MiR-148a increases glioma cell migration and invasion by downregulating GADD45A in human gliomas with IDH1 R132H mutations.
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ABSTRACT:
SUBMITTER: Cui D
PROVIDER: S-EPMC5421935 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeNumerous studies have reported that glioma patients with isocitrate dehydrogenase 1(IDH1) R132H mutation are sensitive to temozolomide treatment. However, the mechanism of IDH1 mutations on the chemosensitivity of glioma remains unclear. In this study, we investigated the role and the potential mechanism of Nrf2 in IDH1 R132H-mediated drug resistance.MethodsWild type IDH1 (R132H-WT) and mutant IDH1 (R132H) plasmids were constructed. Stable U87 cells and U251 cells overexpressing IDH1 were generated. Phenotypic differences between IDH1-WT and IDH1 R132H overexpressing cells were evaluated using MTT, cell colony formation assay, scratch test assay and flow cytometry. Expression of IDH1 and its associated targets, nuclear factor-erythroid 2-related factor 2 (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1), multidrug resistant protein 1 (MRP1) and p53 were analyzed.ResultsThe IDH1 R132H overexpressing cells were more sensitive to temozolomide than WT and the control, and Nrf2 was significantly decreased in IDH1 R132H overexpressing cells. We found that knocking down Nrf2 could decrease resistance to temozolomide. The nuclear translocation of Nrf2 in IDH1 R132H overexpressing cells was lower than the WT and the control groups after temozolomide treatment. When compared with WT cells, NQO1 expression was reduced in IDH1 R132H cells, especially after temozolomide treatment. P53 was involved in the resistance mechanism of temozolomide mediated by Nrf2 and NQO1.ConclusionsNrf2 played an important role in IDH1 R132H-mediated drug resistance. The present study provides new insight for glioma chemotherapy with temozolomide.
| S-EPMC5438698 | biostudies-literature
Project description:Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.
| S-EPMC4005896 | biostudies-literature
Project description:The prognosis for the WHO grade 4 IDH-mutant astrocytoma is better than IDH-wildtype glioblastoma (GBM) patients. The purpose of this study is to explore the potential mechanism of how IDH1 mutation can increase the efficacy of radiotherapy and to establish a risk-score model to predict the efficacy of radiotherapy in WHO grade 4 gliomas. First, we conducted experimental study on the effect of IDH1R132H mutation on glioma cells in vitro. Radiosensitivity of glioma cells was detected by γ-H2AX after 5 Gy radiation. Cell proliferation, migration and invasion were determined respectively by CCK-8, EDU, monolayer cell migration scratch assay and Transwell assay. Then we analyzed IDH1 gene status and the survival of WHO grade 4 glioma patients received radiotherapy in our center and verified our results by analyzing CGGA and TCGA database. For the risk-score model, we use CGGA data to find genetic differences between WHO grade 4 IDH-mutant astrocytoma and IDH-wildtype GBM patients, and determined a 4-gene radiotherapy-related signature through survival analysis by R software. Evaluation and verification through different glioma validation sets and different statistical methods. For in vitro experiments, we established glioma cells stably overexpressing IDH1 wild-type and IDH1-mutant proteins. γ-H2AX assay showed that IDH1-mutant glioma cells had higher radiosensitivity than wild-type. CCK-8 and EDU assay showed that proliferation capacity of IDH1-mutant glioma cells declined. Transwell assay and monolayer cell migration scratch assay also showed that IDH1-mutant glioma cells reduced migration and invasion capabilities. Among the 83 WHO grade 4 glioma patients who received radiotherapy in our center, WHO grade 4 IDH-mutant astrocytoma patients had longer OS and PFS versus IDH-wildtype GBM (P = 0.0336, P = 0.0324, respectively). TCGA and CGGA database analysis had the similar results. Through complex analysis of CGGA and TCGA databases, we established a risk-model that can predict the efficacy of radiotherapy for WHO grade 4 glioma patients. The 4-gene radiotherapy-related signature including ADD3, GRHPR, RHBDL1 and SLC9A9. Patients in the high-risk group had worse OS compared to low-risk group (P = 0.0001). High- and low-risk groups of patients receiving radiotherapy have significant survival differences, while patients who did not receive radiotherapy have no survival difference both in CGGA and TCGA databases. WHO grade 4 IDH-mutant astrocytoma is more radiosensitive than IDH-wildtype GBM patients. Our 4-gene radiotherapy-related signature can predict the radiation efficacy of WHO grade 4 glioma patients, and it may provide some reference for clinical treatment options.
| S-EPMC10640646 | biostudies-literature
Project description:Isocitrate dehydrogenase 1 (IDH1) is the most frequently mutated gene in World Health Organization grade II-III and secondary glioma. The majority of IDH1 mutation cases involve the substitution from arginine to histidine at codon 132 (IDH1-R132H). Although the oncogenic role of IDH1-R132H has been confirmed, patients with IDH1-R132H brain tumors exhibit a better response to radiotherapy compared with those with wild-type (WT) IDH1. In the present study, the potential mechanism of radiosensitization mediated by IDH1-R132H was investigated by overexpressing IDH1-R132H in U87MG glioma cells. The results demonstrated decreased clonogenic capacity of IDH1-R132H-expressing cells, as well as delayed repair of DNA double-strand breaks compared with IDH1-WT. Data from The Cancer Genome Atlas were analyzed, which demonstrated that the expression of TP53-induced glycolysis and apoptosis regulator (TIGAR) was lower in patients with glioma harboring IDH1 mutations compared with that in patients with IDH1-WT. TIGAR-knockdown increases the radiosensitivity of glioma cells; in U87MG cells, IDH1-R132H suppressed TIGAR expression. Chromatin immunoprecipitation assays revealed increased levels of repressive H3K9me3 markers at the TIGAR promoter in IDH1-R132H compared with IDH1-WT. These data indicated that IDH1-R132H may overcome radioresistance in glioma cells through epigenetic suppression of TIGAR expression. However, these favorable effects were not observed in U87MG glioma stem-like cells. The results of the present study provide an improved understanding of the functionality of IDH1 mutations in glioma cells, which may improve the therapeutic efficacy of radiotherapy.
| S-EPMC6956398 | biostudies-literature
Project description:Recurrence and progression to higher grade lesions are key biological events and characteristic behaviors in the evolution process of glioma. A small residual population of cells always escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence or progression. IDH mutation (isocitrate dehydrogenase) and ATRX (alpha-thalassemia/mental retardation, X-linked) loss/mutation occur in association and may represent early genetic alterations in the development of gliomas. However, their prognostic value in the evolution of gliomas still needs further investigation.Two hundreds and eleven serial sampling of gliomas were included in our study. We used immunohistochemistry (IHC) to detect IDH1-R132H mutation and ATRX status and showed that the IDH1-R132H and (or) ATRX status could be necessary to provide the basic molecular information for the "integrated diagnosis" of gliomas. We illustrated an evaluation formula for the evolution of gliomas by IDH1-R132H combined with ATRX immunohistochemistry and identified the association of IDH1-R132H/ATRX loss accompanied by longer progression time interval of patients with gliomas. Furthermore, we observed that most recurrences had a consistent IDH1 and ATRX status with their matched primary tumors and demonstrated the progressive pattern of grade II astrocytoma/oligodendroglial tumors and anaplastic oligoastrocytoma with or without IDH1-R132H. Identification of IDH1-R132H and ATRX loss status in the primary-recurrent gliomas may aid in treatment strategy selection, therapeutic trial design, and clinical prognosis evaluation.
| S-EPMC4941322 | biostudies-literature
Project description:Glioma represents the most common central nervous system neoplasm in adults. Current classification scheme utilizes molecular alterations, particularly IDH1.R132H, to stratify lesions into distinct prognostic groups. Identification of the single nucleotide variant through traditional tissue biopsy assessment poses procedural risks and does not fully reflect the heterogeneous and evolving tumor landscape. Here, we introduce a liquid biopsy assay, mt-IDH1dx. The blood-based test allows minimally invasive detection of tumor-derived extracellular vesicle RNA using only 2 ml plasma volume. We perform rigorous, blinded validation testing across the study population (n = 133), comprising of IDH1.R132H patients (n = 80), IDH1 wild-type gliomas (n = 44), and age matched healthy controls (n = 9). Results from our plasma testing demonstrate an overall sensitivity of 75.0% (95% CI: 64.1%-84.0%), specificity 88.7% (95% CI: 77.0%-95.7%), positive predictive value 90.9%, and negative predictive value 70.1% compared to the tissue gold standard. In addition to fundamental diagnostic applications, the study also highlights the utility of mt-IDH1dx platform for blood-based monitoring and surveillance, offering valuable prognostic information. Finally, the optimized workflow enables rapid and efficient completion of both tumor tissue and plasma testing in under 4 hours from the time of sampling.
| S-EPMC11329733 | biostudies-literature
Project description:Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequent in human glioblastomas1 and cytogenetically normal acute myeloid leukemias (AML)2. These alterations are gain-of-function mutations in that they drive the synthesis of the M-bM-^@M-^\oncometaboliteM-bM-^@M-^] R-2-hydroxyglutarate (2HG)3. It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukemogenesis. Here we report the characterization of conditional knock-in mice in which the most common IDH1 mutation, Idh1-R132H, is inserted into the endogenous murine Idh1 locus and is expressed in cells of the hematopoietic (Vav-KI) or more specifically in cells of the myeloid (LysM-KI) lineage. These mutants show increased numbers of early hematopoietic progenitors and develop splenomegaly and anemia with extramedullary hematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells exhibit both hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1/2-mutant AML. Thus, our study is the first to describe the generation of conditional Idh1-R132H-KI mice. Furthermore, our study is also the first report showing the induction of a leukemic DNA methylation signature in a modeled system and sheds light on the mechanistic links between IDH1 mutation and human AML. DNA methylation profiling in LSK cells from IDH1-R132H knock-in mice vs. control mice
2012-07-22 | E-GEOD-38687 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-03-18 | GSE94976 | GEO
Project description:Heterozygous isocitrate dehydrogenase (IDH) R132H mutation (IDH1R132H/WT) is an early event during gliomagenesis. Clinically, patients with glioma carrying mutant IDH1 respond better to antitumor therapies. However, the mechanism by which IDH1 mutations contribute to gliomagenesis and therapeutic response remains elusive. Here we report that senescence is involved in the improved therapeutic responses of mutant IDH1 glioma cells. Knocking-in IDH1R132H/WT in glioma cells significantly enhanced gliomas cell senescence in response to temozolomide and radiation via a DNA-damage mediated mechanism. We further asked if senescence plays a role in IDH1R132H/WT-induced gliomagenesis. Together with ATRX knockout and p53/RB loss, IDH1R132H/WT transformed nonneoplastic human astroglial cells to form tumors in mouse brains. In-depth characterization revealed that a subset of these precancerous cells underwent senescence-like phenotypic changes, including flat and enlarged-cell morphology, increased senescence marker expression, decreased cell proliferation, and cell-cycle arrest at the G2-M phase. Mechanistic studies indicated that the combination of glioma driver genes (p53/RB/IDH1/ATRX) dramatically increased DNA damage and activated DNAdamage response (DDR) pathways ATR/ATR and Chk1/Chk2 in senescent cells. To determine how senescent cells drive tumor formation, we investigated non-cell-autonomous mechanisms such as senescence-associated secretory phenotype (SASP), a panel of proinflammatory and tissue-remodeling factors implicated in a tumor-permissive microenvironment. We found that astroglial cells carrying p53/RB/ATRX loss and IDH1R132H/WT upregulated key factors in SASP via an epigenetic-mediated mechanism. Our work suggests that drugs that specifically eliminate senescent cells could help kill precancerous cells and senescent tumor cells following antitumor therapies. IMPLICATIONS: The mechanisms by which IDH1 mutations contribute to gliomagenesis and therapeutic responses remain incompletely characterized; this work reveals senescence as a novel mechanism of IDH-mutant-mediated biological impact and describes new therapeutic opportunities concerning IDH1-mutant gliomas.
| S-EPMC8568642 | biostudies-literature
Project description:Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.
| S-EPMC8113211 | biostudies-literature