High expression of PIM2 induces HSC proliferation in myelodysplastic syndromes via the IDH1/HIF1-signaling pathway
High expression of PIM2 induces HSC proliferation in myelodysplastic syndromes via the IDH1/HIF1-signaling pathway
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PIM2 的高表达通过 IDH1/HIF1 信号通路诱导骨髓增生异常综合征中 HSC 增殖
DOI：
10.3892/ol.2019.10256
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发表时间：
2019-06-01
期刊：
影响因子：
2.9
通讯作者：
Fu, Rong
中科院分区：
文献类型：
--
作者：
Liu, Zhaoyun;Tian, Mengyue;Fu, Rong
PM 2原癌基因，丝氨酸/苏氨酸激酶（PM 2）是一种丝氨酸/苏氨酸蛋白激酶，在不同类型的癌症中上调，并在调节信号转导级联中发挥重要作用，从而促进细胞存活和细胞增殖。目前的研究表明，PIM 2在骨髓增生异常综合征（MDS）/急性髓系白血病患者的骨髓来源的CD 34（+）细胞中高度表达。在MDS细胞系中定量PIM 2的mRNA表达水平，并且与KG-1细胞相比，PIM 2的mRNA表达显著降低。在体外，短干扰RNA（siRNA）下调PIM 2抑制细胞增殖和延迟G（0）/G（1）细胞周期的进展在MDS细胞系SKM-1。Western blotting结果显示，转染PIM 2 siRNA后，细胞周期蛋白依赖性激酶2（cyclin dependent kinase 2，cyclin dependent kinase inhibitor 1A）表达明显下调，细胞周期蛋白依赖性激酶抑制因子1A（cyclin dependent kinase inhibitor 1A，cyclin dependent kinase inhibitor 1A）表达明显上调。Cell Counting Kit-8分析表明，与对照细胞相比，si-PIM 2转染细胞的细胞增殖显著降低。逆转录定量聚合酶链反应（RT-PCR）和免疫印迹（Western blotting）结果显示，在CD 34（+）MDS细胞中，PIM 2的表达与异柠檬酸脱氢酶[NADP（+）]1胞浆（IDH 1）呈负相关，与缺氧诱导因子1亚基（HIF 1A）呈正相关。总之，这些结果表明，PIM 2的表达通过降低IDH 1的表达诱导HIF 1A的表达增加，导致CD 34（+）细胞增殖增加。因此，PIM 2可能是诊断MDS和AML的潜在生物标志物或新型治疗药物的靶点。
PIM2 proto-oncogene, serine/threonine kinase (PIM2) is a serine/threonine protein kinase that is upregulated in different types of cancer and serves essential roles in the regulation of signal transduction cascades, which promote cell survival and cell proliferation. The present study demonstrated that PIM2 was highly expressed in CD34(+) cells derived from the bone marrow of patients with myelodysplastic syndromes (MDS)/acute myeloid leukemia. The mRNA expression level of PIM2 was quantified in MDS cell lines and mRNA expression was significantly decreased compared with that in KG-1 cells. In vitro, downregulation of PIM2 by short interfering RNA (siRNA) inhibited cell proliferation and delayed G(0)/G(1) cell cycle progression in the MDS cell line SKM-1. Western blotting revealed that cyclin dependent kinase 2 was markedly downregulated and cyclin dependent kinase inhibitor 1A was markedly upregulated following transfection with PIM2 siRNA. Cell Counting Kit-8 analysis demonstrated that cell proliferation of si-PIM2-transfected cells was significantly decreased compared with control cells. Reverse-transcription quantitative polymerase chain reaction and western blotting revealed that PIM2 expression was negatively correlated with isocitrate dehydrogenase [NADP(+)]1 cytosolic (IDH1) and positively correlated with hypoxia inducible factor 1 subunit (HIF1A) in CD34(+) MDS cells. Collectively, these results suggested that the expression of PIM2 induced increased expression of HIF1A by decreasing the expression of IDH1, resulting in increased CD34(+) cell proliferation. Therefore, PIM2 may be a potential biomarker for the diagnosis of MDS and AML or a target for novel therapeutic agents.