PDAC cell lines, a normal pancreatic epithelial cell line HPNE was 3-6 times less sensitive to LP184 (IC50 670 nM). Ex vivo cultures of 4 out of 5 low-passage patient-derived xenografts with HR deficiency showed nanomolar sensitivity to LP184 with IC50s ranging from 45 to 270 nM. These tumor graft models which were at least 6 times less sensitive to olaparib in the same assay. Depletion of ERCC4 enhanced sensitivity to LP184 about 2-fold relative to the parental cell line. To define PTGR1 as a biomarker for LP184 activity, we used CRISPR/Cas9-mediated gene editing to deplete PTGR1 expression. We found PTGR1-null Capan-1 cell line-derived xenografts were poorly sensitive to LP184, whereas PTGR1-expressing xenografts showed near complete tumor regression in all LP184 treated animals with 109% tumor growth inhibition relative to the control group in this study. Furthermore, PTGR1 depleted cells were completely resistant to LP184 in vitro. Our preclinical data demonstrate that PDAC models carrying a range of DNA repair pathway mutations are highly sensitive to LP-184 in vitro and in vivo. Increased PTGR1 expression is a validated biomarker for LP184 cytotoxicity, and is the exclusive convertase of LP184 to an active alkylator drug. We anticipate LP184 will extend the therapeutic opportunities to a large subset of PDAC patients carrying these genetic alterations. Citation Format: Diana Restifo, Aditya Kulkarni, Caleb Schimke, Joseph McDermott, Umesh Kathad, Kishor Bhatia, Panna Sharma, Igor Astsaturov. LP184, a novel alkylating agent, is highly effective in pancreatic cancers with DNA damage repair defects [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-036.
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ZHANG, Nan, Wei MAO, Ying ZHANG, Na HUANG, Bo LIU, Long GAO, Shuangyi ZHANG, and Jinshan CAO. "The prostaglandin E2 receptor PTGER2 and prostaglandin F2α receptor PTGFR mediate oviductal glycoprotein 1 expression in bovine oviductal epithelial cells." Journal of Reproduction and Development 64, no. 2 (2018): 101–8. http://dx.doi.org/10.1262/jrd.2017-076.
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