MiR‐199a‐5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer

Abstract

Cancer cells possess a unique metabolic phenotype that allows them to preferentially utilize glucose through aerobic glycolysis. This phenomenon is referred to as the "Warburg effect." Accumulating evidence suggests that microRNAs (miRNAs), a class of small noncoding regulatory RNAs, interact with oncogenes/tumor suppressors and induce such metabolic reprograming in cancer cells. To systematically study the metabolic roles of miRNAs in cancer cells, we developed a gain-of-function miRNA screen in HeLa cells. Subsequent investigation of the characterized miRNAs indicated that miR-199a-5p acts as a suppressor for glucose metabolism. Furthermore, miR-199a-5p is often down-regulated in human liver cancer, and its low expression level was correlated with a low survival rate, large tumor size, poor tumor differentiation status, high tumornode-metastasis stage and the presence of tumor thrombus of patients. MicroRNA-199a-5p directly targets the 3 0 -untranslated region of hexokinase 2 (HK2), an enzyme that catalyzes the irreversible first step of glycolysis, thereby suppressing glucose consumption, lactate production, cellular glucose-6-phosphate and adenosine triphosphate levels, cell proliferation, and tumorigenesis of liver cancer cells. Moreover, HK2 is frequently up-regulated in liver cancer tissues and associated with poor patient outcomes. The up-regulation of hypoxiainducible factor-1a under hypoxic conditions suppresses the expression of miR-199a-5p and promotes glycolysis, whereas reintroduction of miR-199a-5p interferes with the expression of HK2, abrogating hypoxia-enhanced glycolysis. Conclusion: miR-199a-5p/HK2 reprograms the metabolic process in liver cancer cells and provides potential prognostic predictors for liver cancer patients. (HEPATOLOGY 2015;62:1132-1144

miR-199a-5p confers tumor-suppressive role in triple-negative breast cancer

“…Our results also demonstrated that miR-199a-5p retarded proliferation, migration, invasion and stem cell-like characteristics in breast cancer. Recent studies revealed that miR-199a-5p exhibited downregulation and tumor-suppressive role in various types of cancers both in vitro and in vivo [22]. Our cell cycle and apoptosis assay results indicated that decreased S phase cells, G0/G1 phase arrest and enrichment of late apoptotic cells may be the potential mechanisms of the inhibitory role of miR-199a-5p.…”

WITHDRAWN: Lack of miR-216b-5p, miR-33a-5p or miR-122-5p in MSCs exosomes promotes breast cancer glycolysis by targeting HK2, LDHA and PKM2

“…There was no significant difference for PKM2 mRNA in the breast cancer with miR-122-5p or the miRNA control transfection, but, PKM2 protein showed down-regulation in the cells. HK2 was regulated by miR-143 [24], miR-155 [25], miR-199a-5p [26], miR-29b [27,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43], miR-140-5p in various cancers like bladder cancer, liver cancer and prostate cancer. LDHA was regulated by miR-383, miR34a, miR-122, miR-30a-5p and other miRNAs in cancer.…”

MicroRNA-124 Reduces the Pentose Phosphate Pathway and Proliferation by Targeting PRPS1 and RPIA mRNAs in Human Colorectal Cancer Cells

“…26 In the current study, to search the miRNA candidates to be involved in the CRC glucose metabolism, we firstly analyzed previously reported miRNA expression datasets and summarized 66 miRNAs that are often deregulated in CRC (Table S4). The intersection between the 100 candidate glycometabolism-regulating miRNAs and the 66 deregulated miRNAs in CRC was defined as the candidate miRNAs involved in the CRC glucose metabolism ( Figure 1A).…”