Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Harnessing the Activation of RIG-I Like Receptors to Inhibit Glioblastoma Tumorigenesis.

ABSTRACT: Glioblastoma (GB) is an incurable form of brain malignancy in an adult with a median survival of less than 15 months. The current standard of care, which consists of surgical resection, radiotherapy, and chemotherapy with temozolomide, has been unsuccessful due to an extensive inter- and intra-tumoral genetic and molecular heterogeneity. This aspect represents a serious obstacle for developing alternative therapeutic options for GB. In the last years, immunotherapy has emerged as an effective treatment for a wide range of cancers and several trials have evaluated its effects in GB patients. Unfortunately, clinical outcomes were disappointing particularly because of the presence of tumor immunosuppressive microenvironment. Recently, anti-cancer approaches aimed to improve the expression and the activity of RIG-I-like receptors (RLRs) have emerged. These innovative therapeutic strategies attempt to stimulate both innate and adaptive immune responses against tumor antigens and to promote the apoptosis of cancer cells. Indeed, RLRs are important mediators of the innate immune system by triggering the type I interferon (IFN) response upon recognition of immunostimulatory RNAs. In this mini-review, we discuss the functions of RLRs family members in the control of immune response and we focus on the potential clinical application of RLRs agonists as a promising strategy for GB therapy.

SUBMITTER: Bufalieri F

PROVIDER: S-EPMC8295747 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

MiRNA203 suppresses the expression of protumorigenic STAT1 in glioblastoma to inhibit tumorigenesis.

Project description:MicroRNAs (miRNAs) play critical roles in regulating cancer cell proliferation, migration, survival and sensitivity to chemotherapy. The potential application of using miRNAs for cancer prognosis holds great promise but miRNAs with predictive value remain to be identified and underlying mechanisms of how they promote or suppress tumorigenesis are not completely understood. Here, we show a strong correlation between miR203 expression and brain cancer patient survival. Low miR203 expression is found in subsets of brain cancer patients, especially glioblastoma. Ectopic miR203 expression in glioblastoma cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon or temozolomide in vitro, and inhibited tumorigenesis in vivo. We further show that STAT1 is a direct functional target of miR203, and miR203 level is negatively correlated with STAT1 expression in brain cancer patients. Knockdown of STAT1 expression mimicked the effect of overexpression of miR203 in glioblastoma cell lines, and inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by IFN or temozolomide in vitro, and inhibited glioblastoma tumorigenesis in vivo. High STAT1 expression significantly correlated with poor survival in brain cancer patients. Mechanistically, we found that enforced miR203 expression in glioblastoma suppressed STAT1 expression directly, as well as that of a number of STAT1 regulated genes. Taken together, our data suggest that miR203 acts as a tumor suppressor in glioblastoma by suppressing the pro-tumorigenic action of STAT1. MiR203 may serve as a predictive biomarker and potential therapeutic target in subsets of cancer patients with low miR203 expression.

| S-EPMC5341291 | biostudies-literature

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I.

Project description:Glioblastoma multiforme (GB) is the most malignant primary brain tumor in humans, with an overall survival of approximatively 15 months. The molecular heterogeneity of GB, as well as its rapid progression, invasiveness and the occurrence of drug-resistant cancer stem cells, limits the efficacy of the current treatments. In order to develop an innovative therapeutic strategy, it is mandatory to identify and characterize new molecular players responsible for the GB malignant phenotype. In this study, the RNA-binding ubiquitin ligase MEX3A was selected from a gene expression analysis performed on publicly available datasets, to assess its biological and still-unknown activity in GB tumorigenesis. We find that MEX3A is strongly up-regulated in GB specimens, and this correlates with very low protein levels of RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune response. We demonstrate that MEX3A binds RIG-I and induces its ubiquitylation and proteasome-dependent degradation. Further, the genetic depletion of MEX3A leads to an increase of RIG-I protein levels and results in the suppression of GB cell growth. Our findings unveil a novel molecular mechanism involved in GB tumorigenesis and suggest MEX3A and RIG-I as promising therapeutic targets in GB.

| S-EPMC7072305 | biostudies-literature

Structural insights into RNA recognition and activation of RIG-I-like receptors.

Project description:RIG-I like receptors (RLR) that recognize non-self RNA play critical roles in activating host innate immune pathways in response to viral infections. Not surprisingly, RLRs and their associated signaling networks are also targeted by numerous antagonists that facilitate viral pathogenesis. Although the role of RLRs in orchestrating antiviral signaling has been recognized for some time, our knowledge of the complex regulatory mechanisms that control signaling through these key molecules is incomplete. A series of recent structural studies shed new light into the structural basis for dsRNA recognition and activation of RLRs. Collectively, these studies suggest that the repression of RLRs is facilitated by a cis element that makes multiple contacts with domains within the helicase and that RNA binding initiated by the C-terminal RNA binding domain is important for ATP hydrolysis and release of the CARD domain containing signaling module from the repressed conformation. These studies also highlight potential differences between RIG-I and MDA5, two RLR members. Together with previous studies, these new results bring us a step closer to uncovering the complex regulatory process of a key protein that protects host cells from invading pathogens.

| S-EPMC3383332 | biostudies-literature

The SKIV2L RNA exosome limits activation of the RIG-I-like receptors.

Project description:Sensors of the innate immune system that detect intracellular nucleic acids must be regulated to prevent inappropriate activation by endogenous DNA and RNA. The exonuclease Trex1 regulates the DNA-sensing pathway by metabolizing potential DNA ligands that trigger it. However, an analogous mechanism for regulating the RIG-I-like receptors (RLRs) that detect RNA remains unknown. We found here that the SKIV2L RNA exosome potently limited the activation of RLRs. The unfolded protein response (UPR), which generated endogenous RLR ligands through the cleavage of cellular RNA by the endonuclease IRE-1, triggered the production of type I interferons in cells depleted of SKIV2L. Humans with deficiency in SKIV2L had a type I interferon signature in their peripheral blood. Our findings reveal a mechanism for the intracellular metabolism of immunostimulatory RNA, with implications for specific autoimmune disorders.

| S-EPMC4139417 | biostudies-literature

Harnessing the immune system in glioblastoma.

Project description:Glioblastoma is the most common primary malignant brain tumour. Survival is poor and improved treatment options are urgently needed. Although immunotherapies have emerged as effective treatments for a number of cancers, translation of these through to brain tumours is a distinct challenge, particularly due to the blood-brain barrier and the unique immune tumour microenvironment afforded by CNS-specific cells. This review discusses the immune system within the CNS, mechanisms of immune escape employed by glioblastoma, and the immunological effects of conventional glioblastoma treatments. Novel therapies for glioblastoma that harness the immune system and their current clinical progress are outlined, including cancer vaccines, T-cell therapies and immune checkpoint modulators.

| S-EPMC6251037 | biostudies-literature

PRMT2 links histone H3R8 asymmetric dimethylation to oncogenic activation and tumorigenesis of glioblastoma.

Project description:Transcriptional deregulation has a vital role in glioblastoma multiforme (GBM). Thus, identification of epigenetic modifiers essential for oncogenic transcriptional programs is a key to designing effective therapeutics for this deadly disease. Here we report that Protein Arginine Methyltransferase 2 (PRMT2) is highly expressed in GBM and correlated with poor prognosis. The silencing or inactivation of PRMT2 inhibits GBM cell growth and glioblastoma stem cell self-renewal in vitro, and suppresses orthotopic tumor growth, accompanied with significant deregulation of genes mainly associated with cell cycle progression and pathways in cancer. Mechanistically PRMT2 is responsible for H3R8 asymmetric methylation (H3R8me2a), whose enrichment at promoters and enhancers is closely correlated with known active histone marks and is required for the maintenance of target gene expression. Together, this study demonstrates that PRMT2 acts as a transcriptional co-activator for oncogenic gene expression programs in GBM pathogenesis and provides a rationale for PRMT2 targeting in aggressive gliomas.

| S-EPMC6208368 | biostudies-literature

Receptors That Inhibit Macrophage Activation: Mechanisms and Signals of Regulation and Tolerance.

Project description:A variety of receptors perform the function of attenuating or inhibiting activation of cells in which they are expressed. Examples of these kinds of receptors include TIM-3 and PD-1, among others that have been widely studied in cells of lymphoid origin and, though to a lesser degree, in other cell lines. Today, several studies describe the function of these molecules as part of the diverse mechanisms of immune tolerance that exist in the immune system. This review analyzes the function of some of these proteins in monocytes and macrophages and as well as their participation as inhibitory molecules or elements of immunological tolerance that also act in innate defense mechanisms. We chose the receptors TIM-3, PD-1, CD32b, and CD200R because these molecules have distinct functional characteristics that provide examples of the different regulating mechanisms in monocytes and macrophages.

| S-EPMC5828319 | biostudies-literature

Harnessing Radiation Biology to Augment Immunotherapy for Glioblastoma.

Project description:Glioblastoma is the most common adult primary brain tumor and carries a dismal prognosis. Radiation is a standard first-line therapy, typically deployed following maximal safe surgical debulking, when possible, in combination with cytotoxic chemotherapy. For other systemic cancers, standard of care is being transformed by immunotherapies, including checkpoint-blocking antibodies targeting CTLA-4 and PD-1/PD-L1, with potential for long-term remission. Ongoing studies are evaluating the role of immunotherapies for GBM. Despite dramatic responses in some cases, randomized trials to date have not met primary outcomes. Challenges have been attributed in part to the immunologically "cold" nature of glioblastoma relative to other malignancies successfully treated with immunotherapy. Radiation may serve as a mechanism to improve tumor immunogenicity. In this review, we critically evaluate current evidence regarding radiation as a synergistic facilitator of immunotherapies through modulation of both the innate and adaptive immune milieu. Although current preclinical data encourage efforts to harness synergistic biology between radiation and immunotherapy, several practical and scientific challenges remain. Moreover, insights from radiation biology may unveil additional novel opportunities to help mobilize immunity against GBM.

| S-EPMC6395389 | biostudies-literature

Cytoplasmic Viral RNA Sensors: RIG-I-Like Receptors

Project description:The interferon (IFN) response is a powerful system that was evolutionarily acquired by vertebrates including mammals to protect against viral infection. The cytoplasmic RNA helicases, RIG-I-like receptors (RLRs), were discovered in 2004 as viral sensors that trigger the antiviral IFN response by recognizing the nonself signatures of viral RNAs. The mechanisms underlying the recognition of viral RNAs and signal transduction leading to the production of type I IFN have been intensively studied following the discovery of RLRs. Moreover, a dysregulation in the expression of RLR or aberrant RLR signaling has been implicated in the development of a number of autoimmune diseases. We herein provide an overview of recent advances in RLR research and discussed future directions.

| S-EPMC7151769 | biostudies-literature

Intracellular pathogen detection by RIG-I-like receptors.

Project description:The RIG-I-like receptors (RLRs) RIG-I, MDA5, and LGP2 trigger innate immune responses against viral infections that serve to limit virus replication and to stimulate adaptive immunity. RLRs are cytosolic sensors for virus-derived RNA and thus responsible for intracellular immune surveillance against infection. RLR signaling requires the adapter protein MAVS to induce type I interferon, interferon-stimulated genes, and proinflammatory cytokines. This review focuses on the molecular and cell biological requirements for RLR signal transduction.

| S-EPMC3947775 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data