Abstract
Leucine-rich repeat (LRR) genes encode transmembrane proteins that are essential for normal brain development and are often dysregulated in central nervous system tumors. Leucine-rich repeat C4 (LRRC4) is a member of the LRR protein superfamily and specifically expressed in brain tissue. Importantly it acts as a tumor suppressor in the pathogenesis of malignant gliomas. However, the molecular mechanisms by which LRRC4 regulates glioma tumorigenesis are largely unknown. In this report, we found that miR-185 is markedly upregulated by LRRC4. We also found that miR-185 was downregulated in glioma, and overexpression of miR-185 inhibited glioma cell invasion. Low expressions of LRRC4 and miR-185 were associated with a poor outcome in glioma patients. Further investigation revealed that LRRC4 mediated its tumor suppressor function by regulating miR-185 targets CDC42 and RhoA. LRRC4 overexpression inhibited glioma cell invasion through miR-185-mediated CDC42 and RhoA direct regulation and VEGFA indirect regulation. Together, our findings suggest that the altered expression of the tumor suppressor LRRC4 may be an important event that leads to the dysregulation of miR-185 in human gliomas. LRRC4 and miR-185 may also be good prognostic markers and therapeutic targets in glioma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism
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Brain Neoplasms / mortality
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Brain Neoplasms / pathology
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Cell Proliferation
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Central Nervous System Neoplasms / genetics
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Central Nervous System Neoplasms / metabolism
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Central Nervous System Neoplasms / mortality
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Central Nervous System Neoplasms / pathology*
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Cyclin-Dependent Kinase 6 / genetics
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Cyclin-Dependent Kinase 6 / metabolism
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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Gene Expression Regulation, Neoplastic
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Glioma / genetics
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Glioma / metabolism
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Glioma / mortality
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Glioma / pathology*
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Humans
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Male
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Mice
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Mice, Nude
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Survival Analysis
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Up-Regulation
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cdc42 GTP-Binding Protein / genetics
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cdc42 GTP-Binding Protein / metabolism
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rhoA GTP-Binding Protein / genetics
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rhoA GTP-Binding Protein / metabolism
Substances
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LRRC4 protein, human
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MIRN185 microRNA, human
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MicroRNAs
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Nerve Tissue Proteins
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RHOA protein, human
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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CDK6 protein, human
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Cyclin-Dependent Kinase 6
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cdc42 GTP-Binding Protein
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rhoA GTP-Binding Protein