Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

Wang, Jiping; Leavenworth, Jianmei W.; Hjelmeland, Anita B.; Smith, Reed; Patel, Nilesh A.; Borg, Ben; Si, Ying; King, Peter H.

doi:10.1002/glia.23696

Cited by 26 publications

(37 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A recent study has shown that manipulation of RNA regulator in tumor-associated microglia and macrophages stimulates antitumor immunity and reduces glioma growth (31). More recently, we found that the compromised monocyte, macrophages and microglia from patients with glioma could be reactivated by amphotericin B to reduce BTIC growth in culture and to prolong the lifespan of mice with intracranial patient-derived BTIC xenografts (26).…”

Section: Introductionmentioning

confidence: 85%

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Sarkar

Mirzaei

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth. Monocytes were selected for study as they would be exposed to demeclocycline in the circulation prior to entry into brain tumors to become macrophages. We found that demeclocycline increased the activity of monocytes in culture, as determined by tumor necrosis factor-α production and chemotactic capacity. The conditioned medium of demeclocycline-stimulated monocytes attenuated the growth of BTICs generated from human glioblastoma resections, as evaluated using neurosphere and alamarBlue assays, and cell counts. Demeclocycline also had direct effects in reducing BTIC growth. A global gene expression screen identified several genes, such as DNA damage inducible transcript 4, frizzled class receptor 5 and reactive oxygen species modulator 1, as potential regulators of demeclocycline-mediated BTIC growth reduction. Amongst several tetracycline derivatives, only demeclocycline directly reduced BTIC growth. In summary, we have identified demeclocycline as a novel inhibitor of the growth of BTICs, through direct effect and through indirect stimulation of monocytes. Demeclocycline is a candidate to reactivate compromised immune cells to improve the prognosis of patients with gliomas.

show abstract

Section: Introductionmentioning

confidence: 85%

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Sarkar

Mirzaei

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Moreover, there is evidence showing that small molecules and pathways were involved in the development of GBM. For example, RNA regulatory factors can regulate the activity of microglia and participate in tumor progression and can act as a therapeutic target in GBM [9]. Runt-related transcription factor 1 (RUNX1) would impact the prognosis of GBM via the TGFβ pathway [10].…”

Section: Introductionmentioning

confidence: 99%

Computational analysis and verification of molecular genetic targets for glioblastoma

Li¹,

Liu²,

Chen³

et al. 2020

Bioscience Reports

View full text Add to dashboard Cite

Background: Glioblastoma (GBM) is the most common malignant brain tumor with a poor prognosis. The initial treatment for high-grade gliomas is surgical excision. However, even with concomitant use of radiation or chemotherapy, patients are still prone to recurrence. The specific pathogenesis of GBM is still controversial. Methods: Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) between GBM and normal brain tissues were screened. P-value was obtained by Bayes test based on the limma package. Statistical significance was set as P-value <0.05 and |Fold change (FC)| > 0.2 (GSE90886); P-value <0.05 and |FC| > 1 (GSE116520, GSE103228). Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG), protein–protein interaction (PPI) network were performed. Hub genes were selected from miRNA target genes and DEGs. GBM and normal brain tissues were extracted to verify the expression. Results: A total of 100 DEGs were overlapped in both datasets. Analysis of pathways and process enrichment tests indicated that ion transport, positive regulation of macromolecule metabolic process, cell cycle, axon guidance were enriched in the GBM. Sixteen hub genes were identified. Hub genes ADARB1 and neuropilin 1 (NRP1) were significantly associated with overall survival (OS) and disease-free survival (DFS) (P<0.05). Eukaryotic translation termination factor 1 (ETF1) was associated with DFS (P<0.05). Conclusions: DEGs and DEMs were found between GBM tumor tissues and normal brain tissues. These biomarkers may be used as targets for early diagnosis and specific treatment.

show abstract

“…Hypoxia, mechanical stress, chronic inflammation, cytotoxic stress, and oncometabolites associated with free radical formations are reported to potentiate intercellular membrane fusion events, and these conditions are often associated with the glioma microenvironment [ 14 , 20 , 21 , 22 , 23 , 27 , 35 , 44 , 45 , 46 , 47 ]. The mRNA-binding protein of ELAV-family HuR is a valuable biomarker of brain tumor progression [ 48 , 49 , 50 , 51 ] and is involved in the regulation of the key cell-signaling pathways responsible for the inflammatory glioma microenvironment, the hypoxia-related stress response, the transitions of classic and proneural glioma subtypes to the mesenchymal subtype, the metabolic stress, and the reactive oxygen species (ROS) generation associated with D-2HG oncometabolite production in low-grade gliomas harboring single alleles with IDH1-R132H/C/S mutations [ 52 , 53 , 54 , 55 ]. HuR exhibits strong overexpression in gliomas and shuttles from the nucleus to the cytoplasm to stabilize and promote the transfer and translation of mRNA transcripts enriched with adenine/uridine motifs in 3‘UTR [ 53 , 54 , 55 , 56 ].…”

Section: Hur-dependent Cell-signaling Pathways Of Cell Fusion and mentioning

confidence: 99%

ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity

Filippova

Nabors

2020

Cancers

View full text Add to dashboard Cite

Homotypic and heterotypic cell fusions via permanent membrane fusions and temporal tunneling nanotube formations in the glioma microenvironment were recently documented in vitro and in vivo and mediate glioma survival, plasticity, and recurrence. Chronic inflammation, a hypoxic environment, aberrant mitochondrial function, and ER stress due to unfolded protein accumulation upregulate cell fusion events, which leads to tumor heterogeneity and represents an adaptive mechanism to promote tumor cell survival and plasticity in cytotoxic, nutrient-deprived, mechanically stressed, and inflammatory microenvironments. Cell fusion is a multistep process, which consists of the activation of the cellular stress response, autophagy formation, rearrangement of cytoskeletal architecture in the areas of cell-to-cell contacts, and the expression of proinflammatory cytokines and fusogenic proteins. The mRNA-binding protein of ELAV-family HuR is a critical node, which orchestrates the stress response, autophagy formation, cytoskeletal architecture, and the expression of proinflammatory cytokines and fusogenic proteins. HuR is overexpressed in gliomas and is associated with poor prognosis and treatment resistance. Our review provides a link between the HuR role in the regulation of cell fusion and tunneling nanotube formations in the glioma microenvironment and the potential suppression of these processes by different classes of HuR inhibitors.

show abstract

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

Cited by 26 publications

References 77 publications

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Computational analysis and verification of molecular genetic targets for glioblastoma

ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity

Contact Info

Product

Resources

About