臺灣博碩士論文加值系統

子宮內膜異位症 (子宮內膜組織在子宮腔之外的地方增生)是一種常見的婦女疾病。子宮內膜異位症發生的成因很多也很複雜, 至今仍無一致的學說。子宮內膜異位症的形成過程與雌性激素的存在有高度相關性。雌性激素的作用是透過數種細胞生長因子促進細胞增長。目前已證實雌激素可以刺激正位子宮內膜組織表現纖維母細胞生長因子-9 (FGF-9)，並進而可以促進正位子宮內膜組織增生。由此可知FGF-9可能是促成子宮內膜異位症發生的成因之一。然而，FGF-9是透過何種細胞及分子機制去達成此作用目前仍不清楚。先前的研究也提出前列腺素E2 (PGE2) 的表現與子宮內膜異位症之嚴重度有高度的正相關性，腹膜液中過度表現的PGE2已證實是因異位組織及巨噬細胞過度表現前列腺素合成媒-2所造成。既然PGE2可以誘發固醇類賀爾蒙生成急性調控蛋白 (StAR) 及芳香環轉化脢 (aromatase)這兩個控制雌激素合成的基因的表現，我們合理的假設PGE2可能透過增加雌激素的合成進一步去誘發FGF-9的表現。所以本研究將主要探討PGE2如何作用去調控FGF-9。針對此目的，我將驗證以下兩個假說。 首先，異位基質細胞可以自行生成雌激素進而誘發 FGF-9的表現。接下來，PGE2可能促進異位基質細胞合成雌激素，而後進一步去誘發FGF-9的表現。實驗結果發現FGF-9及它的高親合性接受體FGFR2IIIc及FGFR3IIIc大量表現在異位內膜組織。若我們將細胞處理雌激素接受器的拮抗劑 (ICI 182,780)或是苯環酵素催化脢抑制劑 (4-hydroxyandrostenedione; 4-HA) 則會抑制異位基質細胞FGF-9表現，表示由異位內膜組織不正常表現之雌激素可以作用於異位內膜組織本身而促進FGF-9表現。相同的，另外我們也使用及ICI 182,780 以及4-HA去抑制細胞的增生，然而如此的抑制效果可藉由外給FGF-9而恢復。甚至，PGE2可以直接透過FGF-9促進異位基質細胞的增生表現，而此作用並不需要透過促進雌激素而達成。我們發現PGE2主要是透過與PGE2接受器EP3接合進而活化蛋白質磷酸化脢C-�� (PKC-�n��)誘發FGF-9表現。PKC-�堈i而活化細胞訊息傳遞因子ERK1/2 及轉錄因子Elk-1進而活化FGF-9轉錄表現。在FGF-9的促進子區域(-1324/-1329 及 -1046/-1051)各有一個轉錄因子Elk-1作用位置並由實驗證明對於PGE2誘發FGF-9表現具有關鍵性的意義。總而言之，我們是首度證實PGE2可以直接誘發FGF-9表現，並發現了一個新的訊息傳遞路徑:由PGE2藉由結合到其特異性接受器EP3後所活化之訊息傳遞分子PKC-�n�唌A及ETS家族之轉錄因子Elk-1。總而言之，PGE2可以直接或間接透過FGF-9促進異位基質細胞的增生表現。就直接的途徑而言， PGE2是透過與EP3達成此作用; 而就間接的途徑而言，PGE2是透過促進雌激素而達成。PGE2可以藉由過度表現StAR及aromatase促進異位基質細胞合成雌激素。然而在生理上的意義，則是在人類動情週期中當卵巢雌激素表現很低時，異位內膜組織所不正常表現之雌激素可以藉由作用回異位內膜組織本身而誘發FGF-9及FGF-9接受器表現並進一步促進細胞增生以利於子宮內膜異位症之形成。雌激素誘發FGF-9表現可以增加異位內膜組織存活及生長以利於長期維持異位內膜異位症。我的研究發現對於PGE2作用在FGF-9所調控的胚胎發育及疾病，提供了一個重要的分子機制去解釋。進而針對過度表現環狀氧化脢(cyclooxygenase) 的疾病，亦可以依循此分子機制的脈絡用以發展治療及預防的方針。

Endometriosis, one of the commonest gynecological disorders, is defined as the presence of endometria-like tissues outside the uterine cavity. The etiology of endometriosis is complex and remains largely unknown. The progression of endometriosis is estrogen-dependent. However, estrogen rarely exerts direct growth effect but often mediates through peptide growth factors. Fibroblast growth factor-9 (FGF-9) is reported as an estromedin in normal endometrium and acts as a mitogen for uterine endometrial stromal cells. It indicates FGF-9 is one of the potential candidates involving in the etiology of endometriosis. Nevertheless, cellular and molecular mechanisms responsible for regulation of FGF-9 expression are mostly unknown. Previous study shows that concentration of prostaglandin (PG) E2 in peritoneal cavity is elevated due to aberrant expression of cyclooxygenase-2 (COX-2) in endometriotic tissue and peritoneal macrophage. Since PGE2 is a potent inducer for steroidogenic acute regulatory protein (StAR) and aromatase, two genes that control estrogen biosynthesis, it is reasonable to hypothesize that PGE2 might act through estrogen to regulate FGF-9. Therefore, this study aims to examine action of PGE2 on FGF-9 gene expression. Two hypotheses will be tested. First, FGF-9 is autonomously expressed by ectopic endometriotic stromal cell due to aberrant expression of estrogen. Second, PGE2 may stimulate FGF-9 gene expression possibly through increasing estrogen production in ectopic endometriotic stromal cells. Results reveal that FGF-9 and its high affinity receptors, FGF receptor 2IIIc (FGFR2IIIc), and FGF receptor 3IIIc (FGFR3IIIc), are effectively expressed by ectopic endometriotic tissues. In addition, expression of FGF-9 in ectopic endometriotic stromal cell is inhibited by treatment with ICI 182,780 (an estrogen receptor antagonist) and 4-hydroxyandrostenedione (an aromatase inhibitor) indicating it is likely regulated by estrogen in an autocrine manner. Concordantly with these results, proliferation of ectopic endometriotic stromal cells is inhibited by treatment with ICI and is reversed by exogenous addition of recombinant FGF-9. Moreover, PGE2 can induce ectopic endometriotic stromal cells proliferation in a FGF-9-dependent manner. Further study reveals that PGE2-induced FGF-9 expression is independent of estrogen. I find that PGE2 induces FGF-9 expression through the EP3 receptor activated protein kinase C�� (PKC��) signaling pathway. Activation of PKC�� leads to phosphorylation of ERK1/2 and the transcription factor Elk-1 thereby promoting transcription of FGF-9. Two Elk-1 cis-binding sites locating at -1324/-1329 and -1046/-1051 of human FGF-9 promoter are identified to be crucial for mediating PGE2 actions. These data demonstrate, for the first time, that PGE2 can directly induce FGF-9 expression via a novel signaling pathway involving EP3, PKC�� and a member of ETS domain-containing transcription factor superfamily. Taken together, results from my current study demonstrate that PGE2 can induce FGF-9 expression thus endometriotic stromal cell proliferation through direct and indirect pathways. The direct pathway is carried out via EP3 signaling while indirect one is mediated via induction of estrogen biosynthesis. PGE2 may cause overexpression of StAR and aromatase result in aberrant production of estrogen. It serves as primary source for induction of FGF-9 and its high affinity receptors via an autocrine mechanism when systemic estrogen is low. Estrogen-induced expression of FGF-9 may increase the chance for ectopic endometriotic lesions to survive and growth involving long-term maintenance of endometriosis. In a sense, my findings provide a new thinking direction of reevaluating effects of PGE2, estrogen, and peptide growth factors on the etiology of endometriosis and a molecular framework for future considerations in designing new regimens for therapeutic or preventive purpose against diseases with overexpression of cyclooxygenase.

Abstract 1
Chinese abstract 3
I. LITERATURE REVIEW 5
1.1 Historical overview of endometriosis 5
1.2. Classification of endometriosis 6
1.3. Etiology of endometriosis 6
1.3.1. Proposed hypothesis for histogenesis of endometriosis 6
1.3.2. Factors contribute to the susceptibility of a woman to develop endometriosis 7
1.3.2.1. Immune system and endometriosis…………………………….7
1.3.2.2. Intrinsic molecular aberrations in pelvic endometriotic implants8
1.4. Steroid hormone and endometriosis 9
1.4.1. 17��-estradiol is critical for development and maintenance of endometriosis 9
1.4.2. Regulation of 17��-estradiol biosynthesis 10
1.4.3. 17��-estradiol exerts its growth-promoting effect through some peptide growth factors via an autocrine/paracrine manner 11
1.4.3.1. Epidermal growth factor and insulin growth factor-I in endometriosis………………………………………………...11
1.4.3.2. Fibroblast growth factors in endometriosis …………………. 12
1.5. FGF-9 is an estromedin in normal endometrium and acts as a mitogen uterine endometrial stromal cells 14
1.5.1. Roles of FGF-9 in other physiological functions…………………...14
1.5.2. Signaling pathways of FGFs utilize in endometriosis 15
1.6. Prostaglandin E2 and endometriosis 17
1.6.1. Physiological function of prostaglandin E2 17
1.6.2. Aberrant production of PGE2 in endometriosis 18
1.6.3. Signaling pathways of PGE2 receptors 19
1.7. Hypothesis 20
II. Materials and Methods 23
2.1. Patients and tissue collection 23
2.2. Cell culture 24
2.3. Chemicals and Antibodies 26
2.4. Plasmids, transfection, and promoter activity assays 27
2.5. Regulation of FGF-9 gene expression in stromal cells 28
2.6. Bromodeoxyuridine (BrdU) cell proliferation assay 29
2.7. Quantification of mRNA concentrations using standard curve quantitative competitive (QC)-RT-PCR methodology 30
2.8. Detection of FGF-9 protein by Western blotting 32
2.9. Calcium measurement 32
2.10. Electrophoretic mobility shift assay 34
2.11. Chromatin immunoprecipitation (ChIP)-PCR assay 34
2.12. Statistical analysis 35
III. Results 36
3.1. Expression of FGF-9 and its receptors in endometriotic tissues 36
3.2. Effect of exogenous E2 on FGF-9 and FGFRs in ectopic endometriotic stromal cells………………………………………………………………………... 40
3.3. FGF-9 stimulated ectopic endometriotic stromal cell proliferation 40
3.4. Effect of endogenous E2 on FGF-9 expression and endometriotic stromal cell proliferation 40
3.5. PGE2 induces FGF-9 mRNA expression independent of estrogen 44
3.6. E2-induced FGF-9 expression is not augmented by PGE2 49
3.7. PGE2-induced FGF-9 expression is independent of transactivation of ER by IGF-1 and EGF 51
3.8. PGE2-induced FGF-9 expression is independent of new protein synthesis 51
3.9. PGE2-induced FGF-9 expression is mediated via EP3 receptor 54
3.10. Calcium/calmodulin dependent kinase II and IV are not the downstream effectors of the PGE2-induced intercellular Calcium in endometriotic stromal cells………………………………………………………………………...60
3.11. PGE2-induced FGF-9 expression is mediated by PKC�� 63
3.12. Effects of PMA on phosphorylation of certain PKC isoforms in endometriotic stromal cells. 63
3.13. Small interference of protein kinase C�� �nsubstantially disrupted PGE2 or sulprostone-induced FGF-9 mRNA and protein expression 68
3.14. ERK1/2 is activated by PGE2 and is downstream of PKC�� 71
3.16. The -886 to -1346 region was critical for PGE2-mediated FGF-9 promoter activity……………. 75
3.17. Elk-1 is the downstream transcription factor of PKC�� in PGE2-induced FGF-9 expression 75
3.18. Binding of Elk-1 to the fgf-9 promoter is enhanced after PGE2 treatment. 77
3.19. FGF-9 mediates PGE2-induced endometriotic stromal cell proliferation 83
IV. Discussion 86
VI. References 95


LIST OF FIGURES

Figure 1. Production of PRL and E2 by ectopic endometriotic stromal cells. 25
Figure 2. Standard curve QC-RT-PCR using FGF-9 as an example. 33
Figure 3. Expression of FGF-9 mRNA and protein in endometriotic tissues. 37
Figure 4. Expression of specific splicing variants of FGFR2 (A) and FGFR3 (B) in ectopic endometriotic stromal cell. 39
Figure. 5. Induction of FGF-9 by E2. 41
Figure. 6. Induction of FGF-9 receptors by E2. 42
Figure. 7. FGF-9 induced endometriotic stromal cell proliferation in a dose-dependent manner. 43
Figure 8. Expression of FGF-9 mRNA (A) and protein (B) in endometriotic 45
stromal cells were controlled by autocrine effect of E2. 45
Figure 9. Effect of ER antagonist (ICI) and aromatase inhibitor (4-HA) on 46
FGF-9-stimulated endometriotic stromal cell proliferation. 46
Figure 10. PGE2 induces FGF-9 expression in endometriotic stromal cells. 47
Figure 11. E2-induced FGF-9 expression is not augmented by PGE2. 50
Figure 12. PGE2-induced FGF-9 expression is independent of transactivation of ER by certain peptide growth factors. 52
Figure 13. PGE2-induced FGF-9 expression is independent of new protein synthesis. 53
Figure 14. PGE2-induced FGF-9 expression is mediated via EP3 receptor-dependent signaling pathway. 56
Figure 15. PGE2-induced FGF-9 mRNA expression indicating activation of MEK is not dependent on Ras signaling. 58
Figure 16. PGE2-induced FGF-9 mRNA expression is not mediated by transactivation of RTKs. 59
Figure 17. PGE2-induced intercellular calcium concentration in endometriotic stromal cells. 61
Figure 18. Calcium/calmodulin dependent kinase II and IV are not the downstream effectors of the PGE2-induced intercellular calcium in endometriotic stromal cells. 62
Figure 19. PGE2 induces phosphorylation of certain PKC isoforms. 65
Figure 20. Effects of PMA on phosphorylation of certain PKC isoforms in endometriotic stromal cells. 67
Figure 21. PKC�� �nis critical for PGE2-induced FGF-9 expression. 69
Figure 22. ERK1/2 is activated by PGE2 and is downstream of PKC���| 73
Figure 23. PGE2 induces FGF-9 expression is mediated by ERK1/2. 74
Figure 24. The -886 to -1346 region was critical for PGE2-mediated FGF-9 promoter activity. 78
Figure 25. Elk-1 is the downstream effectors of PKC�� �nin PGE2-induced FGF-9 expression. 79
Figure 26. Elk-1 is the downstream effectors of PKC�� in PGE2-induced FGF-9 expression. 81
Figure 27. Binding of Elk-1 to the FGF-9 promoter is enhanced after PGE2 treatment. 82
Figure 28. FGF-9 mediates PGE2-induced endometriotic stromal cell proliferation. 84
Figure 29. A schematic drawing shows the signal transduction pathways mediating estrogen and PGE2-induced FGF-9 gene transcription in ectopic endometriotic stromal cells. 85
Figure 30: New insight of current working model in endometriosis. 94

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