BACKGROUND Myelodysplastic syndromes (MDS) represent a family of hematopoietic stem cell disorders characterized by ineffective hematopoiesis. While the functions of many microRNAs have been identified in MDS, microRNA-144 (miR-144) remains poorly understood. Thus, the aim of the present study was to determine the effects of miR-144 on cell proliferation and apoptosis in MDS cells and mechanism thereof. METHODS MDS-related microarrays were used for screening differentially expressed genes in MDS. The relationship between miR-144 and A-kinase anchoring protein 12 (AKAP12) was determined by a dual luciferase reporter gene assay. Subsequently, gain- and loss-function approaches were used to assess the effects of miR-144 and AKAP12 on cell proliferation, cell cycle and cell apoptosis by MTT assay and flow cytometry. Following the induction of a mouse model with MDS, the tumor tissues were extract for evaluation of apoptosis and the expression of miR-144, AKAP12, and the relevant genes associated with extracellular-regulated protein kinases 1/2 (ERK1/2) signaling pathway and apoptosis. RESULTS We observed significantly diminished expression of AKAP12 in MDS samples. miR-144 directly bound to AKAP12 3'UTR and reduced its expression in hematopoietic cells. Downregulation of miR-144 or upregulation of AKAP12 was observed to prolong cell cycle, inhibit cell proliferation, and induce apoptosis, accompanied by increased expression of AKAP12, p-ERK1/2, caspase-3, caspase-9, Bax, and p53, as well as decreased expression of Bcl-2. The transplanted tumors in mice with down-regulated miR-144 exhibited a lower mean tumor diameter and weight, and increased apoptosis index and expression of AKAP12 and ERK1/2. CONCLUSION Taken together, these studies demonstrate the stimulative role of miR-144 in MDS progression by regulating AKAP12-dependent ERK1/2 signaling pathway.

中文翻译：

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microRNA-144的下调通过激活AKAP12依赖性ERK1 / 2信号通路来抑制增殖并促进骨髓增生异常综合征细胞的凋亡。

背景技术骨髓增生异常综合症（MDS）代表一族以无效的造血作用为特征的造血干细胞疾病。尽管已在MDS中鉴定了许多microRNA的功能，但对microRNA-144（miR-144）的了解仍然很少。因此，本研究的目的是确定miR-144对MDS细胞中细胞增殖和凋亡的作用及其机制。方法采用MDS相关的微阵列芯片筛选MDS中差异表达的基因。miR-144和A激酶锚定蛋白12（AKAP12）之间的关系是通过双重萤光素酶报告基因测定法确定的。随后，通过MTT分析和流式细胞术，使用增益和损失功能方法评估miR-144和AKAP12对细胞增殖，细胞周期和细胞凋亡的影响。用MDS诱导小鼠模型后，提取肿瘤组织以评估细胞凋亡以及miR-144，AKAP12的表达以及与细胞外调节蛋白激酶1/2（ERK1 / 2）信号通路相关的相关基因和凋亡。结果我们观察到MDS样品中AKAP12的表达明显减少。miR-144直接与AKAP12 3'UTR结合并减少其在造血细胞中的表达。观察到miR-144的下调或AKAP12的上调可延长细胞周期，抑制细胞增殖并诱导凋亡，并伴随着AKAP12，p-ERK1 / 2，caspase-3，caspase-9，Bax和p53表达的增加，以及Bcl-2的表达下降。miR-144表达下调的小鼠移植肿瘤的平均肿瘤直径和重量更低，并增加细胞凋亡指数以及AKAP12和ERK1 / 2的表达。结论总之，这些研究证明了miR-144通过调节AKAP12依赖性ERK1 / 2信号通路在MDS进程中的刺激作用。