Identification of 14-3-3β Gene as a Novel miR-152 Target Using a Proteome-based Approach
Identification of 14-3-3β Gene as a Novel miR-152 Target Using a Proteome-based Approach
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DOI：
10.1074/jbc.m114.556290
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发表时间：
2014-11-07
影响因子：
4.8
通讯作者：
Seliger, Barbara
中科院分区：
文献类型：
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作者：
Jasinski-Bergner, Simon;Stehle, Franziska;Seliger, Barbara
最近的研究表明，miR-152过表达下调了人类肿瘤中非经典的人类白细胞抗原(HLAI)类分子HLAG的表达，从而有助于肿瘤的免疫监视。利用双向凝胶电泳法和MALDI-TOF质谱仪，比较了人类白细胞抗原G(+)、miR-152(低)和它们的miR-152过表达(miR(高))细胞的蛋白质表达谱，从而鉴定出24个差异表达的蛋白质。根据它们的功能和定位进行分类，表明它们中的大多数在肿瘤的发生和发展中起着重要的作用。新的miR-152靶蛋白14-3-3蛋白β/α/YWHAB(14-3-3β)在miR-152过表达的基础上下调，尽管它经常在不同来源的肿瘤中发现过表达。MiR-152介导的14-3-3β表达的降低伴随着Bax蛋白表达的上调，导致了促凋亡的表型。相反，在miR-152(高)细胞中14-3-3β表达的重建增加了抗凋亡基因bcl2的表达，在细胞抑制药物紫杉醇存在下增强了细胞的增殖活性，并导致了对该药物诱导的凋亡的抵抗。通过将临床微阵列数据与患者预后相关联，发现1.4-3-3β与人类白细胞抗原G的表达有关，这可能与肿瘤患者的不良预后和总生存期有关。由于miR-152同时控制14-3-3β和人类白细胞抗原-G的表达，因此它通过改变肿瘤细胞的免疫原性和致瘤性而在肿瘤细胞中发挥双重作用。
Recent studies demonstrated that miR-152 overexpression down-regulates the nonclassical human leukocyte antigen (HLA) class I molecule HLA-G in human tumors thereby contributing to their immune surveillance. Using two-dimensional gel electrophoresis followed by MALDI-TOF mass spectrometry, the protein expression profile of HLA-G(+), miR-152(low) cells, and their miR-152-overexpressing (miR(high)) counterparts was compared leading to the identification of 24 differentially expressed proteins. These were categorized according to their function and localization demonstrating for most of them an important role in the initiation and progression of tumors. The novel miR-152 target 14-3-3 protein beta/alpha/YWHAB (14-3-3 beta) is down-regulated upon miR-152 overexpression, although its overexpression was often found in tumors of distinct origin. The miR-152-mediated reduction of the 14-3-3 beta expression was accompanied by an up-regulation of BAX protein expression resulting in a pro-apoptotic phenotype. In contrast, the reconstitution of 14-3-3 beta expression in miR-152(high) cells increased the expression of the anti-apoptotic BCL2 gene, enhances the proliferative activity in the presence of the cytostatic drug paclitaxel, and causes resistance to apoptosis induced by this drug. By correlating clinical microarray data with the patients' outcome, a link between 1.4-3-3 beta and HLA-G expression was found, which could be associated with poor prognosis and overall survival of patients with tumors. Because miR-152 controls both the expression of 14-3-3 beta and HLA-G, it exerts a dual role in tumor cells by both altering the immunogenicity and the tumorigenicity.