探討慢性骨髓性白血病細胞中IL-8在Bcr-Abl調控的細胞作用中所扮演的角色

The Role of IL-8 in Bcr-Abl-mediated Cell Activities in Chronic Myeloid Leukemia Cells

郭雪琴(Swat Kim Kerk)

指導教授 ： 黃惠美

臺北醫學大學/醫學院/醫學科學研究所/碩士(2015年)

摘要

過去的研究顯示IL-8在許多癌症中都有異常的表現量。但是，IL-8在由Bcr-Abl所引起的慢性骨髓性白血病 (CML) 的作用至目前爲止仍屬未知。此外，我們過去的研究顯示於Bcr-Abl訊號下，IL-8是CD69和CD24的下游調控分子。本篇研究顯示，於CD34+人類臍帶血幹細胞和CML細胞株K562中，Bcr-Abl可以正調控IL-8的表現量。同時，在K562細胞中，CD69和CD24也被發現可以增加IL-8的promoter activity。另外，從IL-8 promoter analysis和染色體免疫沉澱(ChIP assay)中，我們也發現Bcr-Abl透過NF-κB和c-Jun，這兩個轉錄因子結合至IL-8 promoter上並誘導其表現。我們也再次證明在Bcr-Abl-transfecting CD34+人類臍帶血幹細胞中，CD69和CD24 knock-down可以增加由Bcr-Abl抑制劑，imatinib，所誘導的生長抑制和凋亡。但是，IL-8，這個CD69和CD24的下游分子，卻對K562 細胞的生長沒有作用。最後，我們也發現在K562細胞中，IL-8會抑制紅血球分化基因的mRNA表現，例如hemoglobin-α, hemoglobin-ζ 和CD71。本篇研究的價值在於，我們是第一個發現IL-8的表現量可以被Bcr-Abl/CD69/CD24 signaling pathway所調控。此外，IL-8可能扮演紅血球分化抑制的角色於Bcr-Abl positive細胞中。

關鍵字

IL-8 ； Interleukin-8 ； CXCL8 ； CML ； 慢性骨髓性白血病 ； 紅血球分化 ； Hemoglobin-α ； hemoglobin-ζ ； K562 ； CD34+人類臍帶血幹細胞 ； CD69 ； CD24 ； Bcr-Abl

並列摘要

Aberrant expression of IL-8 is associated with various human cancers. However, the roles of IL-8 in Bcr-Abl-positive chronic myeloid leukemia (CML) cells are unknown. From our previous studies, we found that IL-8 might be the downstream molecule of CD69 and CD24 in Bcr-Abl signaling. In this study, we found that Bcr-Abl can up-regulate IL-8 expression in human cord blood CD34+ cells and CML cell line, K562 cells. In addition, IL-8 promoter activity can be positive up-regulated by CD69 and CD24 in K562 cells. Furthermore, promoter analysis combined with the chromatin immuneprecipitation (ChIP) assay demonstrated that the binding of NF-κB and c-Jun to IL-8 gene promoter increased the expression of IL-8 under Bcr-Abl signaling. In this study, we further enforced our previous finding that CD69 and CD24 knock-down can enhanced imatinib-induced growth inhibition and cell apoptosis by using Bcr-Abl-transfecting human cord blood CD34+ cells. However, IL-8 had no effects on K562 cell proliferation. Lastly, IL-8 was found inhibiting the erythroid gene expression including hemoglobin-α, hemoglobin-ζ and CD71 in K562 cells. Taken together, we are the first to demonstrate that IL-8 expression can be up-regulated by Bcr-Abl/CD69/CD24 and might play a role in the regulation of erythroid differentiation in Bcr-Abl positive cells.

並列關鍵字

IL-8 ； Interleukin-8 ； CXCL8 ； CML ； Chronic Myelogenous Leukemia ； Chronic Myeloid Leukemia ； Erythroid differentiation ； Hemoglobin-α ； hemoglobin-ζ ； K562 ； human cord blood CD34+ cells ； CD69 ； CD24 ； Bcr-Abl

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