Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-grade astrocytic tumors, such as glioblastoma, possess rich vascular components, which are necessary for their growth. VEGF-A is considered to be the major mediator of angiogenesis in malignant neoplasms including high-grade astrocytic tumors. The upregulation of VEGF-A expression in tumor cells is induced by two mechanisms: the transcriptional activation and the post-transcriptional stabilization of VEGF-A mRNA. While the former mechanism mediated by hypoxia inducible factor-1 alpha (HIF-1alpha) has been revealed, the latter mediated by mRNA stability factor HuR remains unclear in astrocytic tumors. In the present study, we investigated the expression of VEGF-A and mRNA stability factor HuR in supratentorial astrocytic tumors of 27 adults using RT-PCR, ELISA, and immunohistochemistry. Furthermore, we studied the involvement of HuR in the upregulation of VEGF-A expression using malignant astrocytoma cell lines. In higher-grade astrocytic tumors, the level of VEGF-A and microvascular density were elevated, cytoplasmic expression of HuR, which potentially means the protection of VEGF-A mRNA from degradation by ribonucleases, appeared, and they were correlated positively. In in vitro experiments, the inhibition of the cytoplasmic translocation of HuR protein by leptomycin B (LMB) reduced the upregulation of VEGF-A expression in malignant astrocytic tumor cells under hypoxic conditions. These findings suggest that the expression of VEGF-A and cytoplasmic translocation of HuR relates to the histological grade, and that HuR is involved in the upregulation of VEGF-A expression, in human astrocytic tumors.
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PMID:Expression of vascular endothelial growth factor-A and mRNA stability factor HuR in human astrocytic tumors. 1849 84

In recent clinical observation, the growth of endothelial tumors, such as hemangiomas of infancy, was repressed by the non-selective beta-adrenergic antagonist propranolol possibly through targeting of the vascular endothelial compartment. As human brain microvascular endothelial cells (HBMEC) play an essential role as structural and functional components in tumor angiogenesis, we assessed whether propranolol could target HBMEC's in vitro angiogenic properties. We found that biopsies from human glioblastoma as well as from experimental brain tumor-associated vasculature expressed high levels of the beta2-adrenergic receptor, suggesting adrenergic adaptative processes could take place during tumor vascularization. We observed that in vitro tubulogenesis was significantly reduced by propranolol when HBMEC were seeded on Matrigel. Propranolol, as much as 100microM, did not reduce cell viability and did not alter HBMEC migration as assessed with Boyden chambers. Secretion of the key angiogenic and extracellular matrix degrading enzymes MMP-2 and MMP-9 was assessed by zymography. Propranolol significantly reduced MMP-9 secretion upon treatment with the tumor-promoting agent phorbol 12-myristate 13-acetate, while secretion of MMP-2 remained unaffected. This was correlated with a decrease in MMP-9 gene expression which is, in part, explained by a decrease in the nucleocytoplasmic export of the mRNA stabilizing factor HuR. Our data are therefore indicative of a selective role for propranolol in inhibiting MMP-9 secretion and HBMEC tubulogenesis which could potentially add to propranolol's anti-angiogenic properties.
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PMID:Propranolol adrenergic blockade inhibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion. 1946 30

Posttranscriptional regulation is a critical control point for the expression of genes that promote or retard tumor growth. We previously found that the mRNA-binding protein, ELAV 1 (HuR), is upregulated in primary brain tumors and stabilizes growth factor mRNAs such as VEGF and IL-8. To better understand the role of HuR in brain tumor growth, we altered levels of HuR in glioma cells by short hairpin RNA or ectopic expression and measured tumor cell phenotype using in vitro and in vivo models. In HuR-silenced cells, we found a significant decrease in anchorage-independent growth and cell proliferation with a concomitant induction of apoptosis. Using an intracranial tumor model with primary glioblastoma cells, HuR silencing produced a significant decrease in tumor volume. In contrast, overexpression of HuR produced in vitro chemoresistance to standard glioma therapies. Because bcl-2 is abundantly expressed in glioma and associated with tumor growth and survival, we determined the impact of HuR on its regulation as a molecular validation to the cellular and animal studies. Using UV cross-linking and RNA immunoprecipitation, we show that HuR bound to the 3'-untranslated region of all bcl-2 family members. Silencing of HuR led to transcript destabilization and reduced protein expression. Polysome profiling indicated loss of HuR from the translational apparatus. In summary, these findings reveal a HuR-dependent mechanism for cancer cell survival and sensitivity to chemotherapeutic drugs suggesting that HuR should be considered as a new therapeutic target.
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PMID:The RNA-binding protein HuR promotes glioma growth and treatment resistance. 2149 45

Musashi1 (Msi1) is an evolutionarily conserved RNA-binding protein (RBP) that has profound implications in cellular processes such as stem cell maintenance, nervous system development, and tumorigenesis. Msi1 is highly expressed in many cancers, including glioblastoma, whereas in normal tissues, its expression is restricted to stem cells. Unfortunately, the factors that modulate Msi1 expression and trigger high levels in tumors are largely unknown. The Msi1 mRNA has a long 3' untranslated region (UTR) containing several AU- and U-rich sequences. This type of sequence motif is often targeted by HuR, another important RBP known to be highly expressed in tumor tissue such as glioblastoma and to regulate a variety of cancer-related genes. In this report, we show an interaction between HuR and the Msi1 3'-UTR, resulting in a positive regulation of Msi1 expression. We show that HuR increased MSI1 mRNA stability and promoted its translation. We also present evidence that expression of HuR and Msi1 correlate positively in clinical glioblastoma samples. Finally, we show that inhibition of cell proliferation, increased apoptosis, and changes in cell-cycle profile as a result of silencing HuR are partially rescued when Msi1 is ectopically expressed. In summary, our results suggest that HuR is an important regulator of Msi1 in glioblastoma and that this regulation has important biological consequences during gliomagenesis.
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PMID:The oncogenic RNA-binding protein Musashi1 is regulated by HuR via mRNA translation and stability in glioblastoma cells. 2225 4

The mRNA binding protein HuR is over expressed in cancer cells and contributes to disease progression through post-transcriptional regulation of mRNA. The regulation of HuR and how this relates to glioma is the focus of this report. SRC and c-Abl kinases regulate HuR sub-cellular trafficking and influence accumulation in the pericentriolar matrix (PCM) via a growth factor dependent signaling mechanism. Growth factor stimulation of glioma cell lines results in the associate of HuR with the PCM and amplification of centrosome number. This process is regulated by tyrosine phosphorylation of HuR and is abolished by mutating tyrosine residues. HuR is overexpressed in tumor samples from patients with glioblastoma and associated with a reduced survival. These findings suggest HuR plays a significant role in centrosome amplification and genomic instability, which contributes to a worse disease outcome.
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PMID:Growth factor dependent regulation of centrosome function and genomic instability by HuR. 2580 45

The M2 isoform of pyruvate kinase (PK) is upregulated in most cancers including glioblastoma. Although PKM2 has been reported to use dual kinase activities to regulate cell growth, it also interacts with phosphotyrosine (pY)-containing peptides independently of its kinase activity. The potential for PKM2 to use the binding of pY-containing proteins to control tumor growth has not been fully examined. We here describe a novel mechanism by which PKM2 interacts in the nucleus with the RNA binding protein HuR to regulate HuR sub-cellular localization, p27 levels, cell cycle progression and glioma cell growth. Suppression of PKM2 in U87, T98G and LN319 glioma cells resulted in increased p27 levels, defects in entry into mitosis, increased centrosome number, and decreased cell growth. These effects could be reversed by shRNA targeting p27. The increased levels of p27 in PKM2 knock-down cells were caused by a loss of the nuclear interaction between PKM2 and HuR, and a subsequent cytoplasmic re-distribution of HuR, which in turn led to increased cap-independent p27 mRNA translation. Consistent with these results, the alterations in p27 mRNA translation, cell cycle progression and cell growth caused by PKM2 suppression could be reversed in vitro and in vivo by suppression of HuR or p27 levels, or by introduction of forms of PKM2 that could bind pY, regardless of their kinase activity. These results define a novel mechanism by which PKM2 regulates glioma cell growth, and also define a novel set of potential therapeutic targets along the PKM2-HuR-p27 pathway.
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PMID:PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells. 2687 4

Glioblastoma is a highly malignant and typically fatal tumor of the central nervous system. The tumor is characterized by marked cellular and molecular heterogeneity, including a subpopulation of brain tumor initiating cells (BTICs) that are highly resistant to radiation and chemotherapy. We previously reported that the RNA-binding protein HuR is: (1) overexpressed in glioblastoma, (2) necessary for tumor growth in vivo, and (3) a positive regulator of tumor-promoting genes in glioblastoma. These findings provide strong evidence that HuR might be a viable therapeutic target in glioblastoma. In this report, we investigated the effects of MS-444, a small molecule inhibitor of HuR, in xenograft-derived human glioblastoma cells and BTICs. We found that MS-444 treatment of glioblastoma cells resulted in loss of viability and induction of apoptosis, with evidence implicating death receptor 5. BTICs were particularly sensitive to MS-444. At sub-lethal doses, MS-444 attenuated invasion of glioblastoma cells and BTICs in a transwell model. At the molecular level, MS-444 treatment led to an attenuation of mRNAs in different tumor promoting pathways including angiogenesis, immune evasion and suppression of apoptosis. Although cytoplasmic HuR was reduced with MS-444 treatment, the attenuation of mRNAs could not be explained by RNA destabilization. In summary, this report provides proof of concept that small molecule inhibition of HuR could be a viable approach for treatment of glioblastoma.
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PMID:Anti-cancer effects of the HuR inhibitor, MS-444, in malignant glioma cells. 3099 85

Glioblastoma is a malignant brain tumor that portends a poor prognosis. Its resilience, in part, is related to a remarkable capacity for manipulating the microenvironment to promote its growth and survival. Microglia/macrophages are prime targets, being drawn into the tumor and stimulated to produce factors that support tumor growth and evasion from the immune system. Here we show that the RNA regulator, HuR, plays a key role in the tumor-promoting response of microglia/macrophages. Knockout (KO) of HuR led to reduced tumor growth and proliferation associated with prolonged survival in a murine model of glioblastoma. Analysis of tumor composition by flow cytometry showed that tumor-associated macrophages (TAMs) were decreased, more polarized toward an M1-like phenotype, and had reduced PD-L1 expression. There was an overall increase in infiltrating CD4+ cells, including Th1 and cytotoxic effector cells, and a concomitant reduction in tumor-associated polymorphonuclear myeloid-derived suppressor cells. Molecular and cellular analyses of HuR KO TAMs and cultured microglia showed changes in migration, chemoattraction, and chemokine/cytokine profiles that provide potential mechanisms for the altered tumor microenvironment and reduced tumor growth in HuR KO mice. In summary, HuR is a key modulator of pro-glioma responses by microglia/macrophages through the molecular regulation of chemokines, cytokines, and other factors. Our findings underscore the relevance of HuR as a therapeutic target in glioblastoma.
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PMID:Deletion of the RNA regulator HuR in tumor-associated microglia and macrophages stimulates anti-tumor immunity and attenuates glioma growth. 3140 Jan 63