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The lncRNA MALAT1 acts as a competing endogenous RNA to regulate KRAS expression by sponging miR-217 in pancreatic ductal adenocarcinoma.

ABSTRACT: The long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) has been shown to play an important role in tumourigenesis. The aim of this study was to investigate the role of MALAT1 in pancreatic ductal adenocarcinoma. MALAT1 is expressed at higher levels in pancreatic ductal adenocarcinoma (PDAC) tissues than in nontumour tissues and in metastatic PDAC than in localized tumours. Patients with PDAC and high MALAT1 expression levels have shorter overall survival than patients with PDAC and low MALAT1 expression levels. Knocking down MALAT1 reduces pancreatic tumour cell growth and proliferation both in vitro and in vivo. Moreover, MALAT1 knockdown inhibits cell cycle progression and impairs tumour cell migration and invasion. We found that miR-217 can bind MALAT1 and regulate its expression in PDAC cell lines. We also found MALAT1 knockdown attenuates the protein expression of KRAS, a known target of miR-217. After MALAT1 knockdown, KRAS protein expression levels can be rescued through inhibition of miR-217 expression. More importantly, MALAT1 knockdown does not directly affect cellular miR-217 expression but decreases the miR-217 nucleus/cytoplasm ratio, suggesting that MALAT1 inhibits the translocation of miR-217 from the nucleus to the cytoplasm.

SUBMITTER: Liu P

PROVIDER: S-EPMC5507931 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposeMyasthenia gravis (MG) is a T cell-dependent antibody-mediated autoimmune disorder that can seriously affect patients' quality of life. However, few studies have focused on the severity of MG. Moreover, existing therapeutic efforts, including those targeting biomarkers for MG, remain unsatisfactory. Therefore, it is vital that we investigate the pathogenesis of MG and identify new biomarkers that can not only evaluate the severity of the disease but also serve as potential therapeutic targets. Long noncoding RNA LINC00680 has been found to be associated with the progression of a variety of diseases as a competing endogenous RNA (ceRNA). However, the specific role of LINC00680 in MG has yet to be clarified. Here, we aimed to investigate the association between LINC00680 and the severity of MG.MethodsBioinformatics tools, quantitative real-time PCR, Western blotting, and luciferase assays were selected to investigate key signaling pathways and RNA expression in patients with MG. The Quantitative MG Score scale and the MG Composite scale were used to evaluate the severity of MG in the included patients. Cell viability assays and flow cytometry analysis were selected to analyze cell proliferation and apoptosis.ResultsCompared with control subjects, the expression levels of LINC00680 and mitogen-activated protein kinase 1 (MAPK1) in peripheral blood mononuclear cells of patients with MG were both upregulated; the levels of miR-320a were downregulated. A positive correlation was detected between LINC00680 expression and the severity of MG. Luciferase reporter assays identified that LINC00680 acts as a target for miR-320a. The in vitro analysis confirmed that LINC00680 regulates the expression of MAPK1 by sponging miR-320a. Finally, the functional analysis indicated that LINC00680 promoted Jurkat cell proliferation and inhibited cellular apoptosis by sponging miR-320a.ConclusionLINC00680 may be associated with the severity of MG as a ceRNA by sponging miR-320a to upregulate MAPK1. These findings suggest that LINC00680 may represent a potential biomarker which evaluates the severity of MG and may serve as a therapeutic target.

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The lncRNA MALAT1 acts as a competing endogenous RNA to regulate KRAS expression by sponging miR-217 in pancreatic ductal adenocarcinoma.

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