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Long noncoding RNA MALAT1 may be a prognostic biomarker in IDH1/2 wild-type primary glioblastomas.

ABSTRACT: Primary glioblastoma (GB) is the most aggressive type of brain tumors. While mutations in isocitrate dehydrogenase (IDH) genes are frequent in secondary GBs and correlate with a better prognosis, most primary GBs are IDH wild-type. Recent studies have shown that the long noncoding RNA metastasis associated lung adenocarcinoma transcript-1 (MALAT1) is associated with aggressive tumor phenotypes in different cancers. Our aim was to clarify the prognostic significance of MALAT1 in IDH1/2 wild-type primary GB tumors. We analyzed IDH1/2 mutation status in 75 patients with primary GB by DNA sequencing. The expression of MALAT1 was detected in the 75 primary GB tissues and 5 normal brain tissues using reverse transcription quantitative PCR (RT-qPCR). The associations between MALAT1 expression, IDH1/2 mutation status, and clinicopathological variables of patients were determined. IDH1 (R132H) mutation was observed in 5/75 primary GBs. IDH2 (R172H) mutation was not detected in any of our cases. MALAT1 expression was significantly upregulated in primary GB vs. normal brain tissues (p = 0.025). Increased MALAT1 expression in IDH1/2 wild-type primary GBs correlated with patient age and tumor localization (p = 0.032 and p = 0.025, respectively). A multivariate analysis showed that high MALAT1 expression was an unfavorable prognostic factor for overall survival (p = 0.034) in IDH1/2 wild-type primary GBs. High MALAT1 expression may have a prognostic role in primary GBs independent of IDH mutations.

SUBMITTER: Argadal OG

PROVIDER: S-EPMC7029212 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Long noncoding RNA MALAT1 may be a prognostic biomarker in IDH1/2 wild-type primary glioblastomas.

Argadal Omer Gokay OG Mutlu Melis M Ak Aksoy Secil S Kocaeli Hasan H Tunca Berrin B Civan Muhammet Nafi MN Egeli Unal U Cecener Gulsah G Bekar Ahmet A Taskapilioglu Mevlut Ozgur MO Tekin Cagla C Tezcan Gulcin G Tolunay Sahsine S

Bosnian journal of basic medical sciences 20200205 1

Primary glioblastoma (GB) is the most aggressive type of brain tumors. While mutations in isocitrate dehydrogenase (IDH) genes are frequent in secondary GBs and correlate with a better prognosis, most primary GBs are IDH wild-type. Recent studies have shown that the long noncoding RNA metastasis associated lung adenocarcinoma transcript-1 (MALAT1) is associated with aggressive tumor phenotypes in different cancers. Our aim was to clarify the prognostic significance of MALAT1 in IDH1/2 wild-type ...[more]

PMID: 31479414

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Project description:The study was designed to determine the role of long noncoding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (Malat1), in ischemic stroke outcome. Primary mouse brain microvascular endothelial cells (BMECs) were cultured and treated with Malat1 GapmeR before 16 h oxygen and glucose depravation (OGD). Cell death was assayed by LDH and MTT methods. Malat1 knock-out and wild-type mice were subjected to 1 h of middle cerebral artery occlusion (MCAO) and 24-72 h of reperfusion. To explore the underlying mechanism, apoptotic and inflammatory factors were measured by qPCR, ELISA, and Western blotting. The physical interaction between Malat1 and apoptotic or inflammatory factors was measured by RNA immunoprecipitation. Increased Malat1 levels were found in cultured mouse BMECs after OGD as well as in isolated cerebral microvessels in mice after MCAO. Silencing of Malat1 by Malat1 GapmeR significantly increased OGD-induced cell death and Caspase 3 activity in BMECs. Silencing of Malat1 also significantly aggravated OGD-induced expression of the proapoptotic factor Bim and proinflammatory cytokines MCP-1, IL-6, and E-selectin. Moreover, Malat1 KO mice presented larger brain infarct size, worsened neurological scores, and reduced sensorimotor functions. Consistent with in vitro findings, significantly increased expression of proapoptotic and proinflammatory factors was also found in the cerebral cortex of Malat1 KO mice after ischemic stroke compared with WT controls. Finally, we demonstrated that Malat1 binds to Bim and E-selectin both in vitro and in vivo Our study suggests that Malat1 plays critical protective roles in ischemic stroke.SIGNIFICANCE STATEMENT Accumulative studies have demonstrated the important regulatory roles of microRNAs in vascular and neural damage after ischemic stroke. However, the functional significance and mechanisms of other classes of noncoding RNAs in cerebrovascular pathophysiology after stroke are less studied. Here we demonstrate a novel role of Malat1, a long noncoding RNA that has been originally identified as a prognostic marker for non-small cell lung cancer, in cerebrovascular pathogenesis of ischemic stroke. Our experiments have provided the first evidence that Malat1 plays anti-apoptotic and anti-inflammatory roles in brain microvasculature to reduce ischemic cerebral vascular and parenchymal damages. Our studies also suggest that lncRNAs can be therapeutically targeted to minimize poststroke brain damage.

Project description:BackgroundThe aberrant regulation of MALAT1 has been indicated to be involved in various carcinogenic pathways contributing to the tumourigenesis and progression of cancers. The current meta-analysis summarized the research advances of MALAT1 functions and analyzed its prognostic value among multiple types of cancers.MethodsEligible studies were identified through retrieving the PubMed, Web of Science, and CNKI databases, up to Mar 1, 2018. 28 studies of 5436 patients and 36 studies of 3325 patients were enrolled in the meta-analysis to evaluate the association of MALAT1 expression with survival outcomes and clinical parameters.ResultsThe results demonstrated that over-expression of MALAT1 may predict lymph node metastasis (pooled OR = 2.335, 95% CI 1.606-3.395, P = 0.000) and distant metastasis (pooled OR = 2.456, 95% CI 1.407-4.286, P = 0.002). Moreover, MALAT1 was also related with tumour size (pooled OR = 1.875, 95% CI 1.257-2.795, P = 0.002) and TNM stage (pooled OR = 2.034, 95% CI 1.111-3.724, P = 0.021). Additionally, elevated MALAT1 expression could predict poor OS (pooled HR = 2.298, 95% CI 1.953-2.704, P = 0.000), DFS (pooled HR = 2.036, 95% CI 1.240-3.342, P = 0.005), RFS (pooled HR = 2.491, 95% CI 1.505-4.123, P = 0.000), DSS (pooled HR = 2.098, 95% CI 1.372-3.211, P = 0.001) and PFS (pooled HR = 1.842, 95% CI 1.138-2.983, P = 0.013) in multivariate model. Importantly, subgroup analyses disclosed that increased MALAT1 expression had a poor OS among different cancer types (Estrogen-dependent cancer: pooled HR = 2.656, 95% CI 1.560-4.523; urological cancer: pooled HR = 1.952, 95% CI 1.189-3.204; glioma: pooled HR = 2.315, 95% CI 1.643-3.263; digestive cancer: pooled HR = 2.451, 95% CI 1.862-3.227).ConclusionsThe present findings demonstrated that MALAT1 may be a novel biomarker for predicting survival outcome, lymph node metastasis and distant metastasis.

Dataset Information

Long noncoding RNA MALAT1 may be a prognostic biomarker in IDH1/2 wild-type primary glioblastomas.

Publications

Long noncoding RNA MALAT1 may be a prognostic biomarker in IDH1/2 wild-type primary glioblastomas.

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