MiR-34b-3 and miR-449a inhibit malignant progression of nasopharyngeal carcinoma by targeting lactate dehydrogenase A

Abstract

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.

The reverse Warburg effect is likely to be an Achilles' heel of cancer that can be exploited for cancer therapy

“…It has long been recognized that glycolytic phenotypes in cancer cells are closely connected with defective mitochondrial OXPHOs (Figure 1 ). For examples, glycolytic enzymes such as lactate dehydrogenase (LDH), phosphofructokinase (PFK) and hexokinaseII(HKII) increase under hypoxic condition, which has been associated with anti-apoptosis and even ‘chemoresistance’ [ 8 , 9 ]. The overproduced LDHA and LDHB catalyze the conversion of pyruvate into lactate, consequently, lactate is secreted into microenvironment through monocarboxylate transporters (MCTs), which contributes to extracellular acidity [ 10 ].…”

Construction and Analysis of lncRNA-mediated ceRNA Network in Nasopharyngeal Carcinoma Based on Weighted Correlation Network Analysis

“…LDHA is up-regulated in NPC tissues and cells, and it was reported to be an independent adverse prognostic factor of NPC [32,33]. Through inhibition of LDHA, miR-34b-3 and miR-449a suppressed NPC progression and metastasis [34]. Therefore, the ceRNA network was reliable because the regulatory relationship between LDHA and miR-449a was indicated in our ceRNA network.…”

Construction and Analysis of lncRNA-mediated ceRNA Network in Nasopharyngeal Carcinoma Based on Weighted Correlation Network Analysis

“…LDHA is up-regulated in NPC tissues and cells, and it was reported to be an independent adverse prognostic factor of NPC [35,36]. Through inhibition of LDHA, miR-34b-3 and miR-449a suppressed NPC progression and metastasis [37]. Therefore, the ceRNA network was reliable because the regulatory relationship between LDHA and miR-449a was indicated in our ceRNA network.…”