MiR-34b-3 and miR-449a inhibit malignant progression of nasopharyngeal carcinoma by targeting lactate dehydrogenase A.
MiR-34b-3 and miR-449a inhibit malignant progression of nasopharyngeal carcinoma by targeting lactate dehydrogenase A.
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DOI：
10.18632/oncotarget.10761
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发表时间：
2016-08-23
期刊：
影响因子：
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通讯作者：
Li Z
中科院分区：
文献类型：
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作者：
Li H;Li X;Ge X;Jia L;Zhang Z;Fang R;Yang J;Liu J;Peng S;Zhou M;Xiang J;Zeng Z;Zhou W;Xiong W;Xiao G;Fang L;Li GY;Li Z
MicroRNA表达谱分析显示，miR-34b/c和miR-449a在鼻咽癌（NPC）中下调；然而，miR-34b/c和miR-449a在鼻咽癌病理发生中的作用靶点和功能尚不清楚。在本研究中，我们证实miR-34b/c和miR-449a随着鼻咽癌的进展而显著降低。过表达miR-34b-3和miR-449a可抑制培养和小鼠肿瘤异种移植物中鼻咽癌细胞的生长。采用串联质量标签进行定量标记和LC-MS/MS分析，研究miR-34b-3恢复表达后蛋白的变化，发现转染miR-34b-3后有251个蛋白下调。通过3次重复实验，我们发现miR-34b-3调控了15个潜在的靶向基因的表达，这些基因主要聚集在糖酵解代谢的关键酶中，包括乳酸脱氢酶A （LDHA）。进一步的研究表明，miR-34b-3和miR-449a通过结合LDHA的3 '非翻译区来负性调节LDHA。此外，LDHA过表达恢复了CNE2细胞中miR-34b-3和miR-449a诱导的肿瘤抑制作用。此外，miR-34b-3和miR-449a抑制LDH活性，降低LD含量，这是由LDHA下调直接诱导的。我们的研究结果表明，miR-34b-3和miR-449a通过靶向LDHA调控糖酵解来抑制鼻咽癌的发展，可能是治疗鼻咽癌的潜在治疗靶点。
MicroRNA expression profiling assays have shown that miR-34b/c and miR-449a are down-regulated in nasopharyngeal carcinoma (NPC); however, the targets and functions of miR-34b/c and miR-449a in the pathologenesis of NPC remain elusive. In this study, we verified miR-34b/c and miR-449a were significantly reduced with the advance of NPC. Overexpression of miR-34b-3 and miR-449a suppressed the growth of NPC cells in culture and mouse tumor xenografts. Using tandem mass tags for quantitative labeling and LC-MS/MS analysis to investigate protein changes after restoring expression of miR-34b-3, 251 proteins were found to be down-regulated after miR-34b-3 transfection. Through 3 replicate experiments, we found that miR-34b-3 regulated the expression of 15 potential targeted genes mainly clustered in the key enzymes of glycolysis metabolism, including lactate dehydrogenase A (LDHA). Further investigation revealed that miR-34b-3 and miR-449a negatively regulated LDHA by binding to the 3′ untranslated regions of LDHA. Furthermore, LDHA overexpression rescued the miR-34b-3 and miR-449a induced tumor inhibition effect in CNE2 cells. In addition, miR-34b-3 and miR-449a suppressed LDH activity and reduced LD content, which were directly induced by downregulation of the LDHA. Our findings suggest that miR-34b-3 and miR-449a suppress the development of NPC through regulation of glycolysis via targeting LDHA and may be potential therapeutic targets for the treatment of NPC.