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研究生:李怡蓉
研究生(外文):Yi-Rong Lee
論文名稱:骨橋蛋白在子宮內膜中所扮演的角色
論文名稱(外文):The role of osteopontin in endometriosis
指導教授:高淑慧高淑慧引用關係
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:90
中文關鍵詞:子宮內膜異位骨橋蛋白雌激素
外文關鍵詞:endometriosisosteopontinβ-estradiol.
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子宮內膜異位是一種婦產科常見的疾病,而造成此疾病的發病過程及機轉並不清楚。近年來有研究指出在大鼠的子宮內膜異位的模式中,發現骨橋蛋白(osteopontin, OPN)在子宮組織內會大量表現。本論文主旨在探討OPN在子宮內膜異位的形成中所扮演的角色。首先,我們利用西方墨點法發現子宮內膜異位病患的子宮內膜組織、腹膜液、濾泡液和巧克力囊腫體液中OPN會大量表現。此外,我們並以子宮內膜HEC-1A 細胞為細胞模式,觀察OPN對子宮內膜細胞的移行、入侵和增生能力的影響。接著我們以不同劑量的OPN去處理細胞,細胞產生移行及入侵,但不具有增生能力。由OPN引發的細胞移行及入侵可被αvβ3 integrin inhibitor所減緩。另一方面,我們發現β-estradiol和 progesterone會增加細胞內OPN表現及分泌型的OPN釋出,也會誘導細胞產生移行,但當β-estradiol和 progesterone共同作用時,OPN表現及細胞移行現象則降低。接著,我們將細胞中內生性的OPN knockdown後,可減緩β-estradiol所誘導細胞移行的現象及OPN的分泌。接下來我們更進一步探討OPN於細胞內的訊息傳遞路徑,當細胞經由1μM Wortmanin (PI-3k inhibitor)前處理後,OPN仍可引發細胞移行且NF-κB蛋白質表現增加,但是在10μM Wortmanin (PI-3k inhibitor)前處理下,移行現象則被抑制。最後我們從zymography assay中發現OPN會促進細胞表現MMP-2、MMP-9。由上述的結果,我們推測OPN可被β-estradiol刺激而表現及分泌釋出,可再經由 autocrine或paracrine的機制,與細胞上αvβ3 integrin結合而促使細胞移行及侵入,其中訊息傳遞路徑可能是經由 PI-3K路徑活化MMP2/9及產生actin重組(remodeling)。
Endometriosis is a common gynecological disease. The pathology and etiology of endometriosis is still unclear. Recently, enhanced osteopontin(OPN) expression was found in the endometriotic tissue of rat model. We propose that OPN could promote the endometriotic cell migration and invasion. The differential proportion of OPN was detected in the endometrium from the patients with endometrial hyperplasia, myoma, endometriosis or adenomyosis. A significant increase of OPN was found in the eutopic endometrium in the women with adenomyosis. In this study, HEC-1A cell was used as the in vitro enodometriotic cell model to illustrate the effects of OPN on cell migration, invasion and proliferation. A dose-response and time-dependent increase of cell migration and cell invasion was demonstrated. But there was no difference in cell proliferation followed the OPN treatment. Nevertheless, the OPN induced cell migration and invasion was attenuated or inhibited by αvβ3 integrin inhibitor (anti-αvβ3 antibody). On the other hand, we also found β-estradiol or progesterone was found to augment OPN expression and secretion, and induced cell migration. β-estradiol-induced cell migration was attenuat followed the silence the OPN expression by OPN siRNA. In immunoflurescent staining, we observed actin remodeling in the-OPN treated cells. We also found a dose response activation of MMP-2 and MMP-9 followed OPN treatment. Finally, we found cell migration was attenuated by Wortmannin (PI-3k inhibitor). We suggested OPN-induced cell migration and invasion was mediated by the OPN-αvβ3 interaction. The molecular signal pathway of OPN/αvβ3-mediated MMP activation and actin remodeling through PI-3K.
中文摘要 1
Abstract 3
研究動機與目標 5
第一章 文獻回顧 6
文獻回顧 7
子宮內膜異位(endometriosis) 7
一、子宮內膜異位(endometriosis) 7
二、子宮內膜異位形成的機轉 8
三、治療方式 9
四、子宮內膜異位與荷爾蒙關係 10
五、目前與子宮內膜異位相關研究 11
骨橋蛋白(Osteopontin) 12
一、骨橋蛋白(Osteopontin) 12
三、骨橋蛋白的功能 14
四、骨橋蛋白訊息的調控(Mediator of OPN signaling) 15
五、骨橋蛋白在腫瘤細胞中所扮演的角色 16
六、骨橋蛋白在生殖醫學中所扮演的角色 17
六、骨橋蛋白分泌作用機轉 19
基質金屬蛋白酶(Matrix Metalloprotienase, MMP) 19
第二章實驗材料與方法 21
藥品試劑 22
實驗方法 25
一、檢體收集(Tissue collection) 25
二、HEC-1A細胞培養 25
三、 藥物的配製 26
四、 MTS assay 26
五、 Scratch wound assay 27
六、 Matrigel® invasion assay 27
七、組織蛋白質製備(Preparation of tissue lysate) 28
八、細胞蛋白質製備(Preparation of cell lysate) 28
九、培養液蛋白質製備(Preparation of conditional medium) 29
十、 蛋白質定量 29
十一、西方墨點法 30
十二、分析細胞內相關基因的表現 32
十三、 Gelatin zymography 33
十四、 Small interference RNA 35
十五、雷射共軛焦顯微鏡 35
十六、放射免疫測定法(Radioimmunoassay) 36
十七、統計分析 37
第三章 實驗結果與分析 38
一、 子宮內膜組織中OPN含量 39
二、在子宮內膜異位病患的腹膜液、濾泡液、巧克力囊腫體液及精漿中OPN含量。 39
三、OPN對子宮內膜細胞移行能力(migration)的影響 40
四、 OPN對子宮內膜細入侵能力(invasion)的影響 40
五、 OPN對cell proliferation的影響 41
六、 雌激素對子宮內膜細胞OPN表達的影響。 41
六、 黃體素對子宮內膜細胞OPN表達的影響。 42
七、 雌激素及黃體素對子宮內膜細胞OPN表達的影響。 42
八、 雌激素及黃體素對子宮內膜細胞移行能力的影響。 43
九、在子宮內膜異位患者濾泡液中E2 和P4濃度。 43
十、OPN siRNA對細胞移行的影響。 44
十一、Secreted OPN的測定。 44
十二、共軛焦顯微鏡觀察細胞內actin分佈的情形。 45
十三、OPN經由PI-3k訊息路徑調控細胞移行能力。 45
十四、OPN不經由NF-κB訊息路徑調控細胞移行能力。 46
十五、OPN會促進子宮內膜細胞產生MMP-2和MMP-9活性增加。 46
第四章 討論 48
第五章 參考文獻 58
第六章 圖表 67


表目錄
Table 1. 本研究中所使用的引子DNA oligonucleotides序列。 68
Table 2. 本研究所使用siRNA OPN single stranded RNA oligonucleotide。 69

圖目錄
Figure 1. SIBLING family基因的染色體位置與人類骨橋蛋白的基因結構 。 70
Figure 2. 骨橋蛋白functional domain。 71
Figure 3. 骨橋蛋白於細胞中有不同的訊息傳遞路徑。 72
Figure 4. 子宮內膜組織中OPN的含量。 73
Figure 5.在子宮內膜異位病患的腹膜液、濾泡液及巧克力囊腫濾泡液中OPN定量。 74
Figure 6.OPN對子宮內膜細胞移行能力(migration)的影響。 75
Figure 7. OPN對子宮內膜細胞入侵能力(invasion)的影響。 76
Figure 8.OPN對cell proliferation的影響。 77
Figure 9. 雌激素對子宮內膜細胞OPN表達的影響。 78
Figure 10. 黃體素對子宮內膜細胞OPN表達的影響。 79
Figure 11. 雌激素及黃體素對內膜細胞OPN表達的影響。 80
Figure 12. 雌激素與黃體素對子宮內膜細胞移行能力的影響。 81
Figure 13.不同濃度的雌激素與黃體素對子宮內膜細胞移行能力的影響。 82
Figure 14. 在子宮內膜異位患者與正常人濾泡液中E2 和P4含量比例。 83
Figure 15. OPN siRNA對細胞移行的影響。 84
Figure 16 .conditioned medium中Secreted OPN。 85
Figure 17. OPN對HEC-1A細胞中actin 分佈的影響。 86
Figure 18. Wortmannin(PI-3k inhibitor)對由OPN引發子宮內膜細胞移行能力(migration)的影響。 87
Figure 19. Wortmannin(PI-3k inhibitor)對由OPN引發子宮內膜細胞於NF-κB訊息傳遞路徑的影響。 88
Figure 20. OPN會促進子宮內膜細胞產生MMP-2和MMP-9活性增加。 89
Figure 21. OPN於子宮內膜異位中所扮演的角色。 90
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