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• W2165400650 abstract "Lipopolysaccharide-enhanced cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production were compared in endometriotic stromal cells (ESCs) and eutopic endometrial stromal cells. Lipopolysaccharide promotes the proliferation and invasion of ESCs via up-regulation of COX-2 and PGE2 expression, suggesting that pelvic inflammation may promote the progression of endometriosis. Lipopolysaccharide-enhanced cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production were compared in endometriotic stromal cells (ESCs) and eutopic endometrial stromal cells. Lipopolysaccharide promotes the proliferation and invasion of ESCs via up-regulation of COX-2 and PGE2 expression, suggesting that pelvic inflammation may promote the progression of endometriosis. An important recent general concept is that of endometriosis as a local pelvic inflammatory process. Prostaglandins (PGs) are bioactive lipids produced from arachidonic acid by cyclooxygenase (COX) enzymes and specific terminal prostanoid synthetase enzyme. Increased PGE2 levels in the peritoneal fluid (PF) of women with endometriosis have been reported (1Karck U. Reister F. Schäfer W. Zahradnik H.P. Breckwoldt M. PGE2 and PGF2 alpha release by human peritoneal macrophages in endometriosis.Prostaglandins. 1996; 51: 49-60Crossref PubMed Scopus (77) Google Scholar). COX-2 is more abundantly expressed in ectopic endometria than in eutopic endometria (2Chishima F. Hayakawa S. Sugita K. Kinukawa N. Aleemuzzaman S. Nemoto N. et al.Increased expression of cyclooxygenase-2 in local lesions of endometriosis.Am J Reprod Immunol. 2002; 48: 50-56Crossref PubMed Scopus (139) Google Scholar). COX-2 was shown to regulate survival, migration, and invasion of endometriotic cells (3Banu S.K. Lee J. Speights Jr., V.O. Starzinski-Powitz A. Arosh J.A. Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms.Endocrinology. 2008; 149: 1180-1189Crossref PubMed Scopus (117) Google Scholar).Lipopolysaccharide (LPS) is the gram-negative bacterial cell component used as an inflammation model. Interleukin (IL) 8 enhanced the proliferation of endometriotic stromal cells (ESCs), and its expression in the ESCs was up-regulated by tumor necrosis factor (TNF) α through the activation of nuclear factor (NF) κB (4Sakamoto Y. Harada T. Horie S. Iba Y. Taniguchi F. Yoshida S. et al.Tumor necrosis factor-α–induced interleukin-8 (IL-8) expression in endometriotic stromal cells, probably through nuclear factor-κB activation: gonadotropin-releasing hormone agonist treatment reduced IL-8 expression.J Clin Endocrinol Metab. 2003; 88: 730-735Crossref PubMed Scopus (135) Google Scholar). We previously provided the evidence that LPS stimulated TNF-α and IL-8 expression in ESCs through the activation of NF-κB (5Iba Y. Harada T. Horie S. Deura I. Iwabe T. Terakawa N. Lipopolysaccharide-promoted proliferation of endometriotic stromal cells via induction of tumor necrosis factor alpha and interleukin-8 expression.Fertil Steril. 2004; 3: 1036-1042Abstract Full Text Full Text PDF Scopus (52) Google Scholar). To further investigate the relationship between inflammation and the propagation of endometriosis, we sought to assess the effect of LPS on PGE2 synthesis and on the proliferation and invasion of ESCs.Expression and signaling of the EP2 and EP4 receptors (EPRs), which bind PGE2, have been outlined in the human eutopic endometrium, though not in an endometriosis population (6Milne S.A. Perchick G.B. Boddy S.C. Jabbour H.N. Expression, localization, and signaling of PGE2 and EP2/EP4 receptors in human nonpregnant endometrium across the menstrual cycle.J Clin Endocrinol Metab. 2001; 86: 4453-4459Crossref PubMed Scopus (75) Google Scholar). We ascertained that EP4R gene expression was higher than other EP1–3R expression in ESCs (data not shown). Therefore, in the ESCs, EP4R expression would be the crucial factor for PGE2 signaling.With their informed consent, we recruited women who had regular ovulatory cycles. The Institutional Review Board of Tottori University Faculty of Medicine approved this project. The endometriotic tissues were collected from women who underwent laparoscopic surgery for ovarian endometriomas (n = 11; follicular phase: n = 6; luteal phase: n = 5). Endometrial tissues were collected from women who underwent hysterectomy for fibroids (n = 10; follicular phase: n = 4; luteal phase: n = 6). Stromal cells were collected according to the method described previously (4Sakamoto Y. Harada T. Horie S. Iba Y. Taniguchi F. Yoshida S. et al.Tumor necrosis factor-α–induced interleukin-8 (IL-8) expression in endometriotic stromal cells, probably through nuclear factor-κB activation: gonadotropin-releasing hormone agonist treatment reduced IL-8 expression.J Clin Endocrinol Metab. 2003; 88: 730-735Crossref PubMed Scopus (135) Google Scholar). We used the stromal cells in a monolayer culture after the first passage.Lipopolysaccharide (from Escherichia coli serotype 055:B5, 10 ng/mL; Sigma-Aldrich, Tokyo, Japan) was added to the culture medium. PGE2 levels were measured using PGE2 ELISA kits (R&D Systems, Minneapolis, MN). COX-2 Smart-pool siRNA and siControl nontargeting siRNA (50 nmol/L; Dharmacon, Lafayette, CO) delivered in the presence of lipofectamine (Invitrogen, Carlsbad, CA) were used. Total RNA was isolated using RNeasy Mini Kit (Qiagen, Tokyo, Japan). RNA (1 μg) was added to reverse the transcription reaction, and cDNA (1 μL) was subjected to real-time polymerase chain reaction using an ABI 7900HT system (Applied Biosystems, Warrington, U.K.) All primers and probes were designed using the Primer Express program (Applied Biosystems). The gene expression levels were calculated and normalized by dividing the values for the mRNA samples by those of GAPDH.The mitogenic activity was determined by BrdU proliferation ELISA (Amersham Pharmacia, Tokyo, Japan). We assessed the effect of selective COX-2 inhibitor, NS-398 (Sigma-Aldrich, St. Louis, MO), on eutopic endometrial stromal cell (EMSC) or ESC proliferation. Biocoat Matrigel invasion chambers (BD Bioscience, Tokyo, Japan) were used for invasion assay. Invasion of cells was measured as the number of cells invaded through micropores for 24 hours. The micropore filters were stained with a Diff-Quick stain kit (Green Cross, Kobe, Japan). Results were analyzed by analysis of variance, followed by Fisher protected least significant difference test. Data are presented as mean ± SEM. A P value of <.05 was accepted as indicating statistical significance.With LPS addition, ESCs produced much PGE2 at 6 and 12 hours, whereas EMSCs did not (Fig. 1A ). Moreover, NS-398 (1 μmol/L) negated LPS-induced PGE2 production in ESCs (Fig. 1B). Adding LPS significantly enhanced COX-2 gene expression in ESCs compared with EMSCs (Fig. 1C). LPS also significantly enhanced EP4R gene expression in ESCs compared with EMSCs (data not shown). Although highest expression pattern of EP4R in the late proliferative phase of endometrium was previously reported (6Milne S.A. Perchick G.B. Boddy S.C. Jabbour H.N. Expression, localization, and signaling of PGE2 and EP2/EP4 receptors in human nonpregnant endometrium across the menstrual cycle.J Clin Endocrinol Metab. 2001; 86: 4453-4459Crossref PubMed Scopus (75) Google Scholar), no cyclical differences in EP4R gene expression of ESCs or EMSCs were detected in the present study. After LPS addition, immunoreactive COX-2 expression (IBL, Tokyo, Japan) in ESCs was markedly elevated compared with EMSCs (data not shown).The number of ESCs increased in the presence of 5 ng/mL (P=.015) or 10 ng/mL (P=.004) LPS (Fig. 1D). ESCs constitutively had more invasive activity than EMSCs. LPS addition increased the number of penetrated cells (P=.021; Fig. 1E). NS-398 or COX-2 siRNA diminished the stimulatory effects of LPS.We previously showed that LPS stimulated TNF-α expression, which triggers the cytokine cascade and promotes the proliferation of ESCs (5Iba Y. Harada T. Horie S. Deura I. Iwabe T. Terakawa N. Lipopolysaccharide-promoted proliferation of endometriotic stromal cells via induction of tumor necrosis factor alpha and interleukin-8 expression.Fertil Steril. 2004; 3: 1036-1042Abstract Full Text Full Text PDF Scopus (52) Google Scholar). We provided the first evidence that LPS significantly enhanced cell proliferation, cell invasion, PGE2 production, and EP4R expression in ESCs. Exogenous COX-2 inhibitor or COX-2 gene silencing suppressed LPS-induced ESCs proliferation and invasion, suggesting that COX-2 and PGE2 activation by the inflammation stimuli may be indispensable to the pathogenesis of endometriosis. In the present study, EMSCs did not exhibit LPS-induced cell proliferation and cell invasion. This difference between ESCs and EMSCs may be caused by: 1) the sensitivity for LPS; 2) the degree of EPR expression; and 3) innate characteristics of these cells derived from tissues of two different locations. Like LPS, the inflammation stimuli can induce a variety of chemokines, cytokines, and cell regulators, which may have a close relationship and mutually communicate during the establishment and progression of endometriosis.Cyclooxygenase enzymes and PGs are known as important regulators of reproductive function. COX enzyme expression and EPR signaling are enhanced in heavy menstruation, suggesting that COX-PGE2 pathways may be potential therapeutic targets in the treatment of heavy menstruation (7Smith O.P. Jabbour H.N. Critchley H.O. Cyclooxygenase enzyme expression and E series prostaglandin receptor signaling are enhanced in heavy menstruation.Hum Reprod. 2007; 22: 1450-1456Crossref PubMed Scopus (52) Google Scholar). COX-2 overexpression in endometriotic tissues has been noted. Yuan et al. (8Yuan L. Shen F. Lu Y. Liu X. Guo S.W. Cyclooxygenase-2 overexpression in ovarian endometriomas is associated with higher risk of recurrence.Fertil Steril. 2009; 66: 76-83Google Scholar) reported that COX-2 overexpression in ovarian endometriomas is associated with a higher risk of recurrence. COX-2 inhibitors were shown in animal models to prevent implantation of eutopic endometrium to ectopic sites (9Matsuzaki S. Canis M. Pouly J.L. Wattiez A. Okamura K. Mage G. Cyclooxygenase-2 expression in deep endometriosis and matched eutopic endometrium.Fertil Steril. 2004; 82: 1309-1315Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar) and to suppress the growth of endometriosis xenografts (10Ozawa Y. Murakami T. Tamura M. Terada M. Yaegashi N. Okamura K. A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis xenografts via immunodeficiency mice.Fertil Steril. 2006; 4: 1146-1151Abstract Full Text Full Text PDF Scopus (65) Google Scholar).Endometriosis is an estrogen-dependent disease, and steroidogenic acute regulatory protein (StAR) regulates the first committed step of 17β-E2 biosynthesis. Aberrant expression of StAR is seen exclusively in ectopic endometriotic implants and is stimulated by PGE2 (11Kitawaki J. Noguchi T. Amatsu T. Maeda K. Tsukamoto K. Yamamoto T. et al.Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomayotic tissue but not in normal endometrium.Biol Reprod. 1997; 573: 514-519Crossref Scopus (251) Google Scholar). Aromatase activity is absent in normal endometrium, but high in patients with endometriosis (12Izawa M. Harada T. Taniguchi F. Ohama Y. Takenaka Y. Terakawa T. An epigenetic disorder may cause aberrant expression of aromatase gene in endometriotic stromal cells.Fertil Steril. 2008; 5: 1390-1396Abstract Full Text Full Text PDF Scopus (67) Google Scholar, 13Bulun S.E. Gurates B. Fang Z. Tamura M. Sebastian S. Zhou J. et al.Mechanisms of excessive estrogen formation in endometriosis.J Reprod Immunol. 2002; 55: 21-33Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Estrogen promotes PGE2 synthesis, establishing a positive feedback loop to induce transcription of COX-2, synthesis of PGE2, and expression of aromatase (13Bulun S.E. Gurates B. Fang Z. Tamura M. Sebastian S. Zhou J. et al.Mechanisms of excessive estrogen formation in endometriosis.J Reprod Immunol. 2002; 55: 21-33Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). This positive feedback cycle is partially mediated by ligand binding to the cyclic adenosine monophosphate–linked EPRs, induction of COX-2, accumulation of estrogen, and synthesis of PGs to potentiate inflammation.Fibroids are also estrogen dependent, and the eutopic endometrium with fibroids might be different from that without fibroids and endometriosis. However, it is difficult to obtain endometrial tissue from cycling women without fibroids, and to collect cultured eutopic endometrial stromal cells without the disease. Because we did not examine eutopic endometrial cells with endometriosis, that is an indispensable issue for future study. Selective COX-2 inhibitors (e.g., celecoxib, rofecoxib, and valdecoxib) should be studied in clinical trials in patients with endometriosis to expand the spectrum of currently available treatment options.The present data indicate that COX enzymes and PGs can promote endometriotic cell invasion of surrounding tissues and may be important in the development and survival of endometriotic cells in ectopic sites. An important recent general concept is that of endometriosis as a local pelvic inflammatory process. Prostaglandins (PGs) are bioactive lipids produced from arachidonic acid by cyclooxygenase (COX) enzymes and specific terminal prostanoid synthetase enzyme. Increased PGE2 levels in the peritoneal fluid (PF) of women with endometriosis have been reported (1Karck U. Reister F. Schäfer W. Zahradnik H.P. Breckwoldt M. PGE2 and PGF2 alpha release by human peritoneal macrophages in endometriosis.Prostaglandins. 1996; 51: 49-60Crossref PubMed Scopus (77) Google Scholar). COX-2 is more abundantly expressed in ectopic endometria than in eutopic endometria (2Chishima F. Hayakawa S. Sugita K. Kinukawa N. Aleemuzzaman S. Nemoto N. et al.Increased expression of cyclooxygenase-2 in local lesions of endometriosis.Am J Reprod Immunol. 2002; 48: 50-56Crossref PubMed Scopus (139) Google Scholar). COX-2 was shown to regulate survival, migration, and invasion of endometriotic cells (3Banu S.K. Lee J. Speights Jr., V.O. Starzinski-Powitz A. Arosh J.A. Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms.Endocrinology. 2008; 149: 1180-1189Crossref PubMed Scopus (117) Google Scholar). Lipopolysaccharide (LPS) is the gram-negative bacterial cell component used as an inflammation model. Interleukin (IL) 8 enhanced the proliferation of endometriotic stromal cells (ESCs), and its expression in the ESCs was up-regulated by tumor necrosis factor (TNF) α through the activation of nuclear factor (NF) κB (4Sakamoto Y. Harada T. Horie S. Iba Y. Taniguchi F. Yoshida S. et al.Tumor necrosis factor-α–induced interleukin-8 (IL-8) expression in endometriotic stromal cells, probably through nuclear factor-κB activation: gonadotropin-releasing hormone agonist treatment reduced IL-8 expression.J Clin Endocrinol Metab. 2003; 88: 730-735Crossref PubMed Scopus (135) Google Scholar). We previously provided the evidence that LPS stimulated TNF-α and IL-8 expression in ESCs through the activation of NF-κB (5Iba Y. Harada T. Horie S. Deura I. Iwabe T. Terakawa N. Lipopolysaccharide-promoted proliferation of endometriotic stromal cells via induction of tumor necrosis factor alpha and interleukin-8 expression.Fertil Steril. 2004; 3: 1036-1042Abstract Full Text Full Text PDF Scopus (52) Google Scholar). To further investigate the relationship between inflammation and the propagation of endometriosis, we sought to assess the effect of LPS on PGE2 synthesis and on the proliferation and invasion of ESCs. Expression and signaling of the EP2 and EP4 receptors (EPRs), which bind PGE2, have been outlined in the human eutopic endometrium, though not in an endometriosis population (6Milne S.A. Perchick G.B. Boddy S.C. Jabbour H.N. Expression, localization, and signaling of PGE2 and EP2/EP4 receptors in human nonpregnant endometrium across the menstrual cycle.J Clin Endocrinol Metab. 2001; 86: 4453-4459Crossref PubMed Scopus (75) Google Scholar). We ascertained that EP4R gene expression was higher than other EP1–3R expression in ESCs (data not shown). Therefore, in the ESCs, EP4R expression would be the crucial factor for PGE2 signaling. With their informed consent, we recruited women who had regular ovulatory cycles. The Institutional Review Board of Tottori University Faculty of Medicine approved this project. The endometriotic tissues were collected from women who underwent laparoscopic surgery for ovarian endometriomas (n = 11; follicular phase: n = 6; luteal phase: n = 5). Endometrial tissues were collected from women who underwent hysterectomy for fibroids (n = 10; follicular phase: n = 4; luteal phase: n = 6). Stromal cells were collected according to the method described previously (4Sakamoto Y. Harada T. Horie S. Iba Y. Taniguchi F. Yoshida S. et al.Tumor necrosis factor-α–induced interleukin-8 (IL-8) expression in endometriotic stromal cells, probably through nuclear factor-κB activation: gonadotropin-releasing hormone agonist treatment reduced IL-8 expression.J Clin Endocrinol Metab. 2003; 88: 730-735Crossref PubMed Scopus (135) Google Scholar). We used the stromal cells in a monolayer culture after the first passage. Lipopolysaccharide (from Escherichia coli serotype 055:B5, 10 ng/mL; Sigma-Aldrich, Tokyo, Japan) was added to the culture medium. PGE2 levels were measured using PGE2 ELISA kits (R&D Systems, Minneapolis, MN). COX-2 Smart-pool siRNA and siControl nontargeting siRNA (50 nmol/L; Dharmacon, Lafayette, CO) delivered in the presence of lipofectamine (Invitrogen, Carlsbad, CA) were used. Total RNA was isolated using RNeasy Mini Kit (Qiagen, Tokyo, Japan). RNA (1 μg) was added to reverse the transcription reaction, and cDNA (1 μL) was subjected to real-time polymerase chain reaction using an ABI 7900HT system (Applied Biosystems, Warrington, U.K.) All primers and probes were designed using the Primer Express program (Applied Biosystems). The gene expression levels were calculated and normalized by dividing the values for the mRNA samples by those of GAPDH. The mitogenic activity was determined by BrdU proliferation ELISA (Amersham Pharmacia, Tokyo, Japan). We assessed the effect of selective COX-2 inhibitor, NS-398 (Sigma-Aldrich, St. Louis, MO), on eutopic endometrial stromal cell (EMSC) or ESC proliferation. Biocoat Matrigel invasion chambers (BD Bioscience, Tokyo, Japan) were used for invasion assay. Invasion of cells was measured as the number of cells invaded through micropores for 24 hours. The micropore filters were stained with a Diff-Quick stain kit (Green Cross, Kobe, Japan). Results were analyzed by analysis of variance, followed by Fisher protected least significant difference test. Data are presented as mean ± SEM. A P value of <.05 was accepted as indicating statistical significance. With LPS addition, ESCs produced much PGE2 at 6 and 12 hours, whereas EMSCs did not (Fig. 1A ). Moreover, NS-398 (1 μmol/L) negated LPS-induced PGE2 production in ESCs (Fig. 1B). Adding LPS significantly enhanced COX-2 gene expression in ESCs compared with EMSCs (Fig. 1C). LPS also significantly enhanced EP4R gene expression in ESCs compared with EMSCs (data not shown). Although highest expression pattern of EP4R in the late proliferative phase of endometrium was previously reported (6Milne S.A. Perchick G.B. Boddy S.C. Jabbour H.N. Expression, localization, and signaling of PGE2 and EP2/EP4 receptors in human nonpregnant endometrium across the menstrual cycle.J Clin Endocrinol Metab. 2001; 86: 4453-4459Crossref PubMed Scopus (75) Google Scholar), no cyclical differences in EP4R gene expression of ESCs or EMSCs were detected in the present study. After LPS addition, immunoreactive COX-2 expression (IBL, Tokyo, Japan) in ESCs was markedly elevated compared with EMSCs (data not shown). The number of ESCs increased in the presence of 5 ng/mL (P=.015) or 10 ng/mL (P=.004) LPS (Fig. 1D). ESCs constitutively had more invasive activity than EMSCs. LPS addition increased the number of penetrated cells (P=.021; Fig. 1E). NS-398 or COX-2 siRNA diminished the stimulatory effects of LPS. We previously showed that LPS stimulated TNF-α expression, which triggers the cytokine cascade and promotes the proliferation of ESCs (5Iba Y. Harada T. Horie S. Deura I. Iwabe T. Terakawa N. Lipopolysaccharide-promoted proliferation of endometriotic stromal cells via induction of tumor necrosis factor alpha and interleukin-8 expression.Fertil Steril. 2004; 3: 1036-1042Abstract Full Text Full Text PDF Scopus (52) Google Scholar). We provided the first evidence that LPS significantly enhanced cell proliferation, cell invasion, PGE2 production, and EP4R expression in ESCs. Exogenous COX-2 inhibitor or COX-2 gene silencing suppressed LPS-induced ESCs proliferation and invasion, suggesting that COX-2 and PGE2 activation by the inflammation stimuli may be indispensable to the pathogenesis of endometriosis. In the present study, EMSCs did not exhibit LPS-induced cell proliferation and cell invasion. This difference between ESCs and EMSCs may be caused by: 1) the sensitivity for LPS; 2) the degree of EPR expression; and 3) innate characteristics of these cells derived from tissues of two different locations. Like LPS, the inflammation stimuli can induce a variety of chemokines, cytokines, and cell regulators, which may have a close relationship and mutually communicate during the establishment and progression of endometriosis. Cyclooxygenase enzymes and PGs are known as important regulators of reproductive function. COX enzyme expression and EPR signaling are enhanced in heavy menstruation, suggesting that COX-PGE2 pathways may be potential therapeutic targets in the treatment of heavy menstruation (7Smith O.P. Jabbour H.N. Critchley H.O. Cyclooxygenase enzyme expression and E series prostaglandin receptor signaling are enhanced in heavy menstruation.Hum Reprod. 2007; 22: 1450-1456Crossref PubMed Scopus (52) Google Scholar). COX-2 overexpression in endometriotic tissues has been noted. Yuan et al. (8Yuan L. Shen F. Lu Y. Liu X. Guo S.W. Cyclooxygenase-2 overexpression in ovarian endometriomas is associated with higher risk of recurrence.Fertil Steril. 2009; 66: 76-83Google Scholar) reported that COX-2 overexpression in ovarian endometriomas is associated with a higher risk of recurrence. COX-2 inhibitors were shown in animal models to prevent implantation of eutopic endometrium to ectopic sites (9Matsuzaki S. Canis M. Pouly J.L. Wattiez A. Okamura K. Mage G. Cyclooxygenase-2 expression in deep endometriosis and matched eutopic endometrium.Fertil Steril. 2004; 82: 1309-1315Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar) and to suppress the growth of endometriosis xenografts (10Ozawa Y. Murakami T. Tamura M. Terada M. Yaegashi N. Okamura K. A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis xenografts via immunodeficiency mice.Fertil Steril. 2006; 4: 1146-1151Abstract Full Text Full Text PDF Scopus (65) Google Scholar). Endometriosis is an estrogen-dependent disease, and steroidogenic acute regulatory protein (StAR) regulates the first committed step of 17β-E2 biosynthesis. Aberrant expression of StAR is seen exclusively in ectopic endometriotic implants and is stimulated by PGE2 (11Kitawaki J. Noguchi T. Amatsu T. Maeda K. Tsukamoto K. Yamamoto T. et al.Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomayotic tissue but not in normal endometrium.Biol Reprod. 1997; 573: 514-519Crossref Scopus (251) Google Scholar). Aromatase activity is absent in normal endometrium, but high in patients with endometriosis (12Izawa M. Harada T. Taniguchi F. Ohama Y. Takenaka Y. Terakawa T. An epigenetic disorder may cause aberrant expression of aromatase gene in endometriotic stromal cells.Fertil Steril. 2008; 5: 1390-1396Abstract Full Text Full Text PDF Scopus (67) Google Scholar, 13Bulun S.E. Gurates B. Fang Z. Tamura M. Sebastian S. Zhou J. et al.Mechanisms of excessive estrogen formation in endometriosis.J Reprod Immunol. 2002; 55: 21-33Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Estrogen promotes PGE2 synthesis, establishing a positive feedback loop to induce transcription of COX-2, synthesis of PGE2, and expression of aromatase (13Bulun S.E. Gurates B. Fang Z. Tamura M. Sebastian S. Zhou J. et al.Mechanisms of excessive estrogen formation in endometriosis.J Reprod Immunol. 2002; 55: 21-33Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). This positive feedback cycle is partially mediated by ligand binding to the cyclic adenosine monophosphate–linked EPRs, induction of COX-2, accumulation of estrogen, and synthesis of PGs to potentiate inflammation. Fibroids are also estrogen dependent, and the eutopic endometrium with fibroids might be different from that without fibroids and endometriosis. However, it is difficult to obtain endometrial tissue from cycling women without fibroids, and to collect cultured eutopic endometrial stromal cells without the disease. Because we did not examine eutopic endometrial cells with endometriosis, that is an indispensable issue for future study. Selective COX-2 inhibitors (e.g., celecoxib, rofecoxib, and valdecoxib) should be studied in clinical trials in patients with endometriosis to expand the spectrum of currently available treatment options. The present data indicate that COX enzymes and PGs can promote endometriotic cell invasion of surrounding tissues and may be important in the development and survival of endometriotic cells in ectopic sites." @default.
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• W2165400650 title "Lipopolysaccharide promoted proliferation and invasion of endometriotic stromal cells via induction of cyclooxygenase-2 expression" @default.
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• W2165400650 isRetracted "false" @default.
• W2165400650 magId "2165400650" @default.
• W2165400650 workType "article" @default.