MiR-34b-3 and miR-449a inhibit malignant progression of nasopharyngeal carcinoma by targeting lactate dehydrogenase A
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Huiling Li1,2, Xiaoling Li2, Xiaolu Ge2, Liqing Jia2, Zhezhe Zhang2, Renpeng Fang4, Jing Yang2, Jianpin Liu3, Shuping Peng2, Ming Zhou2, Juanjuan Xiang2, Zhaoyang Zeng2, Wen Zhou2, Wei Xiong2, Gaoming Xiao1, Li Fang1, Gui-yuan Li1,2, Zheng Li1,2,3
1Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
2The Key Laboratory of Carcinogenesis of The Chinese Ministry of Health and The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
3High Resolution Mass Spectrometry Laboratory of Advanced Research Center, Central South University, Changsha, China
4Xiangya School of Medicine, Central South University, Changsha, China
Zheng Li, email: [email protected]
Keywords: nasopharyngeal carcinoma, miR-34b-3, miR449a, LC-MS/MS, lactate dehydrogenase A(LDHA)
Received: January 19, 2016 Accepted: July 06, 2016 Published: July 21, 2016
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.
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