子宮內膜異位症是生殖年齡婦女當中常見的婦科疾病之一。常見的症狀包括經痛、性交痛、骨盆腔疼痛以及不孕症，雖然不會致命，但是卻大大降低了患者的生活品質。子宮內膜異位症就是子宮的內膜組織因為不明原因出現在子宮腔以外的地方生長，但可以確定的是當子宮內膜組織的貼附能力增加時，因為經血逆流而跑到腹腔的組織塊的附著以及存活的能力也會隨之增加。本篇研究主要是為了探討在子宮內膜異位症當中，子宮內膜組織的貼附能力對於異位子宮內膜細胞生存能力的影響及其分子機制。炭疽毒素受體-2 在過去研究中已經被發現在血管新生以及對細胞外基質的貼附中具有關鍵性的角色。在此，我們發現炭疽毒素受體-2在子宮內膜異位組織以及其中的異位基質細胞中的mRNA以及蛋白表現量都有過度表現的情況。為了確定炭疽毒素受體-2是否真的會增加子宮內膜異位細胞對細胞外基質的貼附能力，在此利用抑制劑1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose (PGG)抑制炭疽毒素受體-2後，結果顯示抑制炭疽毒素受體-2後，不僅會抑制子宮內膜異位基質細胞的貼附能力，也會抑制異位細胞的生長力。同時在此也發現利用PGG抑制炭疽毒素受體-2會降低Focal adhesion kinase (FAK) 及Extracellular signal-regulated kinases (ERK)的磷酸化，顯示炭疽毒素受體-2可能參與在FAK的訊息傳遞路徑調控細胞貼附，同時也參與ERK的訊息傳遞路徑來調控細胞生長。接著我們想要探討再子宮內膜異位症當中，是甚麼分子機制調控炭疽毒素受體-2的表現進而影響子宮內膜異位症的進程。過去研究已經知道子宮內膜異位症在腹腔中會發生發炎反應，並且會有異常過度表現的促發炎因子在病人的腹腔液當中，而這些促發炎因子可能會因此影響異位到腹腔環境的子宮內膜細胞。所以我們將子宮內膜原位基質細胞處理患有子宮內膜異位症病人的腹腔液後發現炭疽毒素受體-2的表現量增加。若進一步用腹腔液當中大量表現的促發炎因子處理原位基質細胞，發現處理腫瘤壞死因子-α (TNF-α)也可以看到相同的結果。綜合以上，我們得知炭疽毒素受體-2透過病人腹腔液當中的腫瘤壞死因子-α的刺激而表現量增加，進而促進子宮內膜基質細胞對細胞外基質的貼附能力，在子宮內膜異位症當中扮演關鍵性的角色。

Endometriosis is one of the most common gynecological diseases in women of reproductive age. The common symptoms of endometriosis are dysmenorrhea, dyspareunia, pelvic pain and infertility, which reduces life quality of patients. Endometriosis is defined as the endometrial tissue present outside of the uterus with an unknown etiology. However, it is clear that an increase in the adhesion ability should enhance the retrograded endometrial tissues to attach and survive outside the uterus. This study was designed to investigate the underlying mechanism responsible for the survival of ectopic endometriotic cells with the focus on adhesion ability. Anthrax toxin receptor 2 (ANTXR2) has been known to play a crucial role in angiogenesis and the binding to extracellular matrix. Herein, we found that ANTXR2 was overexpressed in ectopic endometriotic tissues and purified stromal cells by using real time RT-PCR and Western blotting. To test whether ANTXR2 promotes endometriotic lesion attachment and survival at the early stage of endometriosis, stromal cells were treated with 1,2,3,4,6 -penta-O-galloyl-β-D-glucopyranose (PGG), an inhibitor of ANTXR2. Results demonstrated that treatment with PGG not only reduced adhesion ability but also inhibited the growth of endometriotic stromal cells. We also found that treatment with ANTXR2 inhibitor can decrease phosphorylation of focal adhesion kinase (FAK) and extracellular signal–regulated kinases (ERK), suggesting that ANTXR2 might regulate cell adhesion ability through FAK signaling transduction and regulate cell growth through ERK pathway. Next, we aimed to characterize how ANXTR2 is regulated during the development of endometriosis. Since chronic inflammation is a key feature of endometriosis and the abnormal increase of proinflammatory cytokines, such as interleukin 1 beta (IL1-β), tumor necrosis factor alpha (TNF-α) and transforming growth factor-β1 (TGF-β1) in peritoneal fluid secreted by endometriotic lesion had been documented, we tested whether peritoneal fluid from patients with endometriosis and also these proinflammatory cytokines in peritoneal fluid can induce ANXTR2 expression. Indeed, treatment with peritoneal fluid from patients with endometriosis stimulated ANTXR2 expression. But only treatment with TNF-α can significantly increase ANTXR2 expression. Finally, treatment of normal endometrial stromal cells with TNF-α markedly enhanced adhesion ability. Taken together, our results suggest that ANTXR2 is a critical factor in endometrial physiology and TNF-α might be a driving force to promote the early development of endometriosis via increase ANTXR2 expression.

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