探討內皮素在人類軟骨肉瘤轉移之機制

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题名:	探討內皮素在人類軟骨肉瘤轉移之機制 Studies of endothelin-1 in metastasis of human chondrosarcoma
作者:	吳旻寰;Min-Huan Wu
贡献者:	基礎醫學研究所博士班
关键词:	內皮素;基質金屬蛋白脢;環氧合?;血管內皮生長因子;endothelin-1;MMP;COX-2;VEGF
日期:	2013-06-27
上传时间:	2013-10-02 11:15:12 (UTC+8)
出版者:	中國醫藥大學
摘要:	軟骨肉瘤是一種高度惡化的腫瘤具有原位侵略及遠距離轉移的潛力。細胞轉移與血管新生的現象則是癌症轉移必要的過程。過去的研究指出內皮素與腫瘤的血管新生及轉移現象有關。然而，內皮素(endothelin-1)對血管新生及轉移能力的影響在人類軟骨肉瘤細胞上並不清楚。在此，我們發現ET-1會促進人類軟骨肉瘤細胞爬行的能力並且增加腫瘤中基質金屬蛋白脢(matrix metalloproteinase； MMP)-13、環氧合?(cyclooxygenase； COX)-2以及血管內皮生長因子(VEGF)的表現量。相較於一般正常的軟骨而言，人類軟骨肉瘤細胞中的COX-2與VEGF等蛋白質表現量較正常的軟骨細胞要高。異常的ET-1會增加細胞爬行的能力並使細胞釋放MMP-13與COX-2。此外， MMP-13、COX-2蛋白質表現量與細胞爬行能力都會受到內皮素接收器阻抗劑所抑制。額外給予ET-1會促使VEGF蛋白質表現量增加而增加內皮前驅細胞的轉移與血管新生現象。此外、降低ET-1蛋白質的量同時會降低細胞轉移並且抑制軟骨肉瘤細胞條件培養液所調控的體外的血管新生實驗以及雞胚?毛尿囊膜(chick chorioallantoic membrane)、在裸鼠中植入的質凝膠分析法(matrigel-plug)等活體的血管新生實驗模式。值得注意的是，使用異種移植(xenograft)的動物模式，一旦減低細胞中ET-1的含量便會減少老鼠體內腫瘤的生長以及腫瘤血管新生的能力。總而言之，這些結果都認為ET-1會增加人類肉瘤軟骨細胞中MMP-13、COX-2、VEGF的蛋白質表現量增加，進而促使腫瘤生成、血管新生以及後續癌症轉移的結果。 Chondrosarcoma is a type of highly malignant tumor with a potent capacity of local invasion and distant metastasis. Cell migration and angiogenesis is essential for the caner metastasis. Endothelin-1 (ET-1) has been implicated in tumor angiogenesis and metastasis. However, the effect of ET-1 on metastasis and angiogenesis activity in human chondrosarcoma cells is not clearly understood. Here, we found that ET-1 increased the migration, angiogenesis and expression of matrix metalloproteinase (MMP)-13, cyclooxygenase (COX)-2, and vascular endothelial growth factor (VEGF) in human chondrosarcoma cells. Human chondrosarcoma tissues had significant expression levels of ET-1, COX-2, and VEGF which significantly higher than those in normal cartilage. Aberrant ET-1 increased cell migration and the expression of MMP-13 and COX-2. In addition, MMP-13 and COX-2 expression as well as cell migration ability were abolished by ET receptor antagonists. Exogenous ET-1 with chondrosarcoma cells promoted VEGF expression and subsequently increased migration and tube formation in endothelial progenitor cells. Furthermore, knockdown of ET-1 decreased cell metastasis also abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and matrigel-plug nude mice model in vivo. In addition, using xenograft tumor model, knockdown ET-1 significantly reduced tumor growth and tumor-associated angiogenesis. Taken together, these results suggest that ET-1 increased MMP-13, COX-2, and VEGF expression and contributing the tumor growth, angiogenesis, and metastasis of human chondrosarcoma cells.
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