mPGES-1在前列腺癌中的表达及其意义
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摘要
背景:前列腺癌(Pca)是常见的男性恶性肿瘤,在我国的发生率已位居城市男性肿瘤发病的第十位,男性泌尿生殖系统肿瘤的首位,严重危害了男性健康。在早期,Pca多为雄激素依赖性前列腺癌(ADPC),采用抗雄药物或手术去势等治疗多可达满意的效果。但是,经过一定时间的雄激素剥夺治疗后,几乎所有Pca将会逐渐发展为雄激素非依赖性前列腺癌(AIPC),其确切的转化机制目前尚不清楚,亦无理想的治疗方法。
膜结合型前列腺素E2合酶1(mPGES-1)是一种介导前列腺素E2(Prostaglandin E2)合成的重要末端诱导酶,在许多肿瘤的发生、发展中起着重要作用,并与肿瘤对抗癌药物的敏感性以及预后存在显著相关性。但mPGES-1在Pca中的作用目前尚不清楚。
目的:研究mPGES-1在不同前列腺组织以及AIPC细胞中的表达及其意义。
方法:收集我院Pca组织标本40例、良性前列腺增生症(Benign Prostatic Hyperp lasia,BPH)标本40例和正常前列腺组织5例,采用免疫组织化学法,对上述标本进行mPGES-1和Beclin-1检测,分析mPGES-1在不同前列腺组织中的表达特征以及与TNM分期、Gleason评分和PSA值等临床指标的相关性;进行DU-145细胞培养,采用不同浓度mPGES-1特异性抑制剂(CAY10526)干预,同时设立完全培养基组(complete medium,CM)无血清培养组(serum-free medium,SF),MTT试验筛选最佳抑制浓度,Western Blot技术检测干预前后mPGES-1和Beclin-1蛋白表达水平,观察下调mPGES-1对DU-145细胞活性以及Beclin-1的影响。
结果:mPGES-1在Pca组织中呈过表达,在BPH和正常前列腺组织中低表达或不表达;Beclin-1在BPH和正常前列腺组织中过表达,在Pca组织中低表达;mPGES-1和Beclin-1在同一前列腺组织中的表达存在显著性差异(P<0.05),在前列腺癌中呈负相关关系(r= -0.427;P<0.05);两种蛋白表达的阳性率与不同前列腺癌TNM分级、Gleason评分和PSA值存在显著差异(P<0.05),与患者年龄分层不存在显著差异(P>0.05);mPGES-1在AIPC中的表达显著高于ADPC(P<0.05)。经不同浓度(10μM、20μM、50μM)CAY10526干预DU-145细胞,12h后,上述细胞活性和mPGES-1蛋白表达均显著降低(P<0.05),CAY10526的最佳抑制浓度为20μM,并具有剂量依赖性特征;Beclin-1在SF组中的表达较CM组出现显著上调(P<0.05);采用CAY10526(10μM)部分阻断mPGES-1,Beclin-1表达显著上调(P<0.05);当癌细胞完全失去活性时,mPGES-1和Beclin-1表达则同时下调(P<0.05)。
结论:mPGES-1在Pca的病情进展以及激素非依赖性转化中发挥重要作用,抑制mPGES-1表达可降低Pca细胞活性,mPGES-1可能为Pca治疗的重要靶点,有待进一步研究。
Background: Prostate cancer (Pca) is a common male malignant neoplasm. The morbidity and mortality has a rising trend in the past few years. The occurrence of Pca was the tenth leading cause of male cancer and the first place of urogenital neoplasms in our country. Pca is seriously harming to men’s health. Majority of PCa patients manifested androgen dependent prostate cancer(ADPC) in prophase of pathogenesis. However, most patients will develop AIPC after the initiation of androgen deprivation. The exact mechanism of transformation remained not clear and there is no any effective therapy for this disease today. Therefore, further studies will be needed to investigate the pathogenesis and therapy of Pca. Membrane bound prostaglandin E2 synthase-1(mPGES-1) is an important terminal inducible enzyme which mediates the synthetic of Prostaglandin E2(PGE2) and plays an important role in carcinogenesis and development of Pca. Downregulating the expression of mPGES-1 could decrease the vitality of AIPC cells and increase apoptosis and make a decrement of the rate of oncogenesis in nude mouse. Otherwise, another considering factor is that downregulating autophagy of Pca cells could make them survival. Inducing cancer cells autophagy could trigger the autophagic death and increase the sensibility to antitumor drug by upregulating the Beclin-1.However, in Pca, it is not clear that mPGES-1 could effect on Beclin-1 to affect the development of Pca whether or not.
Objective: To research the expression characteristics of mPGES-1 and Beclin-1 in different prostate tissues and investigate the significance of mPGES-1 effecting on Beclin-1.
Methods: Immunohistochemistry was performed on paraffin-embedded sections with rabbit polyclonal against mPGES-1 and Beclin-1 in 40 Prostate Cancer(PCa) and 40 benign prostatic hyperplasia (BPH) and 5 normal prostate specimens to explore the relationship of the expression of mPGES-1 and Beclin-1. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to study the expression of mPGES-1 and Beclin-1 on mRNA levels in above three specimens. Applying different concentration of mPGES-1 inhibitor(CAY10526) intervened DU-145 cells and erecting complete medium (CM) group and serum-free medium(SF) group. The purpose of MTT assay is to ascertain the best working concentration of CAY10526. The effect of CAY10526 treatments on the expression of Beclin-1 in DU-145 cells was studied using Western blot analysis.
Results: A significant difference of mPGES-1 and Beclin-1 expression was found among PCa, BPH and normal issues,respectively(P<0.05).Beclin-1 expression was inversely correlated with mPGES-1 expression in PCa tissue(P<0.05). There was obviously negative correlation between mPGES-1 and Beclin-1 in PCa(r=-0.427 P<0.05). The positive rate of mPGES-1 in AIPC was significantly higher than that in ADPC (P<0.05). A significant association was observed between mPGES-1 expression and higher Gleason scores(p<0.05) and tumor stage(P<0.05).However, there was no significant association between mPGES-1 expression and age(P>0.05). A significant association was observed between Beclin-1 expression and lower Gleason scores (P < 0.05) and tumor stage (P < 0.05),the Beclin-1 expression has no significant association with age(P>0.05).CAY10526 could significantly block mPGES-1 expression and the proliferation of DU-145 cells(P<0.05). DU-145 cells cytoactive descended with the does of CAY10526 increasing from 10 to 50μM although there is a plateau phase beyond 20μM. The expression of Beclin-1 in the SF group was higher than that in the CM group(P<0.05). After being intervened by CAY10526 at 10μM, Beclin-1 expression down-regulated, however, the expression of Beclin-1 remained higher than that in control group (P<0.05). Nevertheless, with the cytoactive decreasing, mPGES-1 and Beclin-1 both down-regulated significantly (P<0.05).
Conclusion: mPGES-1 may play an important role in progression and transformation of androgen independent.Inhibiting mPGES-1 could decrease cytoactive of Pca cells significantly and effectively. That mPGES-1 would be an significant therapeutic target should be a further research.
膜结合型前列腺素E2合酶1(mPGES-1)是一种介导前列腺素E2(Prostaglandin E2)合成的重要末端诱导酶,在许多肿瘤的发生、发展中起着重要作用,并与肿瘤对抗癌药物的敏感性以及预后存在显著相关性。但mPGES-1在Pca中的作用目前尚不清楚。
目的:研究mPGES-1在不同前列腺组织以及AIPC细胞中的表达及其意义。
方法:收集我院Pca组织标本40例、良性前列腺增生症(Benign Prostatic Hyperp lasia,BPH)标本40例和正常前列腺组织5例,采用免疫组织化学法,对上述标本进行mPGES-1和Beclin-1检测,分析mPGES-1在不同前列腺组织中的表达特征以及与TNM分期、Gleason评分和PSA值等临床指标的相关性;进行DU-145细胞培养,采用不同浓度mPGES-1特异性抑制剂(CAY10526)干预,同时设立完全培养基组(complete medium,CM)无血清培养组(serum-free medium,SF),MTT试验筛选最佳抑制浓度,Western Blot技术检测干预前后mPGES-1和Beclin-1蛋白表达水平,观察下调mPGES-1对DU-145细胞活性以及Beclin-1的影响。
结果:mPGES-1在Pca组织中呈过表达,在BPH和正常前列腺组织中低表达或不表达;Beclin-1在BPH和正常前列腺组织中过表达,在Pca组织中低表达;mPGES-1和Beclin-1在同一前列腺组织中的表达存在显著性差异(P<0.05),在前列腺癌中呈负相关关系(r= -0.427;P<0.05);两种蛋白表达的阳性率与不同前列腺癌TNM分级、Gleason评分和PSA值存在显著差异(P<0.05),与患者年龄分层不存在显著差异(P>0.05);mPGES-1在AIPC中的表达显著高于ADPC(P<0.05)。经不同浓度(10μM、20μM、50μM)CAY10526干预DU-145细胞,12h后,上述细胞活性和mPGES-1蛋白表达均显著降低(P<0.05),CAY10526的最佳抑制浓度为20μM,并具有剂量依赖性特征;Beclin-1在SF组中的表达较CM组出现显著上调(P<0.05);采用CAY10526(10μM)部分阻断mPGES-1,Beclin-1表达显著上调(P<0.05);当癌细胞完全失去活性时,mPGES-1和Beclin-1表达则同时下调(P<0.05)。
结论:mPGES-1在Pca的病情进展以及激素非依赖性转化中发挥重要作用,抑制mPGES-1表达可降低Pca细胞活性,mPGES-1可能为Pca治疗的重要靶点,有待进一步研究。
Background: Prostate cancer (Pca) is a common male malignant neoplasm. The morbidity and mortality has a rising trend in the past few years. The occurrence of Pca was the tenth leading cause of male cancer and the first place of urogenital neoplasms in our country. Pca is seriously harming to men’s health. Majority of PCa patients manifested androgen dependent prostate cancer(ADPC) in prophase of pathogenesis. However, most patients will develop AIPC after the initiation of androgen deprivation. The exact mechanism of transformation remained not clear and there is no any effective therapy for this disease today. Therefore, further studies will be needed to investigate the pathogenesis and therapy of Pca. Membrane bound prostaglandin E2 synthase-1(mPGES-1) is an important terminal inducible enzyme which mediates the synthetic of Prostaglandin E2(PGE2) and plays an important role in carcinogenesis and development of Pca. Downregulating the expression of mPGES-1 could decrease the vitality of AIPC cells and increase apoptosis and make a decrement of the rate of oncogenesis in nude mouse. Otherwise, another considering factor is that downregulating autophagy of Pca cells could make them survival. Inducing cancer cells autophagy could trigger the autophagic death and increase the sensibility to antitumor drug by upregulating the Beclin-1.However, in Pca, it is not clear that mPGES-1 could effect on Beclin-1 to affect the development of Pca whether or not.
Objective: To research the expression characteristics of mPGES-1 and Beclin-1 in different prostate tissues and investigate the significance of mPGES-1 effecting on Beclin-1.
Methods: Immunohistochemistry was performed on paraffin-embedded sections with rabbit polyclonal against mPGES-1 and Beclin-1 in 40 Prostate Cancer(PCa) and 40 benign prostatic hyperplasia (BPH) and 5 normal prostate specimens to explore the relationship of the expression of mPGES-1 and Beclin-1. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to study the expression of mPGES-1 and Beclin-1 on mRNA levels in above three specimens. Applying different concentration of mPGES-1 inhibitor(CAY10526) intervened DU-145 cells and erecting complete medium (CM) group and serum-free medium(SF) group. The purpose of MTT assay is to ascertain the best working concentration of CAY10526. The effect of CAY10526 treatments on the expression of Beclin-1 in DU-145 cells was studied using Western blot analysis.
Results: A significant difference of mPGES-1 and Beclin-1 expression was found among PCa, BPH and normal issues,respectively(P<0.05).Beclin-1 expression was inversely correlated with mPGES-1 expression in PCa tissue(P<0.05). There was obviously negative correlation between mPGES-1 and Beclin-1 in PCa(r=-0.427 P<0.05). The positive rate of mPGES-1 in AIPC was significantly higher than that in ADPC (P<0.05). A significant association was observed between mPGES-1 expression and higher Gleason scores(p<0.05) and tumor stage(P<0.05).However, there was no significant association between mPGES-1 expression and age(P>0.05). A significant association was observed between Beclin-1 expression and lower Gleason scores (P < 0.05) and tumor stage (P < 0.05),the Beclin-1 expression has no significant association with age(P>0.05).CAY10526 could significantly block mPGES-1 expression and the proliferation of DU-145 cells(P<0.05). DU-145 cells cytoactive descended with the does of CAY10526 increasing from 10 to 50μM although there is a plateau phase beyond 20μM. The expression of Beclin-1 in the SF group was higher than that in the CM group(P<0.05). After being intervened by CAY10526 at 10μM, Beclin-1 expression down-regulated, however, the expression of Beclin-1 remained higher than that in control group (P<0.05). Nevertheless, with the cytoactive decreasing, mPGES-1 and Beclin-1 both down-regulated significantly (P<0.05).
Conclusion: mPGES-1 may play an important role in progression and transformation of androgen independent.Inhibiting mPGES-1 could decrease cytoactive of Pca cells significantly and effectively. That mPGES-1 would be an significant therapeutic target should be a further research.
引文
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[1] Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 2005; 310: 1504-1510.
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[3] McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006; 296: 1633-1644.
[4] Murakami M, Nakashima K, Kamei D, Masuda S, Ishikawa Y, Ishii T, Ohmiya Y, Watanabe K, Kudo I. Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J Biol Chem 2003; 278: 37937-37947.
[5] Watanabe K, Kurihara K, Suzuki T. Purification and characterization of membrane-bound prostaglandin E synthase from bovine heart. Biochim Biophys Acta 1999; 1439: 406-414.
[6] Samuelsson B, Morgenstern R, Jakobsson PJ. Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev 2007; 59: 207-224.
[7] Forsberg L, Leeb L, Thoren S, Morgenstern R, Jakobsson P. Human glutathione dependent prostaglandin E synthase: gene structure and regulation. FEBS Lett 2000; 471: 78-82.
[8] Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B. Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci U S A 1999; 96: 7220-7225.
[9] Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F, Ikeda T,Fueki M, Ueno A, Oh S, Kudo I. Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 2000; 275: 32783-32792.
[10] Naraba H, Yokoyama C, Tago N, Murakami M, Kudo I, Fueki M, Oh-Ishi S, Tanabe T. Transcriptional regulation of the membrane-associated prostaglandin E2 synthase gene. Essential role of the transcription factor Egr-1. J Biol Chem 2002; 277: 28601-28608.
[11] Yucel-Lindberg T, Olsson T, Kawakami T. Signal pathways involved in the regulation of prostaglandin E synthase-1 in human gingival fibroblasts. Cell Signal 2006; 18: 2131-2142.
[12]Jungel A, Distler O, Schulze-Horsel U, Huber LC, Ha HR, Simmen B, Kalden JR, Pisetsky DS, Gay S, Distler JH. Microparticles stimulate the synthesis of prostaglandin E(2) via induction of cyclooxygenase 2 and microsomal prostaglandin E synthase 1. Arthritis Rheum 2007; 56: 3564-3574.
[13] Subbaramaiah K, Yoshimatsu K, Scherl E, Das KM, Glazier KD, Golijanin D, Soslow RA, Tanabe T, Naraba H, Dannenberg AJ. Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease. Evidence for involvement of the transcription factor Egr-1. J Biol Chem 2004; 279: 12647-12658.
[14] Uematsu S, Matsumoto M, Takeda K, Akira S. Lipopolysaccharide-dependent prostaglandin E(2) production is regulated by the glutathione-dependent prostaglandin E(2) synthase gene induced by the Toll-like receptor 4/MyD88/NF-IL6 pathway. J Immunol 2002; 168: 5811-5816.
[15] Nagataki M, Moriyuki K, Sekiguchi F, Kawabata A. Evidence that PAR2-triggered prostaglandin E2 (PGE2) formation involves the ERK-cytosolic phospholipase A2-COX-1-microsomal PGE synthase-1 cascade in human lung epithelial cells. Cell Biochem Funct 2008; 26: 279-282.
[16] Wu T, Wu H, Wang J. Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain. J Neuroinflammation 2011; 8: 22.
[17] Li P, Lu J, Kaur C, Sivakumar V, Tan KL, Ling EA. Expression of cyclooxygenase-1/-2, microsomal prostaglandin-E synthase-1 and E-prostanoid receptor 2 and regulation of inflammatory mediators by PGE(2) in the amoeboid microglia in hypoxic postnatal rats and murine BV-2 cells. Neuroscience 2009; 164: 948-962.
[18] Schneider A, Zhang Y, Zhang M, Lu WJ, Rao R, Fan X, Redha R, Davis L, Breyer RM, Harris R, Guan Y, Breyer MD. Membrane-associated PGE synthase-1 (mPGES-1) is coexpressed with both COX-1 and COX-2 in the kidney. Kidney Int 2004; 65: 1205-1213.
[19] Ikeda-Matsuo Y, Hirayama Y, Ota A, Uematsu S, Akira S, Sasaki Y. Microsomal prostaglandin E synthase-1 and cyclooxygenase-2 are both required for ischaemic excitotoxicity. Br J Pharmacol 2010; 159: 1174-1186.
[20] de Oliveira AC, Candelario-Jalil E, Bhatia HS, Lieb K, Hull M, Fiebich BL. Regulation of prostaglandin E2 synthase expression in activated primary rat microglia: evidence for uncoupled regulation of mPGES-1 and COX-2. Glia 2008; 56: 844-855.
[21] Jia RP, Xu LW, Su Q, Zhao JH, Li WC, Wang F, Xu Z. Cyclooxygenase-2 expression is dependent upon epidermal growth factor receptor expression or activation in androgen independent prostate cancer. Asian J Androl, 2008,10(5):758-764.5.
[22] Su Q, Jia RP, Lin JZ, Xu LW, Wang ZZ, Li WC and WANG SK. Effect of endothelin-1 on cyclooxygenase-2 expression in human hormone refractory prostate cancer cells. Oncology Letters, 2010,(01):495-499.
[23] Yoshimatsu K, Altorki NK, Golijanin D, Zhang F, Jakobsson PJ, Dannenberg AJ,Subbaramaiah K. Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer. Clin Cancer Res 2001; 7: 2669-2674.
[24] Kamei D, Murakami M, Sasaki Y, Nakatani Y, Majima M, Ishikawa Y, Ishii T, Uematsu S, Akira S, Hara S, Kudo I. Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis. Biochem J 2010; 425: 361-371.
[25] Mehrotra S, Morimiya A, Agarwal B, Konger R, Badve S. Microsomal prostaglandin E2 synthase-1 in breast cancer: a potential target for therapy. J Pathol 2006; 208: 356-363.
[26] Payner T, Leaver HA, Knapp B, Whittle IR, Trifan OC, Miller S, Rizzo MT. Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E(2)-dependent activation of type II protein kinase A. Mol Cancer Ther 2006; 5: 1817-1826.
[27] Sheng H, Shao J, Dixon DA, Williams CS, Prescott SM, DuBois RN, Beauchamp RD. Transforming growth factor-beta1 enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J Biol Chem 2000; 275: 6628-6635.
[28] Hanaka H, Pawelzik SC, Johnsen JI, Rakonjac M, Terawaki K, Rasmuson A, Sveinbjornsson B, Schumacher MC, Hamberg M, Samuelsson B, Jakobsson PJ, Kogner P, Radmark O. Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells. Proc Natl Acad Sci U S A 2009; 106: 18757-18762.
[29] Nardone G, Rocco A, Vaira D, Staibano S, Budillon A, Tatangelo F, Sciulli MG, Perna F, Salvatore G, Di Benedetto M, De Rosa G, Patrignani P. Expression of COX-2, mPGE-synthase1, MDR-1 (P-gp), and Bcl-xL: a molecular pathway of H pylori-related gastric carcinogenesis. J Pathol 2004; 202: 305-312.
[30] Wang HW, Hsueh CT, Lin CF, Chou TY, Hsu WH, Wang LS, Wu YC. Clinical implications of microsomal prostaglandin e synthase-1 overexpression in human non-small-cell lung cancer. Ann Surg Oncol 2006; 13: 1224-1234.
[31] Kawata R, Hyo S, Maeda T, Urade Y, Takenaka H. Simultaneous expression of cyclooxygenase-2 and microsomal prostaglandin E synthase in squamous cell carcinoma of the larynx. Acta Otolaryngol 2006; 126: 627-632.
[32] Gudis K, Tatsuguchi A, Wada K, Hiratsuka T, Futagami S, Fukuda Y, Kiyama T, Tajiri T, Miyake K, Sakamoto C. Clinical significance of prostaglandin E synthase expression in gastric cancer tissue. Hum Pathol 2007; 38: 1826-1835.
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[1] Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 2005; 310: 1504-1510.
[2] Ghosh N, Chaki R, Mandal V, Mandal SC. COX-2 as a target for cancer chemotherapy. Pharmacol Rep 2010; 62: 233-244.
[3] McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006; 296: 1633-1644.
[4] Murakami M, Nakashima K, Kamei D, Masuda S, Ishikawa Y, Ishii T, Ohmiya Y, Watanabe K, Kudo I. Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J Biol Chem 2003; 278: 37937-37947.
[5] Watanabe K, Kurihara K, Suzuki T. Purification and characterization of membrane-bound prostaglandin E synthase from bovine heart. Biochim Biophys Acta 1999; 1439: 406-414.
[6] Samuelsson B, Morgenstern R, Jakobsson PJ. Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev 2007; 59: 207-224.
[7] Forsberg L, Leeb L, Thoren S, Morgenstern R, Jakobsson P. Human glutathione dependent prostaglandin E synthase: gene structure and regulation. FEBS Lett 2000; 471: 78-82.
[8] Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B. Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci U S A 1999; 96: 7220-7225.
[9] Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F, Ikeda T,Fueki M, Ueno A, Oh S, Kudo I. Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 2000; 275: 32783-32792.
[10] Naraba H, Yokoyama C, Tago N, Murakami M, Kudo I, Fueki M, Oh-Ishi S, Tanabe T. Transcriptional regulation of the membrane-associated prostaglandin E2 synthase gene. Essential role of the transcription factor Egr-1. J Biol Chem 2002; 277: 28601-28608.
[11] Yucel-Lindberg T, Olsson T, Kawakami T. Signal pathways involved in the regulation of prostaglandin E synthase-1 in human gingival fibroblasts. Cell Signal 2006; 18: 2131-2142.
[12]Jungel A, Distler O, Schulze-Horsel U, Huber LC, Ha HR, Simmen B, Kalden JR, Pisetsky DS, Gay S, Distler JH. Microparticles stimulate the synthesis of prostaglandin E(2) via induction of cyclooxygenase 2 and microsomal prostaglandin E synthase 1. Arthritis Rheum 2007; 56: 3564-3574.
[13] Subbaramaiah K, Yoshimatsu K, Scherl E, Das KM, Glazier KD, Golijanin D, Soslow RA, Tanabe T, Naraba H, Dannenberg AJ. Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease. Evidence for involvement of the transcription factor Egr-1. J Biol Chem 2004; 279: 12647-12658.
[14] Uematsu S, Matsumoto M, Takeda K, Akira S. Lipopolysaccharide-dependent prostaglandin E(2) production is regulated by the glutathione-dependent prostaglandin E(2) synthase gene induced by the Toll-like receptor 4/MyD88/NF-IL6 pathway. J Immunol 2002; 168: 5811-5816.
[15] Nagataki M, Moriyuki K, Sekiguchi F, Kawabata A. Evidence that PAR2-triggered prostaglandin E2 (PGE2) formation involves the ERK-cytosolic phospholipase A2-COX-1-microsomal PGE synthase-1 cascade in human lung epithelial cells. Cell Biochem Funct 2008; 26: 279-282.
[16] Wu T, Wu H, Wang J. Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain. J Neuroinflammation 2011; 8: 22.
[17] Li P, Lu J, Kaur C, Sivakumar V, Tan KL, Ling EA. Expression of cyclooxygenase-1/-2, microsomal prostaglandin-E synthase-1 and E-prostanoid receptor 2 and regulation of inflammatory mediators by PGE(2) in the amoeboid microglia in hypoxic postnatal rats and murine BV-2 cells. Neuroscience 2009; 164: 948-962.
[18] Schneider A, Zhang Y, Zhang M, Lu WJ, Rao R, Fan X, Redha R, Davis L, Breyer RM, Harris R, Guan Y, Breyer MD. Membrane-associated PGE synthase-1 (mPGES-1) is coexpressed with both COX-1 and COX-2 in the kidney. Kidney Int 2004; 65: 1205-1213.
[19] Ikeda-Matsuo Y, Hirayama Y, Ota A, Uematsu S, Akira S, Sasaki Y. Microsomal prostaglandin E synthase-1 and cyclooxygenase-2 are both required for ischaemic excitotoxicity. Br J Pharmacol 2010; 159: 1174-1186.
[20] de Oliveira AC, Candelario-Jalil E, Bhatia HS, Lieb K, Hull M, Fiebich BL. Regulation of prostaglandin E2 synthase expression in activated primary rat microglia: evidence for uncoupled regulation of mPGES-1 and COX-2. Glia 2008; 56: 844-855.
[21] Jia RP, Xu LW, Su Q, Zhao JH, Li WC, Wang F, Xu Z. Cyclooxygenase-2 expression is dependent upon epidermal growth factor receptor expression or activation in androgen independent prostate cancer. Asian J Androl, 2008,10(5):758-764.5.
[22] Su Q, Jia RP, Lin JZ, Xu LW, Wang ZZ, Li WC and WANG SK. Effect of endothelin-1 on cyclooxygenase-2 expression in human hormone refractory prostate cancer cells. Oncology Letters, 2010,(01):495-499.
[23] Yoshimatsu K, Altorki NK, Golijanin D, Zhang F, Jakobsson PJ, Dannenberg AJ,Subbaramaiah K. Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer. Clin Cancer Res 2001; 7: 2669-2674.
[24] Kamei D, Murakami M, Sasaki Y, Nakatani Y, Majima M, Ishikawa Y, Ishii T, Uematsu S, Akira S, Hara S, Kudo I. Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis. Biochem J 2010; 425: 361-371.
[25] Mehrotra S, Morimiya A, Agarwal B, Konger R, Badve S. Microsomal prostaglandin E2 synthase-1 in breast cancer: a potential target for therapy. J Pathol 2006; 208: 356-363.
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