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The Oncogenic and Tumor Suppressive Functions of the Long Noncoding RNA MALAT1: An Emerging Controversy.

ABSTRACT: Long noncoding RNAs are recently emerging as critical factors of tumorigenesis. Originally regarded as a pre-messenger RNA (mRNA) splicing regulator, the long noncoding RNA MALAT1 has been demonstrated to regulate gene transcription by binding histone modification enzymes and transcription factors, and to regulate mRNA and protein expression post-transcriptionally by binding microRNAs (miRNAs) and acting as a sponge. Early studies consistently report that MALAT1 is up-regulated in human cancer tissues of various organ origins, particularly metastatic cancer tissues, that high levels of MALAT1 expression in cancer tissues are associated with poor patient prognosis, and that MALAT1 induces cancer cell proliferation, migration, and invasion in vitro and tumor metastasis in mice. By contrast, by analyzing multiple independent large datasets, MALAT1 have very recently been found to be down-regulated in human colorectal and breast cancer tissues, and low MALAT1 expression is associated with decreased patient survival. By binding to the transcription factor TEAD, MALAT1 suppresses metastasis gene expression, colorectal and breast cancer cell migration, invasion, and metastasis in vitro and in mice. MALAT1 has therefore been proposed to function as a tumor suppressor in colorectal and breast cancers. More comprehensive studies with multiple independent cohorts of human cancer tissues of various organ origins, in vitro and in vivo function, and mechanism studies with rescue experiments are required to confirm the oncogenic or tumor suppressive role of MALAT1 in other cancers.

SUBMITTER: Chen Q

PROVIDER: S-EPMC7056701 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Oncogenic and Tumor Suppressive Functions of the Long Noncoding RNA MALAT1: An Emerging Controversy.

Chen Qingjuan Q Zhu Chenjing C Jin Yingying Y

Frontiers in genetics 20200227

Long noncoding RNAs are recently emerging as critical factors of tumorigenesis. Originally regarded as a pre-messenger RNA (mRNA) splicing regulator, the long noncoding RNA MALAT1 has been demonstrated to regulate gene transcription by binding histone modification enzymes and transcription factors, and to regulate mRNA and protein expression post-transcriptionally by binding microRNAs (miRNAs) and acting as a sponge. Early studies consistently report that MALAT1 is up-regulated in human cancer t ...[more]

PMID: 32174966

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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.

Dataset Information

The Oncogenic and Tumor Suppressive Functions of the Long Noncoding RNA MALAT1: An Emerging Controversy.

Publications

The Oncogenic and Tumor Suppressive Functions of the Long Noncoding RNA MALAT1: An Emerging Controversy.

Similar Datasets

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