中文摘要：

本文主要探讨低氧微环境对慢性粒细胞白血病细胞系K562分化的影响，以及钠氢交换蛋白1（NHEl）在该过程中的作用。利用低氧模拟物CoCl2或于低氧（2％O2、5％CO2和93％N2）环境中培养K562细胞；应用激光共聚焦显微镜测定细胞内pH值，瑞士染色观察细胞形态，实时定量RT-PCR检测基因表达，Westernblot技术检测MAPK磷酸化水平的改变。结果表明：与对照组相比，低氧培养的K562细胞表现出成熟相关的形态学改变，并伴随CCAAT／增强子结合蛋白（C／EBPd）的mRNA水平上调。特异性NHEl抑制剂Cariporide预处理能够促进低氧诱导的K562细胞分化。Cariporide处理后K562细胞的p38和ERK5蛋白激酶磷酸化水平显著增强。结论：低氧及低氧模拟物能够诱导K562细胞系分化。抑制NHEl活性协同促进低氧诱导的K562细胞分化，其机制可能是通过增强细胞内MAPK蛋白激酶磷酸化水平，从而促进分化。

英文摘要：

In this paper has studied the effect of hypoxia microenvironment on K562 leukemic cell differentiation, and characterized the involvement of NHE1 in them. The K562 cells were treated with hypoxia-mimicking agent COC12 or under actual hypoxia culture, and the specific NHE1 inhibitor Cariporide was used to inhibit NHE1 ac- tivity. The fluorescent probe BCECF was used for phi measurements. Gene expression was analyzed by RT-PCR. The morphological characterization was determined by Wright ms staining. Signaling pathways were examined by western blotting using phosphospecific antibodies. Hypoxia or mimetic hypoxia favored K562cells differentiation with up-regulation of C/EBP or. Moreover, treatment with Cariporide under hypoxia synergistically enhanced leukemia cell differentiation. Treatment with Cariporide increased levels phosphorylated ERK5 and p38 mitogen- activated protein kinase （MAPK）. Taken together, these results indicate the enhancement of hypoxia-induced K562 differentiation by Cariporide via MAPK signaling pathway, and suggest a possible therapeutic target of NHE 1 under hypoxia microenvironment in the treatment of leukemic diseases.