https://scholars.lib.ntu.edu.tw/handle/123456789/145806
標題: | 血癌細胞對SDF-1缺乏趨化能之機制的探討 Study on the molecular mechanism of defective SDF-1 response in leukemic cells |
作者: | 陳雅瑩 Chen, Ya-Ying |
關鍵字: | 血癌細胞;趨化激素SDF-1;SDF-1;leukemic cell | 公開日期: | 2004 | 摘要: | 血球形成是一個複雜的過程,骨髓中的多弁鈳y血幹細胞經細胞激素、生長因子等刺激,分裂、分化成各血球系細胞。正常情況下,不成熟的造血細胞會留在骨髓內,直到成熟後才會釋放到周邊血液中。研究顯示,CXC趨化激素SDF-1與受器CXCR4對於維持造血前趨細胞停留在骨髓以及前趨細胞之游移作用有其重要性。相較於正常造血前趨細胞,不成熟血癌細胞亦會游移至周邊血中,但其機制目前並不清楚。我們認為CXCR4/SDF-1訊息途徑參與其中。 先前實驗室針對Jurkat、U937、Raji、HL-60、K562、HL-CZ六種細胞株做研究,發現U937與Jurkat表現CXCR4蛋白且CXCR4弁鄍膨`;Raji、HL-60表現CXCR4蛋白但其弁鄏陳妘插FK562、HL-CZ表面沒有CXCR4蛋白表現,故對SDF-1無反應。 進一步去探討細胞對SDF-1沒有反應之分子機轉;實驗結果發現,fibronectin非造成Raji、HL-60細胞對SDF-1無反應之因素。Raji的內翻現象受到抑制而無法傳遞訊息所造成,但其CXCR4磷酸化之現象正常;而HL-60其內翻弁鄑髡n,卻有訊息傳遞缺陷的情形發生;先前發現,K562及HL-CZ之CXCR4 mRNA有明顯較低的現象,而其細胞質中有CXCR4蛋白的存在,推測其CXCR4蛋白之移位(translocation)有缺陷。利用西方墨點法分析其CXCR4分子量,發現此兩株細胞之CXCR4為40KD,而經過醣化修飾之CXCR4分子量45-47KD。推測此兩株細胞之CXCR4蛋白的修飾作用不完全。 總結來說,CXCR4/SDF-1訊息途徑在不成熟血癌細胞游移到周邊血中扮演重要地位。 Immature hematopoietic cells are normally entrapped in the bone marrow (BM) until differentiation into mature ones. Recent reports indicated that the CXC chemokine SDF-1 and its receptor, CXCR4, play a key role in retaining haematopoietic progenitor cells (HPCs) within the BM and mobilization of HPCs. In contrast to normal HPCs, immature leukemic cells often egress into peripheral blood (PB) with unclear mechanisms. We speculate that impaired CXCR4/SDF-1 chemotaxis axis may play a role in this scenario. We previously studied the expression of CXCR4 and responses toward SDF-1 in six leukemic cell lines (HL-60, HL-CZ, U937, Raji, Jurkat, and K562). We found that U937 and Jurkat had high CXCR4 expression and good response to SDF-1; HL-60 and Raji had high CXCR4 expression but poor response to SDF-1; while K562 and HL-CZ had low CXCR4 expression and poor response to SDF-1. The possible mechanism of the defective SDF-1-response was further explored. We found that fibronectin did not correlate with the poor response to SDF-1 in Raji and HL-60 cell lines. We demonstrated that Raji cells had defect in the process of CXCR4 receptor endocytosis, but there was phosphorylation of CXCR4 in Raji cells after treatment of SDF-1. HL-60 cell had the defect in CXCR4/SDF-1 signaling pathway, although there was perfect function of internalization. Comparing to other leukemic cell lines, the K562 and HL-CZ leukemic cell lines had lower level of CXCR4 mRNA, but still had substantial intracellular CXCR4 protein, suggesting the defective membrane translocaiton for CXCR4 protein. The result of western blot analysis showed that the molecular weight (MW) of CXCR4 in both HL-CZ and K562 cells was 40 kDa, while the predicted MW of glycosylated CXCR4 is 45-47 kDa. It suggested an incompletion that the modification of CXCR4 in HL-CZ and K562. We concluded that dysfunction of the CXCR4/SDF-1 signaling axis may be responsible for egression of immature leukemic cells into peripheral circulation. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/62834 | 其他識別: | zh-TW |
顯示於: | 醫學檢驗暨生物技術學系 |
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ntu-93-R91424002-1.pdf | 23.31 kB | Adobe PDF | 檢視/開啟 |
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