Search

Friedreich’s ataxia (FRDA) is a genetic neurodegenerative disease that is caused by guanine-adenine-adenine (GAA) nucleotide repeat expansions in the first intron of the frataxin (FXN) gene. Although present in the intron, this mutation leads to a substantial decrease in protein expression. Currently, no effective treatment is available for FRDA, and, in addition to FXN, other targets with therapeutic potential are continuously sought. As miRNAs can regulate the expression of a broad spectrum of genes, are used as biomarkers, and can serve as therapeutic tools, we decided to identify and characterize differentially expressed miRNAs and their targets in FRDA cells compared to unaffected control (CTRL) cells. In this study, we performed an integrated miRNAseq and RNAseq analysis using the same cohort of primary FRDA and CTRL cells. The results of the transcriptome studies were supported by bioinformatic analyses and validated by qRT-PCR. miRNA interactions with target genes were assessed by luciferase assays, qRT-PCR, and immunoblotting. In silico analysis identified the FXN transcript as a target of five miRNAs upregulated in FRDA cells. Further studies confirmed that miRNA-224-5p indeed targets FXN, resulting in decreases in mRNA and protein levels. We also validated the ability of miRNA-10a-5p to bind and regulate the levels of brain-derived neurotrophic factor (BDNF), an important modulator of neuronal growth. We observed a significant decrease in the levels of miRNA-10a-5p and increase in the levels of BDNF upon correction of FRDA cells via zinc-finger nuclease (ZFN)-mediated excision of expanded GAA repeats. Our comprehensive transcriptome analyses identified miRNA-224-5p and miRNA-10a-5p as negative regulators of the FXN and BDNF expression, respectively. These results emphasize not only the importance of miRNAs in the pathogenesis of FRDA but also their potential as therapeutic targets for this disease.

MicroRNA (miR)-224-5p has been reported to be associated with multiple types of cancer. However, its biological role and underlying mechanism in hepatocellular carcinoma (HCC) has yet to be fully elucidated. The aim of the present study was to investigate whether miR-224-5p mRNA expression level was increased in hepatocellular carcinoma and whether it was associated with poor prognosis. Decreased mRNA expression level of miR-224-5p was shown to suppress liver cancer cell migration, invasion and epithelial-mesenchymal transition (EMT). Mechanistically, E2F1 was found to regulate miR-224-5p expression by binding to its promoter region. Melanoregulin (MREG) was identified as the direct target of miR-224-5p by searching the TargetScan, miRDB and StarBase databases. Overexpression of MREG could attenuate liver cancer cell migration, invasion and EMT. Rescue experiments further confirmed that MREG was associated with the regulation of miR-224-5p in liver cancer. In addition, the E2F1/miR-224-5p axis was shown to promote liver cancer cell migration, invasion and EMT by regulating MREG expression. These results suggested that E2F1-induced upregulation of miR-224-5p may serve an important role in MREG-induced liver cancer cell migration, invasion and EMT, and highlights the regulatory function of miR-224-5p in liver cancer. Therefore, the E2F1/miR-224-5p/MREG axis may provide a theoretical basis for the clinical treatment of hepatocellular carcinoma.

Pancreatic mucinous cystadenocarcinoma (MCC) is a rare malignant tumor, with a limited number of studies. The present study aimed to investigate the function and mechanism of microRNA (miR)‑224‑5p on proliferation, migration and invasion of MCC of the pancreas. Reverse transcription‑quantitative PCR was used to explorethe expression of miR‑224‑5p and the PTEN gene. MTT, wound healing, Transwell and tumorigenesis assays were conducted to investigate the proliferation, migration and invasion of MCC1 cells in vitro and in vivo. Western blot analysis was employed to test the protein expression of PTEN. The target gene of miR‑224‑5p was assessed and verified by luciferase assay. miR‑224‑5p expression was notably higher, while PTEN expression was lower, in MCC1 cells compared with normal tissues and cells. Overexpression of miR‑224‑5p promoted the proliferation, migration and invasion of MCC and knockdown of miR‑224‑5p inhibited these functions. Bioinformatics analysis and luciferase assay indicated that PTEN was the direct target gene of miR‑224‑5p. The negative correlation between miR‑224‑5p and PTEN was confirmed both in vitro and in vivo. PTEN reversed the effects of miR‑224‑5p on proliferation, migration and invasion of MCC1 cells. The present study revealed for the first time, to the best of the authors' knowledge, that miR‑224‑5p was highly expressed and served an oncogenic role in MCC. miR‑224‑5p not only regulated the proliferation, migration and invasion of pancreatic MCC but may also be a potential therapeutic target for MCC.

The function of the expression of microRNA (miR)-224-5p in prostate adenocarcinoma (PCa) remains to be elucidated, therefore, the present study aimed to investigate the clinical significance and potential molecular mechanism of miR-224-5p in PCa. Data on the expression of miR-224-5p in PCa were extracted from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), ArrayExpress and previous literature, and meta-analyses with standardized mean difference (SMD) and summary receiver operating characteristic (sROC) methods were performed for statistical analyses. The prospective target genes of miR-224-5p were collected by overlapping the differentially expressed mRNAs in TCGA and GEO, and target genes predicted by miRWalk2.0. Subsequently, in silico analysis was performed to examine the associated pathways of miR-224-5p in PCa. The expression of miR-224-5p was markedly lower in PCa; the overall SMD was −0.562, and overall sROC area under the curve was 0.80. In addition, Kyoto Encyclopedia of Genes and Genomes analysis revealed that the prospective target genes of miR-224-5p were largely enriched in the amino sugar and nucleotide sugar metabolism signaling pathway, and three genes [UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1), hexokinase 2 (HK2) and chitinase 1 (CHIT1)] enriched in this pathway showed higher expression (P

The prognosis of invasive pancreatic mucinous cystadenocarcinoma (MCC) is poor, and the molecular mechanism underlying its development remains unclear. The present study aimed to explore the potential role of autophagy in pancreatic MCC. The results demonstrated an increase in autophagy signaling in pancreatic MCC tissues and the MCC1 cell line compared with adjacent tissues and normal human pancreatic ductal epithelium (HPDE) cells. In addition, abnormal autophagy activation facilitated the migration and invasion of MCC1 cells. MicroRNA (miR)-224-5p expression levels were significantly higher in MCC1 cells compared with those in HPDE cells. Treatment with rapamycin further demonstrated that high levels of autophagy elevated miR-224-5p expression in MCC1 cells in a time-dependent manner. BCL2 was identified as a downstream target gene of miR-224-5p, which binds to the 3′-untranslated region of BCL2. In addition, the results of the present study demonstrated that BCL2 knockdown reversed the inhibition of autophagy mediated by the miR-224-5p inhibitor. To the best of our knowledge, this is the first study to evaluate the role of autophagy in pancreatic MCC. Thus, these results suggested that autophagy may be hyperactivated in pancreatic MCC. In addition, the present study identified a positive feedback loop between autophagy signaling and miR-224-5p, which may promote the aggressive migration and invasion of MCC1. These results may provide a new insight into the relationship between autophagy and tumor metastasis in pancreatic MCC.

The aim of the present study was to investigate the potential role and regulatory mechanism of long non‑coding RNA ferritin heavy polypeptide 1 pseudogene 3 (FTH1P3) in glioma development. The expression of FTH1P3 in low‑ and high‑grade glioma tissues was investigated using reverse transcription‑quantitative polymerase chain reaction. FTH1P3 expression was overexpressed or suppressed in U251 glioma cells to examine the involvement of FTH1P3 in glioma cell proliferation and apoptosis using MTT assay and flow cytometry respectively. In addition, the regulatory association between FTH1P3, microRNA (miR)‑224‑5p and tumor protein (TP) D52 was investigated to elucidate the potential underlying mechanisms of FTH1P3 in glioma by luciferase reporter assay. The results revealed that FTH1P3 was up‑regulated in glioma tissues, and FTH1P3 expression in high‑grade glioma tissues was significantly higher compared with that in low‑grade glioma tissues. Upregulation of FTH1P3 promoted glioma cell proliferation and inhibited apoptosis. Furthermore, FTH1P3 inhibited miR‑224‑5p expression, which in turn negatively regulated TPD52 expression. Overexpression of miR‑224‑5p significantly inhibited U251 cell proliferation and induced cellular apoptosis; this effect was clearly reversed following co‑transfection of miR‑224‑5p and TPD52. These data revealed that upregulation of FTH1P3 may have promoted glioma cell proliferation and inhibited apoptosis. Thus, the miR‑224‑5p/TPD52 axis may be a downstream mechanism of FTH1P3 in glioma progression. The findings of the present study may provide a theoretical basis for the study of the treatment of glioma in the future.