MicroRNAs (miRNAs) precipitate in many diseases including cardiovascular disease. In contrast to our original thought, miRNAs exist in circulating blood and they are relatively stable due to binding with other materials. The current translational study is to establish a method to determine the absolute amount of a miRNA in blood and to determine the potential applications of circulating cell-free microRNA-1 (miR-1) in acute myocardial infarction (AMI). The results revealed that miR-1 is the most abundant miRNA in the heart and is also a heart and muscle specific miRNA. In a cardiac cell necrosis model induced by Triton-100 in vitro, we found that cardiac miR-1 can be released into cultured medium and is stable at least for 24 h. In a rat model of AMI induced by coronary ligation, we found that serum miR-1 is quickly increased after AMI with the peak at 6h, in which an over 200-fold increased miR-1 was demonstrated. The miR-1 level was returned to basal level at 3 days after AMI. Moreover, the serum miR-1 level in rats with AMI has a strong positive correlation with the myocardial size. To further verify the relationship between myocardial size and miR-1 level, an ischemic preconditioning model was applied. The result showed that ischemic preconditioning significantly reduced the circulating miR-1 and the myocardial size induced by ischemia-reperfusion injury. Finally, the levels of circulating cell-free miR-1 were significantly increased in patients with AMI and had a positive correlation with serum CK-MB levels. The results suggest that serum miR-1 could be a novel sensitive diagnostic biomarker for AMI.
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
The pathological relevance and significance of microRNAs (miRNAs) in hepatocarcinogenesis have attracted much attention in recent years; however, little is known about the underlying molecular mechanisms through which miRNAs are involved in the development and progression of hepatocellular carcinoma (HCC). In this study, we demonstrate that miR-30d is frequently up-regulated in HCC and that its expression is highly associated with the intrahepatic metastasis of HCC. Furthermore, the enhanced expression of miR-30d could promote HCC cell migration and invasion in vitro and intrahepatic and distal pulmonary metastasis in vivo, while silencing its expression resulted in a reduced migration and invasion. Galphai2 (GNAI2) was identified as the direct and functional target of miR-30d with integrated bioinformatics analysis and messenger RNA array assay. This regulation was further confirmed by luciferase reporter assays. In addition, our results, for the first time, showed that GNAI2 was frequently suppressed in HCC by way of quantitative reverse-transcription polymerase chain reaction and immunohistochemical staining assays. The increase of the GNAI2 expression significantly inhibits, whereas knockdown of the GNAI2 expression remarkably enhances HCC cell migration and invasion, indicating that H epatocellular carcinoma (HCC) is one of the most prevalent malignancies and leading causes of death from cancer worldwide, especially in East Asia and South Africa. 1 The pathogenesis of HCC is a multistage process that is usually associated with preneoplastic liver lesions, chronic inflammation, and/or cirrhosis. Despite great advances in the treatment of the disease, relapse or metastasis is frequently observed in clinics, and the 5-year survival rate is still quite low among patients with HCC. 2 In past decades, studies have been performed to investigate the genes and proteins that underlie the development and progression of HCC. Several factors involved in the pathogenesis of this malignancy, including wnt/catenin, p53, Rb, and Ras/MAPK, 3 have been identified. However, the roles and significances of nonprotein coding genes with a particular focus on a class of endogenous tiny RNA molecules termed microRNA (miRNA) remain to be established in the pathogenic processes of HCC.miRNAs are approximately 21-to 25-nucleotide noncoding RNA molecules that are highly conserved in a variety of eukaryotic organisms. Since their initial discovery in Caenorhabditis elegans, 4 miRNAs have become widely accepted as posttranscriptional regulators of gene expression through directly degrading messenger RNA (mRNA) or indirectly repressing protein translation. 5 Recent progress suggests that deregulation of miRNAs is involved in a wide range of human diseases, including
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