研究介白素-8 、巨噬細胞移動抑制因子及細胞粘著受體的表現對於人類軟骨肉瘤細胞移行的影響

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題名:	研究介白素-8 、巨噬細胞移動抑制因子及細胞粘著受體的表現對於人類軟骨肉瘤細胞移行的影響 Study of the Effect of Migration by Interleukin-8 and Macrophage Migration Inhibitory Factor and Integrin Expression in Human Chondrosarcoma
作者:	李俊億;Lee, Chun-Yi
貢獻者:	臨床醫學研究所博士班
關鍵詞:	軟骨肉瘤;轉移;細胞黏著受體;介白素-8;巨噬細胞移動抑制因子;Chondrosarcoma;Metastasis;Integrin;IL-8;MIF
日期:	2012-07-17
上傳時間:	2012-08-31 16:34:55 (UTC+8)
出版者:	中國醫藥大學
摘要:	軟骨肉瘤(Chondrosarcoma)具高度侵入能力及遠端轉移的能力的惡性腫瘤，且軟骨肉瘤易轉移至肺部。細胞黏著受體(Integrin)為哺乳動物中重要的附著因子，在癌症細胞的轉移上扮演重要的角色。介白素-8 (Interleukin-8, IL-8) 屬於趨化因子CXC家族中的一員，可促進腫瘤生成及血管新生。巨噬細胞移動抑制因子(MIF) 是和發炎相關的細胞激素，最早被發現它可以調控巨噬細胞的移行和活化。然而，IL-8和MIF在軟骨肉瘤細胞的移行能力和integrin的表現目前是未知的。我們第一部分之研究在骨肉瘤細胞株(JJ012和SW1353) 中，IL-8會透過由CXCR1/CXCR2接受器，PI3K，Akt訊息路徑傳遞訊息，活化轉錄因子c-Jun，增加?庮??3 integrin的表現，進而影響軟骨肉瘤細胞的移行能力。更進一步的實驗指出，IL-8 shRNA表現的細胞可以有效抑制73％軟骨肉瘤細胞的移行及?庮、??3 integrin蛋白質的表現。第二部分之研究發現在訊息傳導路徑中，MIF會經由PI3K、Akt、NF-?羠路徑，使integrin的表現增加，進而促使軟骨肉瘤的移行。使用專一性抑制劑和轉染mutant進一步確認PI3K、Akt、NF-?羠路徑的參與。此外，篩選出高度移行力的JJ012細胞 (S10)，利用西方點墨法證明?庮和??3蛋白質表現會高於原JJ012細胞 (S0)。更進一步的實驗指出，MIF-shRNA表現的細胞可以有效抑制70％軟骨肉瘤細胞的移行及?庮、??3 integrin蛋白質的表現。總結，IL-8和MIF，經由PI3K/Akt和AP-1或NF-?羠訊息傳導路徑，增加?庮??3 integrin表現, 促進軟骨肉瘤細胞的移行。因此，IL-8和MIF在未來可成為治療軟骨肉瘤轉移的標靶之一。 Chondrosarcoma is highly malignant tumor with potent capacity to demonstrate local invasion as well as distal metastasis. Chondrosarcoma has a predilection to metastasis to lung. Integrins are the major adhesive molecules in mammalian cells and have been associated with metastasis of cancer cells. Interleukin-8 (IL-8), a chemokine with a defining CXC amino acid motif, is known to possess tumorigenic and proangiogenic properties. The macrophage migration-inhibitory factor (MIF) is a pro-inflammatory cytokine first known for its effect on macrophage migration and activation. However, the effects of IL-8 and MIF in migration and integrin expression in chondrosarcoma cells are still unknown. In the study part I, we found that IL-8 activated transcription factor C-jun via CXCR1/CXCR2 receptor and Akt and AP-1 pathways to increase the expresson ofαvβ3 integrin, and then effect on migration of chondrosarcoma cell lines. In advanced study, chondrosarcoma cell with expression of IL-8 shRNA decreased the migration of cell and protein expression ofαvβ3 integrin. In the study part II, MIF activated transcription factor NF-κB via Akt and AP-1 pathways to increase the expresson ofαvβ3 integrin, and then effect on migration of chondrosarcoma cell lines.In addition, migration-prone sublines demonstrated that increased cell migration ability was correlated with increased expression of MIF and αvβ3 integrin. In conclusion, IL-8 and MIF increased the migration and the expression of αvβ3 integrin in human chondrosarcoma cells. In addition, IL-8 and MIF enhances the migration of chondrosarcoma cells by increasing αvβ3 integrin expression through the PI3K/Akt and AP-1 or NF-κB signal transduction pathway. Therefore, IL-8 and MIF represent promising new targets for preventing metastasis of chondrosarcoma.
顯示於類別:	[臨床醫學研究所] 博碩士論文

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