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Ovarian cancer is the common cause of cancer-related death in women and is considered the most deadly gynecological cancer. It has been established that GATA-binding protein 6 (GATA6) is abnormally expressed in several types of malignant tumors and acts as an oncogenic protein or a tumor suppressor. However, the underlying mechanism of GATA6 in ovarian cancer progression has not been elucidated. Data in the present study revealed that GATA6 expression was negatively correlated to microRNA-10a-5p (miR-10a-5p) in ovarian cancer tissue and cells and that GATA6 is directly targeted by miR-10a-5p. Notably, upregulated miR-10a-5p dramatically inhibited ovarian cancer cell proliferation, tumorigenic ability, migration, and invasion by targeting GATA6. In vitro and in vivo experiments confirmed that miR-10a-5p-mediated downregulation of GATA6 suppressed Akt pathway activation. Overall, our findings suggest that miR-10a-5p could be a novel therapeutic target for ovarian cancer, and targeting the miR-10a-5p/GATA6/Akt axis could improve outcomes in this patient population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Micro RNAs are considered to play critical roles in the pathogenesis of human inflammatory arthritis, including rheumatoid arthritis ( RA). The purpose of this study was to determine the relationship between miR-10a-5p and TBX5 in synoviocytes and evaluate their contribution to joint inflammation. The expression of miR-10a-5p and TBX5 in the synovium of RA and human synovial sarcoma cell line SW982 stimulated by IL-1β was determined by RT- qPCR and Western blotting. The direct interaction between miR-10a-5p and TBX5 3′ UTR was determined by dual-luciferase reporter assay in HeLa cells. Mimics and inhibitors of miR-10a-5p were transfected into SW982 cells. TBX5 was overexpressed by plasmid transfection or knocked down by RNAi. Proinflammatory cytokines and TLR3 and MMP13 expressions were determined by RT- qPCR and Western blotting. Down-regulated expression of miR-10a-5p and up-regulation of TBX5 in human patients with RA were found compared to patients with OA. IL-1β could reduce miR-10a-5p and increase TBX5 expression in SW982 cells in vitro. The direct target relationship between miR-10a-5p and 3′ UTR of TBX5 was confirmed by luciferase reporter assay. Alterations of miR-10-5p after transfection with its mimic and inhibitor caused the related depression and re-expression of TBX5 and inflammatory factors in SW982 cells. Overexpression of TBX5 after pCMV3- TBX5 plasmid transfection significantly promoted the production of TLR3, MMP13 and various inflammatory cytokines, while this effect was rescued after knocking down of TBX5 with its specific si RNA. We conclude that miR-10a-5p in a relation with TBX5 regulates joint inflammation in arthritis, which would serve as a diagnostic and therapeutic target for RA treatment. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effect and mechanism of microRNA (miR)-10a-5p in human cervical cancer. The expression level of miR-10-5p in cervical cancer lines was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In cervical cancer HeLa and SiHa cells, miR-10-5p was ectopically overexpressed by lentiviral transduction. Brain-derived neurotrophic factor (BDNF) was then overexpressed in HeLa and SiHa cells to evaluate its selective effect on miR-10-5p in cervical cancer modulation. The targeting of miR-10-5p on its downstream gene, BDNF, was evaluated using RT-qPCR and western blot analysis. Cervical cancer cell viability and cell cycle was evaluated using an MTT assay and flow cytometry, respectively. The results indicated that miR-10-5p expression was significantly lower in cervical cancer cell lines compared with normal cells (P<0.05). Ectopic overexpression of miR-10-5p significantly inhibited cancer cell viability and induced cell cycle arrest in HeLa and SiHa cells (both P<0.05). miR-10-5p overexpression significantly reduced BDNF gene expression (P<0.05) and also reduced BDNF protein levels in cervical cancer cells compared with the control. In conclusion, the current study indicated that miR-10-5p is a cervical cancer suppressor, which regulates BDNF expression in cervical cancer. [ABSTRACT FROM AUTHOR]

This study was to analyze the dys-regulation of microRNA-10a-5p and microRNA-34c-5p and their correlations with clinicopathological characteristics of laryngeal epithelial premalignant lesions (LEPL). Quantitative real-time polymerase chain reaction was performed to detect the expression of microRNA-10a-5p and microRNA-34c-5p in 94 cases of LEPL and 47 controls. Retrospective follow-up data of all patients were collected and the correlation between the dys-regulation of microRNA-10a-5p/microRNA-34c-5p and clinicopathological characteristics was examined by linear regression analysis. Expression of microRNA-10a-5p was down-regulated in LEPL, showing statistical difference between low-risk lesion group and high-risk lesion group, while microRNA-34c-5p expression was up-regulated gradually in LEPL groups and dropped suddenly in squamous cell carcinoma group. In addition, the differential expression of microRNA-10a-5p is profiled with either LEPL grade or gender, showing a linear correlation; and microRNA-34c-5p expression is correlated with alcohol consumption in LEPL patients ( P < 0.05). The dys-regulation of microRNA-10a-5p and microRNA-34c-5p in LEPL and their correlations with clinicopathological characteristics might provide important theoretical and experimental basis for LEPL classfication and the two microRNAs can serve as more valuable markers in diagnosis and clinical management of LEPL. [ABSTRACT FROM AUTHOR]

Tumor-derived exosomes (exo) could modulate the biological behaviors of human umbilical vein endothelial cells (HUVECs). Here, the role of microRNA (miR)-10a-5p-modified gastric cancer (GC) cells-derived exo for HUVECs was studied. GC tissue specimens were collected, and miR-10a-5p and zinc finger MYND-type containing 11 (ZMYND11) levels were determined. HUVECs interfered with ZMYND11 or miR-10a-5p-related oligonucleotides. Exo was extracted from GC cells (HGC-27 exo), and miR-10a-5p mimic-modified HGC-27 exo were co-cultured with HUVECs. HUVECs viability, migration and angiogenesis were evaluated, and miR-10a-5p/ZMYND11 crosstalk was explored. It was observed that GC patients had raised miR-10a-5p and reduced ZMYND11, and miR-10a-5p negatively mediated ZMYND11 expression. Suppression of miR-10a-5p or overexpression of ZMYND11 inhibited viability, migration and tube formation ability of HUVECs. Notably, miR-10a-5p mimic-modified HGC-27 exo enhanced the viability, migration and tube formation ability of HUVECs, but this effect was impaired after up-regulating ZMYND11. In summary, miR-10a-5p from GC cells-derived exo enhances viability and migration of HUVECs by suppressing ZMYND11.

Long non-coding RNA (lncRNA) myocardial infarction-associated transcript (MIAT) has been widely-demonstrated to function as diagnostic markers for acute myocardial infarction (MI). This study was designed to explore the modulatory role of MIAT and its underlying molecular mechanism in MI. Firstly, MI mouse model was developed via ligation of the descending branch of the left coronary artery, and cell model was established through exposure to hypoxic conditions . Online prediction indicated that MIAT could bind to microRNA-10a-5p (miR-10a-5p), while miR-10a-5p was highlighted to bind to early growth response gene-2 (EGR2). MIAT and EGR2 were subsequently determined to be highly-expressed, whereas miR-10a-5p was found to be poorly-expressed in cardiomyocytes exposed to hypoxia as well as in MI mice using RT-qPCR and Western blot assay. The binding relationships between MIAT and miR-10a-5p, and between miR-10a-5p and EGR2 were further confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. The results of in vitro and in vivo experimentation also suggested that overexpression of miR-10a-5p or silencing of MIAT and EGR2 reduced cardiomyocyte apoptosis and increased ATP content, thus alleviating the impairment of cardiac function following MI. In a word, inhibition of MIAT protects against cardiac dysfunction induced by MI through the crosstalk with miR-10a-5p/EGR2.

Long noncoding RNAs (lncRNAs) contribute to the development of hepatocellular carcinoma (HCC), which could regulate various HCC biological characteristics. Here, the study seeks to investigate the role of lncRNA LEF1-AS1 in HCC cell chemoresistance by regulating microRNA (miR)-10a-5p and Musashi1 (MSI1). The microarray-based analysis was employed to identify the HCC-related lncRNA-miRNA-gene regulatory network. Expression patterns of LEF1-AS1, miR-10a-5p, and MSI1 in the HCC cell lines, tissues were accessed by means of reverse transcription-quantitative polymerase chain reaction. Next, the interaction among LEF1-AS1, miR-10a-5p, and MSI1 in HCC was accessed by bioinformatics and dual-luciferase reporter gene assay. Then, the cell line resistant to cisplatin was established, which was then treated with sh/oe-lncRNA LEF1-AS1, miR-10a-5p-mimic, and oe/sh-MSI1 vectors alone or in combination. Afterward, the effect of LEF1-AS1, miR-10a-5p, and MSI1 on HCC cell chemoresistance, proliferation, and apoptosis was assessed. At last, in vivo experiments confirmed the role of MSI1 in tumor growth and chemoresistance in HCC. LEF1-AS1 might potentially affect the growth and chemoresistance of HCC cells by regulating miR-10a-5p and MSI1. LEF1-AS1 and MSI1 expression patterns were elevated, while miR-10a-5p was repressed in HCC tissues and cell lines. LEF1-AS1 combined to miR-10a-5p and regulated MSI1, thereby activating the protein kinase B (AKT) signaling pathway. Knockdown of LEF1-AS1 and MSI1 or elevation of miR-10a-5p compromised the proliferation of Huh7 cell line resistant to DDP and promoted its chemosensitivity and apoptosis. At last, these in vitro findings were also confirmed in vivo. Our results unraveled LEF1-AS1 acts as a miR-10a-5p modulator to promote chemoresistance of HCC cells by stimulating MSI1 and activating the AKT signaling pathway, which might provide a novel therapeutic target for HCC., (© 2020 Wiley Periodicals LLC.)