MiR-125a-5p inhibits tumorigenesis in hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Xu X
PROVIDER: S-EPMC6781988 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death, and radiotherapy is currently one of the main treatments. Long non-coding RNAs (lncRNAs) are associated with the radiosensitivity and tumorigenesis of HCC. However, the role and molecular mechanism of potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 (KCNQ1OT1) in HCC are still unclear. The relative expression of KCNQ1OT1, microRNA-146a-5p (miR-146a-5p) and alkaline ceramidase 3 (ACER3) was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Clonogenic assay was used to assess the radiosensitivity of cells. Cell apoptosis and metastasis were evaluated by flow cytometry and transwell assays, respectively. The protein levels of apoptosis markers, metastasis markers and ACER3 were detected by western blot (WB) analysis. The relationship between miR-146a-5p and KCNQ1OT1 or ACER3 was determined by dual-luciferase reporter assay. Additionally, animal experiments were carried out to explore the effect of KCNQ1OT1 silencing on HCC tumor growth in vivo. KCNQ1OT1 was highly expressed in HCC, and its knockdown hindered the proliferation and metastasis, while increased the radiosensitivity and apoptosis of HCC cells. MiR-146a-5p could interact with KCNQ1OT1, and its inhibition reversed the effects of silenced-KCNQ1OT1 on the radiosensitivity and tumorigenesis of HCC cells. Besides, ACER3 was a target of miR-146a-5p, and its overexpression inversed the effects of miR-146a-5p mimic on the radiosensitivity and tumorigenesis of HCC cells. The expression of ACER3 was regulated by KCNQ1OT1 and miR-146a-5p. Furthermore, KCNQ1OT1 also could reduce the growth of HCC by regulating the miR-146a-5p/ACER3 axis in vivo. Our study suggested that KCNQ1OT1 improved ACER3 expression to regulate the radiosensitivity and tumorigenesis of HCC through sponging miR-146a-5p, indicating that KCNQ1OT1 might be a new therapeutic target for HCC.
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Project description:Radiation therapy is an effective method in the management of esophageal cancer. MicroRNAs (miRNAs) have been reported to play an important role in tumorigenesis. However, the roles of specific miRNAs in radioresistant esophageal cancer remain to be investigated. In present study, the relative expression level of miR-20b-5p and miR-125a-5p were evaluated by quantitative Real-time polymerase chain reaction. Cell counting Kit-8 assay, wound-healing assay, transwell assay were used to assess cell proliferation, cell migration and cell invasion. TUNEL and Annexin V-FITC assays were applied to evaluate cell apoptosis. Dual-luciferase reporter gene assay was conducted to identify direct targets of miRNAs. The protein expression level was assessed by Western blot. The results indicated that miR-20b-5p was increased in radioresistant KYSE-150R cells compared with KYSE-150 cells, whereas miR-125a-5p was downregulated. MiR-20b-5p upregulation promoted cell proliferation, migration, invasion, and the EMT process, and decreased apoptosis by negatively regulating PTEN. MiR-125a-5p inhibited cell proliferation, migration, invasion, the EMT process and it induced apoptosis by negatively regulating IL6R. These data indicate that miR-20b-5p and miR-125a-5p promote tumorigenesis in radioresistant KYSE-150R cells and have the potential to be used as novel therapeutic targets for the treatment of esophageal cancer.
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Project description:Identifying stably expressed tumor markers that can be used easily to detect cancer is currently an important area of cancer research. By using miRNA microarray, we identified 20 differentially expressed miRNAs in serum samples of breast cancer patients. Expression of miR-125a-5p was relatively lower in patients with shorter survival compared to long-term survivors. In a cohort of breast cancer patients (N = 300), serum expression of miR-125a-5p was negatively and significantly correlated with tumor grade (P = 0.004), lymph-node status (P = 0.004), and tumor size (P < 0.001). Low miR-125a-5p expression was an independent prognostic marker (OR = 0.421; 95% CI = 0.184 to 0.961; P = 0.04) associated with poor survival rates (P = 0.0062). We show that miR-125a-5p directly inhibits expression of the HDAC4 gene, resulting in tumor suppression in vitro and in vivo. Together these results demonstrate that serum miR-125a-5p level in breast cancer may be a useful prognostic biomarker and offer a novel therapeutic avenue by targeting HDAC4 in breast cancer.
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Project description:In this study, we explored the actions of miR-199a/b-5p during hepatocellular carcinoma (HCC) progression and its potential target genes. Through heatmap miRNA expression analysis of 15 matched HCC tumor and adjacent non-tumor liver tissues from the TCGA database, we detected 19 mRNAs that were upregulated and 13 that were downregulated specifically in HCC. Among these, miR-199 family members were downregulated in HCC tumors and cell lines, as compared to controls. Low miR-199a/b-5p expression was also associated with poor overall survival of HCC patients. miR-199a/b-5p overexpression in HCC cell lines inhibited cell proliferation, migration and invasion, both in vitro and in vivo. In addition, miR199-a/b-5p post-transcriptionally suppressed Rho-associated coiled-coil kinase 1 (ROCK1). This in turn led to inhibition of ROCK1/MLC and PI3K/Akt signaling, which is necessary for HCC proliferation and metastasis. These results indicate that miR-199a/b acts as tumor suppressors in HCC and represent promising therapeutic targets.
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Project description:MicroRNAs (miRNAs) inhibit or improve the malignant progression of hepatocellular carcinoma (HCC). We previously reported that compared to health controls, patients with liver cirrhosis present the highest levels of circulating miR-885-5p, followed by those with chronic hepatitis B and those with HCC. However, the molecular involvement of miR-885-5p in HCC metastasis is presently unclear. Here, we demonstrated that the expression of miR-885-5p negatively correlated with the invasive and metastatic capabilities of human HCC tissue samples and cell lines. We found that miR-885-5p expression levels correlated with the survival of patients with HCC. Overexpression of miR-885-5p decreased metastasis of HCC cells in vitro and in vivo. Inhibition of miR-885-5p improved proliferation of non-metastatic HCC cells. Furthermore, we disclosed that miR-885-5p targeted gene encoding ?-catenin CTNNB1, leading to decreased activity of the Wnt/?-catenin signaling pathway. The present study indicates that miR-885-5p suppresses the metastasis of HCC and inhibits Wnt/?-catenin signaling pathway by its CTNNB1 target, which suggests that miR-885-5p to be a promising negative regulator of HCC progression and as a novel therapeutic agent to treat HCC.
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Project description:Circular RNAs (circRNAs) have been increasingly demonstrated to function as novel promising therapeutic RNA molecules for diverse human diseases, including cancer. Although the important role of circRNAs has been well documented in HCC, the complex mechanisms of circRNAs in HCC need to be elucidated. Here, a novel circRNA circ_0001955 was identified from three GSE datasets (GSE7852, GSE94508, and GSE97322) as a differentially expressed circRNA between HCC and normal samples. We revealed that circ_0001955, TRAF6 and MAPK11 levels were increased, while miR-516a-5p levels were decreased in HCC tumor tissues compared to adjacent normal tissues. Knockdown of circ_0001955 repressed HCC tumor growth in vitro and in vivo, while overexpression of circ_0001955 exhibited the opposite effect. Circ_0001955 was identified as a sponge for miR-145-5p and miR-516a-5p, and TRAF6 and MAPK11 were demonstrated to be two target genes of miR-516a-5p. In conclusion, circ_0001955 facilitated HCC tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11 expression.
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Project description:CircRNAs participate in the pathogenesis of a variety of cancers. Previous studies showed that baculoviral IAP repeat containing 5 (BIRC5) can promote tumor progression. But, the mechanisms by which circRNAs regulate BIRC5 expression in hepatocellular carcinoma (HCC) remain unknown. The clinical prognosis of BIRC5 or miR-497-5p expression in patients with HCC was assessed by TCGA RNA-seq dataset. hsa_circ_0026939 (circANKRD52) or BIRC5 was identified to bind with miR-497-5p by luciferase gene report, RIP and circRIP assays. MTT, colony formation, Transwell assays and a xenograft tumor model were used to estimate the role of miR-497-5p or circANKRD52 in HCC cells. As a result, we found that elevated expression of BIRC5 or decreased expression of miR-497-5p was linked to poor survival in HCC. Restored expression of miR-497-5p repressed cell proliferation, colony formation and invasiveness by targeting BIRC5, but its inhibitor showed the opposite results. Furthermore, circANKRD52 possessed a tumor-promoting effect by acting as a sponge of miR-497-5p and thereby upregulated BIRC5 in HCC cells. In conclusion, our findings demonstrated that circANKRD52 enhances the tumorigenesis of HCC by sponging miR-497-5p and upregulating BIRC5 expression.
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Project description:Background:Thyroid cancer is a very common endocrine cancer worldwide. How long noncoding RNA (lncRNA) regulates thyroid cancer is elusive. LncRNA MFI2-AS1 has been demonstrated to initiate colorectal cancer. Nevertheless, the role of MFI2-AS1 in thyroid cancer remains unknown. This study aims to determine the roles of MFI2-AS1 in thyroid cancer. Methods:qRT-PCR was used to determine the expression of MFI2-AS1 in thyroid cancer tissues and cells. Proliferation was determined by using CCK8 and colony formation assays. Transwell assay was utilized to analyze migration and invasion. Luciferase reporter assay was performed to confirm the interaction between MFI2-AS1 and miR-125a-5p. Results:MFI2-AS1 was shown to be highly expressed in thyroid cancer tissues and predicted poor prognosis. Knockdown of MFI2-AS1 inhibited proliferation, colony formation, migration and invasion of thyroid cancer cells in vitro. Bioinformatics screening identified MFI2-AS1 as the sponge for miR-125a-5p. And miR-125a-5p was further confirmed to target TRIAP1 directly. Our data further demonstrated that MFI2-AS1 promoted TRIAP1 expression via repressing miR-125a-5p. Finally, TRIAP1 was found to be upregulated in thyroid cancer tissues and its restoration reversed the effects of MFI2-AS1 depletion. Conclusion:Our results elucidated a novel mechanism that MFI2-AS1 promotes thyroid cancer progression via the miR-125a-5p/TRIAP1 pathway.
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Project description:Although many long non-coding RNAs (lncRNAs) have been identified in muscle, some of their physiological functions and regulatory mechanisms remain elusive. Here we report the functional identification and characterization of a novel lncRNA 2310043L19Rik (lnc-231), which is highly expressed in muscle. The expression level of lnc-231 in skeletal muscle of young mice is higher than that in aged mice. Functional analysis showed that overexpression of lnc-231 restrained differentiation and promoted proliferation of myoblast, while inhibition of lnc-231 revealed completely opposite effects in vitro. RNA molecules of lnc-231 acted mechanistically as competing endogenous RNAs (ceRNA) to target miR-125a-5p, whereas miR-125a-5p binds to the 3'-UTR of E2F3 mRNA to inhibit its function. Collectively, lncRNA 2310043L19Rik promotes proliferation and inhibits differentiation of myoblast cells by attenuating the function of miR-125a-5p.
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Project description:PURPOSE:The aim of this study was to investigate the effect of microRNAs on the proliferation of pulmonary arterial smooth muscle cells (PASMCs) as a result of targeting hexokinase-II (HK-II) and its mechanism of action. RESULTS:Differences in metabolic patterns were found between the normal group and monocrotaline-induced pulmonary arterial hypertension (MCT-PH) group. miR-125a-5p decreased glycolysis levels of monocrotaline (MCT)-induced PASMCs by targeting HK-II and inhibiting its proliferation. In vivo experiments found that miR-125a-5p agomir upregulated HK-II expression in the MCT-PH. Right ventricular hypertrophy was reversed and cardiac function improved as a result of decreased mean pulmonary artery pressure (mPAP). CONCLUSION:In vitro and in vivo experiments both confirmed that miR-125a-5p could inhibit cell glycolysis and PASMC proliferation to improve PAH by targeting HK-II. METHODS:HK-II overexpression was constructed, and differentially expressed microRNAs were screened for using microarrays. Serum metabolites were detected using Nuclear Magnetic Resonance (NMR). Through screening for characteristic metabolites in rat body fluids and by analyzing biological functions, disordered metabolic pathways were identified. Activity of the miR-125a-5p target HK-II was measured using a luciferase reporter assay. Expression of downstream molecules was measured by RT-qPCR and/or western blot. Glucose consumption and lactic acid production were analyzed and used as a reflection of glycolysis.
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