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2-HG Desensitizes Cells to TNFa-Induced Necroptosis via Suppression of RIP3 Expression (A) Western blot to detect the indicated proteins in untreated IDH1 WT/WT , IDH1 WT/Mut , and IDH1 Mut/Mut MEFs. (B) Western blot to detect RIP3 protein in three IDH1 WT/WT , three IDH1 WT/Mut , and two IDH1 Mut/Mut additional MEF lines. (C) Western blot to detect the indicated proteins in IDH1 WT/WT MEFs that were infected with empty lentivirus (vector) or lentivirus expressing FLAGtagged WT IDH1, IDH1-R132Q, or IDH1-R132H and cultured for 7 days. (D) Western blot to detect the indicated proteins in IDH1 WT/WT MEF, L929, and HT-29 cells that were left untreated (À) or treated with 2-HG (+) for 7 days. (E) IDH1 Mut/Mut MEFs were infected with lentivirus expressing Flag-RIP3 or GFP. At 96 hr postinfection, these cells, as well as IDH1 WT/WT MEFs, were treated with DMSO or T + S + Z for 20 hr. Left: western blot to detect RIP3 in these cells is shown. Glyceraldehyde 3-phosphate dehydrogenase (GADPH), loading control. Right: survival of these cells determined by flow cytometric viability analysis as in Figure 1 is shown.
Source publication
2-hydroxyglutarate-(2-HG)-mediated inhibition of TET2 activity influences DNA hypermethylation in cells harboring mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2). Here, we show that 2-HG also regulates DNA methylation mediated by DNA methyltransferase 1 (DNMT1). DNMT1-dependent hypermethylation of the RIP3 promoter occurred in both IDH1 R13...
Contexts in source publication
Context 1
... RIP3, RIP1, and MLKL are all key components of the necroptosis pathway, we determined the levels of these three proteins in IDH1 WT/WT , IDH1 WT/Mut , and IDH1 Mut/Mut MEFs. Interestingly, the expression of RIP3, but not RIP1 or MLKL, was downregulated in MEFs bearing IDH1 R132Q (Figure 3A). Parallel results were obtained for three additional IDH1 WT/WT , three IDH1 WT/Mut , and two IDH1 Mut/Mut MEF lines generated from an independent set of littermate embryos (Fig- ure 3B). To confirm that IDH1 R132Q reduces RIP3 expression, we overexpressed IDH1 R132Q or IDH1 R132H in IDH1 WT/WT MEFs and detected downregulation of RIP3 in cells expressing the IDH1 R132 mutants, but not WT IDH1 ( Figure 3C). Moreover, treatment of IDH1 WT/WT MEFs, or L929 and HT-29 cells, with exogenous 2-HG efficiently decreased RIP3 expression (Fig- ure 3D). Thus, the 2-HG produced by IDH1 R132 mutant en- zymes reduces intracellular RIP3 ...
Context 2
... RIP3, RIP1, and MLKL are all key components of the necroptosis pathway, we determined the levels of these three proteins in IDH1 WT/WT , IDH1 WT/Mut , and IDH1 Mut/Mut MEFs. Interestingly, the expression of RIP3, but not RIP1 or MLKL, was downregulated in MEFs bearing IDH1 R132Q (Figure 3A). Parallel results were obtained for three additional IDH1 WT/WT , three IDH1 WT/Mut , and two IDH1 Mut/Mut MEF lines generated from an independent set of littermate embryos (Fig- ure 3B). To confirm that IDH1 R132Q reduces RIP3 expression, we overexpressed IDH1 R132Q or IDH1 R132H in IDH1 WT/WT MEFs and detected downregulation of RIP3 in cells expressing the IDH1 R132 mutants, but not WT IDH1 ( Figure 3C). Moreover, treatment of IDH1 WT/WT MEFs, or L929 and HT-29 cells, with exogenous 2-HG efficiently decreased RIP3 expression (Fig- ure 3D). Thus, the 2-HG produced by IDH1 R132 mutant en- zymes reduces intracellular RIP3 ...
Context 3
... RIP3, RIP1, and MLKL are all key components of the necroptosis pathway, we determined the levels of these three proteins in IDH1 WT/WT , IDH1 WT/Mut , and IDH1 Mut/Mut MEFs. Interestingly, the expression of RIP3, but not RIP1 or MLKL, was downregulated in MEFs bearing IDH1 R132Q (Figure 3A). Parallel results were obtained for three additional IDH1 WT/WT , three IDH1 WT/Mut , and two IDH1 Mut/Mut MEF lines generated from an independent set of littermate embryos (Fig- ure 3B). To confirm that IDH1 R132Q reduces RIP3 expression, we overexpressed IDH1 R132Q or IDH1 R132H in IDH1 WT/WT MEFs and detected downregulation of RIP3 in cells expressing the IDH1 R132 mutants, but not WT IDH1 ( Figure 3C). Moreover, treatment of IDH1 WT/WT MEFs, or L929 and HT-29 cells, with exogenous 2-HG efficiently decreased RIP3 expression (Fig- ure 3D). Thus, the 2-HG produced by IDH1 R132 mutant en- zymes reduces intracellular RIP3 ...
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... RIP3 is required for necroptosis, the low level of RIP3 in cells carrying an IDH1 mutation could be the cause of their resistance to TNF-a-induced necroptosis. To test this hypothe- sis, we overexpressed RIP3 in IDH1 Mut/Mut MEFs to determine whether RIP3 could rescue the insensitivity of these cells to TNF-a-induced necroptosis and showed that this was indeed the case ( Figure 3E). Collectively, these data demonstrate that the product of IDH1 R132 mutant enzymes can reduce intracel- lular RIP3 such that cells become resistant to TNF-a-induced ...
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... systematically evaluate the in vivo effects of IDH1 R132Q mutation on tumorigenesis, we performed allograft tumor forma- tion assays in nude mice. Necroptosis-resistant IDH1 Mut/Mut MEFs transplanted into nude mice more potently induced tumor formation than did transplanted IDH1 WT/WT MEFs ( Figure 7C). Consistent with this result, inhibition of necroptosis by knock- down of MLKL promoted allograft tumor formation of IDH1 WT/WT MEFs ( Figure S3A). To demonstrate the role of IDH1 R132 muta- tion-mediated RIP3 downregulation in such tumorigenesis, we ectopically expressed RIP3 in IDH1 Mut/Mut MEFs and performed the same assay. Ectopic expression of RIP3 diminished the abil- ity of IDH1 Mut/Mut MEFs to initiate tumor growth ( Figure 7D). The effect of RIP3 was MLKL dependent (Figure S3B), confirming that necroptosis is responsible for RIP3-mediated inhibition of tumorigenesis driven by IDH1 ...
Context 6
... systematically evaluate the in vivo effects of IDH1 R132Q mutation on tumorigenesis, we performed allograft tumor forma- tion assays in nude mice. Necroptosis-resistant IDH1 Mut/Mut MEFs transplanted into nude mice more potently induced tumor formation than did transplanted IDH1 WT/WT MEFs ( Figure 7C). Consistent with this result, inhibition of necroptosis by knock- down of MLKL promoted allograft tumor formation of IDH1 WT/WT MEFs ( Figure S3A). To demonstrate the role of IDH1 R132 muta- tion-mediated RIP3 downregulation in such tumorigenesis, we ectopically expressed RIP3 in IDH1 Mut/Mut MEFs and performed the same assay. Ectopic expression of RIP3 diminished the abil- ity of IDH1 Mut/Mut MEFs to initiate tumor growth ( Figure 7D). The effect of RIP3 was MLKL dependent (Figure S3B), confirming that necroptosis is responsible for RIP3-mediated inhibition of tumorigenesis driven by IDH1 ...
Citations
... 2-HG also directly binds to mutant p53, thereby reducing ubiquitination and degradation of mutant p53, which is proved to inhibit apoptosis of tumor cells [72]. In addition, 2-HG combines with DNA methyltransferase 1 (DNMT1) and mediates receptor interacting serine/threonine kinase 3 (RIP3) promoter hypermethylation, thereby impairing RIP3-dependent necroptosis [73]. The impairment of necroptosis also contributes to IDH1/2-mutation-driven tumorigenesis. ...
The tricarboxylic acid (TCA) cycle is capable of providing sufficient energy for the physiological activities under aerobic conditions. Although tumor metabolic reprogramming places aerobic glycolysis in a dominant position, the TCA cycle remains indispensable for tumor cells as a hub for the metabolic linkage and interconversion of glucose, lipids, and certain amino acids. TCA intermediates such as citrate, α-ketoglutarate, succinate, and fumarate are altered in tumors, and they regulate the tumor metabolism, signal transduction, and immune environment to affect tumorigenesis and tumor progression. This article provides a comprehensive review of the modifications occurring in tumor cells in relation to the intermediates of the TCA cycle, which affects tumor pathogenesis and current therapeutic strategy for therapy through targeting TCA cycle in cancer cells.
... Many studies have shown that the activation of the RIPK1 and RIPK3 necroptosis-related genes or the necroptotic pathway participates in the metabolic process of tumor cells and the regulation of the tumor microenvironment. This activation can play dual roles by either promoting or inhibiting the occurrence and development of tumors, depending on the type of tumor, the surrounding cellular environment, and tumor developmental stage [25][26][27][28]. Therefore, studying necroptosis-related genes and their regulatory mechanisms in tumor cells is expected to provide a new target for the treatment of esophageal cancer. ...
Background
Previous studies have shown that necroptosis-related long noncoding RNA (lncRNA) risk models can be used to predict prognosis and immune infiltration in patients with esophageal cancer. However, further analysis of the regulatory mechanisms of necroptosis-related lncRNAs used in risk models remains to be conducted. The purpose of the present study was to identify valuable necroptosis-related lncRNAs in esophageal cancer and to verify their molecular and cellular functions.
Methods
Esophageal cancer data were downloaded from The Cancer Genome Atlas (TCGA). The expression of eight genes (LINC00299, AC090912.2, AC244197.2, AL158166.1, AC079684.1, AP003696.1, AC079684.1 and AP003696.1) in the necroptosis-related lncRNA risk model, their relationships with clinicopathological stage, and their diagnostic receiver operating characteristic (ROC) curves were analyzed. The prognostic value of these lncRNAs for overall survival (OS) and disease specific survival (DSS) was analyzed, and time-dependent ROC curves were generated. The AP003696.1 target gene (lncRNA ENSG00000253385.1) was further investigated through immune infiltration analysis, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) enrichment analyses, and gene coexpression analysis. Finally, in vitro functional assays based on lncRNA ENSG00000253385.1 were conducted to explore its regulatory role in esophageal cancer.
Results
A bioinformatics approach was used to study the eight genes in the necroptosis-related lncRNA risk model. AP003696.1 (lncRNA ENSG00000253385.1) was highly expressed in esophageal cancer tissues, and its high expression was correlated with poor OS and DFdS. Both univariate and multivariate Cox regression analyses revealed that lncRNA ENSG00000253385.1 is an independent prognostic factor. The lncRNA ENSG00000253385.1 gene was demonstrated to play a definite role in the invasion of esophageal cancer immune cells and in signaling pathways in these cells. In vitro cell functional assays revealed that lncRNA ENSG00000253385.1 expression was elevated in the KYSE150 and KYSE410 esophageal cancer cell lines. Small interfering RNA (siRNA)-mediated silencing of lncRNA ENSG00000253385.1 significantly inhibited the proliferation, migration, and invasion of KYSE150 and KYSE410 cells, as well as promoted their apoptosis.
Conclusions
The ENSG00000253385.1 gene may be a key gene in the occurrence, development, and prognosis of esophageal cancer. These findings provide new ideas and references for the screening of therapeutic targets, as well as the development of targeted drugs, for esophageal cancer treatment.
... Additionally, IDH1/2 mutations not only decrease the ability of NADP + to be reduced to NADPH, but also promote the reverse conversion of NADPH to NADP + [35] . Excessive accumulation of 2-HG and impaired NADPH production jointly result in epigenetic changes, DNA repair damage, and aberrant cell metabolism, thereby promoting tumorigenesis [36] . ...
Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver cancer with limited treatment options and poor prognosis. Although gemcitabine combined with cisplatin (GEMCIS) or newly GEMCIS plus durvalumab is the first-line systemic therapy for iCCA, several promising treatment targets have been identified in the past decade in both first- and subsequent-line settings, including neurotrophic tropomyosin-receptor tyrosine kinase (NTRK) fusions, RET fusions, high microsatellite instability (MSI-H), high tumor mutation burden (TMB-H), as well as fibroblast growth factor receptor 2 (FGFR2) fusions, BRAF V600E mutation, isocitrate dehydrogenase (IDH)-1 and IDH-2 mutations, and human epidermal growth factor receptor 2 [HER2 (ERBB2)] amplifications. Corresponding small molecule inhibitors and monoclonal antibodies have demonstrated improved efficacy and survival benefits in phase 2 or phase 3 studies, gained regulatory approvals or recommendations in guidelines, and reshaped the therapeutic management for advanced cholangiocarcinoma. Numerous novel targeted drugs and combination therapies have been developed and are under evaluation. Despite the progress made in targeted therapy, it still faces challenges such as acquired drug resistance, precise patient selection, and serious adverse events. Therefore, large-scale randomized phase 3 trials of novel targeted agents and innovative regimens are warranted to benefit this population. Herein, we present a comprehensive review of the literature of clinical significance on targeted therapy for iCCA in recent years, focusing on the advances in mutation-based targeted therapy.
... DNMT1 is the most abundant DNMT in mammalian cells and is responsible for routine methylation maintenance 22,23 . A recent study reported that D2HG can bind directly to DNMT1 and regulate DNA methylation 24 , which promotes us to investigate if DNMT1 participates in the suppression of IRF3/7 mediated by D2HG. First, knockdown of DNMT1 dramatically inhibited the replication of VSVΔ51 in glioma cells expressing IDH1(R132H) (Fig. 5a). ...
IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known regarding its regulation in antiviral immunity. Here, we discover that IDH1 mutation inhibits virus-induced interferon (IFN) antiviral responses in glioma cells. Mechanistically, D2HG produced by mutant IDH1 enhances the binding of DNMT1 to IRF3/7 promoters such that IRF3/7 are downregulated, leading to impaired type I IFN response in glioma cells, which enhances the susceptibility of gliomas to viral infection. Furthermore, we identify DNMT1 as a potential biomarker predicting which IDH1mut gliomas are most likely to respond to oncolytic virus. Finally, both D2HG and ectopic mutant IDH1 can potentiate the replication and oncolytic efficacy of VSVΔ51 in female mouse models. These findings reveal a pivotal role for IDH1 mutation in regulating antiviral response and demonstrate that IDH1 mutation confers sensitivity to oncolytic virotherapy.
... It is gradually decomposed within the mitochondria by various metabolic enzymes, and then the metabolites are transported out of the mitochondria to perform their functions respectively. methylation (30,31). Besides, Miao et al. verified that 2-HG can facilitate the differentiation of Th17 cells by forming H3K4me3 (Histone H3, trimethylated lysine 4) modifications in the promoter and CNS2 region of the IL-17A gene locus. ...
To maintain the body’s regular immune system, CD4⁺ T cell homeostasis is crucial, particularly T helper (Th1, Th17) cells and T regulatory (Treg) cells. Abnormally differentiated peripheral CD4⁺ T cells are responsible for the occurrence and development of numerous diseases, including autoimmune diseases, transplantation rejection, and irritability. Searching for an effective interventional approach to control this abnormal differentiation is therefore especially important. As immunometabolism progressed, the inherent metabolic factors underlying the immune cell differentiation have gradually come to light. Mounting number of studies have revealed that glutaminolysis plays an indelible role in the differentiation of CD4⁺ T cells. Besides, alterations in the glutaminolysis can also lead to changes in the fate of peripheral CD4⁺ T cells. All of this indicate that the glutaminolysis pathway has excellent potential for interventional regulation of CD4⁺ T cells differentiation. Here, we summarized the process by which glutaminolysis regulates the fate of CD4⁺ T cells during differentiation and further investigated how to reshape abnormal CD4⁺ T cell differentiation by targeting glutaminolysis.
... In recent years, increasing evidence has shown that necroptosis plays an important role in tumorigenesis, metastasis, and the tumor immune response. It has been reported that activation of the necrosis-related genes RIPK1 and RIPK3 or necrosis-related signaling pathways is involved in the regulation of tumor cell metabolic biological processes and the tumor microenvironment (12)(13)(14)(15). Studies have shown that necroptosis can not only promote the occurrence and development of cancer but also inhibit the occurrence and development of cancer, and its specific role depends on the type of tumor and its developmental stage. ...
Esophageal carcinoma (ESCA) is one of the most common malignancies in the world, and has high morbidity and mortality rates. Necrosis and long noncoding RNAs (lncRNAs) are involved in the progression of ESCA; however, the specific mechanism has not been clarified. The aim of the present study was to investigate the role of necrosis-related lncRNAs (nrlncRNAs) in patients with ESCA by bioinformatics analysis, and to establish a nrlncRNA model to predict ESCA immune infiltration and prognosis. To form synthetic matrices, ESCA transcriptome data and related information were obtained from The Cancer Genome Atlas. A nrlncRNA model was established by coexpression, univariate Cox (Uni-Cox), and least absolute shrinkage and selection operator analyses. The predictive ability of this model was evaluated by Kaplan-Meier, receiver operating characteristic (ROC) curve, Uni-Cox, multivariate Cox regression, nomogram and calibration curve analyses. A model containing eight nrlncRNAs was generated. The areas under the ROC curves for 1-, 3- and 5-year overall survival were 0.746, 0.671 and 0.812, respectively. A high-risk score according to this model could be used as an indicator for systemic therapy use, since the half-maximum inhibitory concentration values varied significantly between the high-risk and low-risk groups. Based on the expression of eight prognosis-related nrlncRNAs, the patients with ESCA were regrouped using the 'ConsensusClusterPlus' package to explore potential molecular subgroups responding to immunotherapy. The patients with ESCA were divided into three clusters based on the eight nrlncRNAs that constituted the risk model: The most low-risk group patients were classified into cluster 1, and the high-risk group patients were mainly concentrated in clusters 2 and 3. Survival analysis showed that Cluster 1 had a better survival than the other groups (P=0.016). This classification system could contribute to precision treatment. Furthermore, two nrlncRNAs (LINC02811 and LINC00299) were assessed in the esophageal epithelial cell line HET-1A, and in the human esophageal cancer cell lines KYSE150 and TE1. There were significant differences in the expression levels of these lncRNAs between tumor and normal cells. In conclusion, the present study suggested that nrlncRNA models may predict the prognosis of patients with ESCA, and provide guidance for immunotherapy and chemotherapy decision making. Furthermore, the present study provided strategies to promote the development of individualized and precise treatment for patients with ESCA.
... The reduced expression of RIPK3 and resistance to necroptosis resulting from epigenetic and genetic changes may benefit the survival of cancer cells. 2-Hydroxyglutarate (2-HG), a product of mutant isocitrate dehydrogenase 1 (IDH1), binds to DNA methyltransferase 1 (DNMT1) and induces the hypermethylation of the RIPK3 promoter, thereby rendering tumor cells more resistant to necroptosis [141]. The reversal of such resistance is potentially vital for the treatment of tumors with IDH1 mutations. ...
Necroptosis refers to a regulated form of cell death induced by a variety of stimuli. Although it has been implicated in the pathogenesis of many diseases, there is evidence to support that necroptosis is not purely a detrimental process. We propose that necroptosis is a "double-edged sword" in terms of physiology and pathology. On the one hand, necroptosis can trigger an uncontrolled inflammatory cascade response, resulting in severe tissue injury, disease chronicity, and even tumor progression. On the other hand, necroptosis functions as a host defense mechanism, exerting antipathogenic and antitumor effects through its powerful pro-inflammatory properties. Moreover, necroptosis plays an important role during both development and regeneration. Misestimation of the multifaceted features of necroptosis may influence the development of therapeutic approaches targeting necroptosis. In this review, we summarize current knowledge of the pathways involved in necroptosis as well as five important steps that determine its occurrence. The dual role of necroptosis in a variety of physiological and pathological conditions is also highlighted. Future studies and the development of therapeutic strategies targeting necroptosis should fully consider the complicated properties of this type of regulated cell death.
... In addition to inhibiting the DNA hypermethylation of IDH1/2 mutant cells by mediated TET2 activity, D-2HG can also regulate DNA methylation through DNA methyltransferase 1 (DNMT1). D-2HG binds to DNMT1 and promotes its separation from the receptor-interacting protein 3 (RIP3) promoter, induces hypermethylation, inhibits RIP3 protein, thereby inhibits RIP3dependent cell necrosis, and promotes tumorigenesis 75 . The D-2HG produced by IDH1 mutant cells promotes the binding of DNMT1 to the Fibulin-5 promoter, leading to methylation, and ultimately enhancing the migration and proliferation of non-small cell lung cancer cells 76 (Fig. 6). ...
Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.
... Tumorigenesis could be driven by IDH1 mutation at position 132 (R132) resulting in high levels of 2-HG production, which regulates DNMT1 activity by promoting its binding to specific DNA regions including the TSS of the RIPK3 promoter. This phenomenon investigated in human brain cancers implies resistance to necroptosis and may support the survival of cancer cells, eventually leading to tumor formation [87]. ...
How do organisms regulate the correct balance between the production of "new" cells and the elimination of the "old" ones, remains an important biology issue under investigation. Cell(s) death represents a fundamental process involved in organism development and cell homeostasis, whose alteration is considered one hallmark of cancer and lead to drug resistance and consequently treatment failure. The recent re-classification of cell death has identified new molecular programs in which several proteins have a pivotal role. Several studies have highlighted a direct link between epigenetic modifications and cell death mechanisms. Different epi-modifications have been described, capable of regulating diverse key players implicated in cell death, leading to uncontrolled proliferation of cancer cells. Scientific efforts are focused on the understanding the epigenetic regulation of cell death mechanisms by developing tools and/or new epi-molecules able to overcome cell death resistance. The development of new epi-molecular tools can overcome cell death deregulation thus potentially improving the sensitivity to the anti-tumor therapies. This chapter focuses on the main epigenetic deregulations in cell death mechanisms in cancer.
... Necroptosis is a type of programmed necrotic cell death that can recognize pathogens and promote tissue repair (6). Some studies have found that NRGs have a role in a variety of tumorrelated activities, however they appear to be a double-edged sword (7,8).MLKL,RIPK1 and RIPK3 are the key mediators among them (9). RIPK1 and RIPK3 activation can alter associated signaling pathways to modulate the TME and perform a beneficial effect in anticancer progression (10)(11)(12). ...
... Necroptosis is a kind of ACD that is involved in tumor development and suppression and may be a novel therapeutic target for GBM patients (24). According to previous studies, IDH-wild-type GBM cells are more likely to undergo necroptosis, and the degree of necroptosis is often associated with the prognosis of GBM (7). However, there is a lack of necroptosis-associated characteristics associated with tumor prognosis. ...
Introduction
Necroptosis-related genes are essential for the advancement of IDH-wild-type GBM. However, the putative effects of necroptosis-related lncRNAs (nrlncRNAs) in IDH-wild-type GBM remain unknown.
Methods
By using the TCGA and GTEx databases, a nrlncRNA prognostic signature was created using LASSO Cox regression. The median risk score was used to categorize the patients into low and high-risk groups. To confirm the validity, univariate, multivariate Cox regression and ROC curves were used. Furthermore, by enrichment analysis, immune correlation analysis, and drug sensitivity analysis, the targeted lncRNAs were selected for further verification. As the highest upregulated expression in tumor than peritumor specimens, RP11-131L12.4 was selected for phenotype and functional experiments in primary GBM cells.
Results
Six lncRNAs were proved to be closely related to necroptosis in IDH-1-wild-type GBM, which were used to create a new signature. For 1-, 2-, and 3-year OS, the AUCs were 0.709, 0.645 and 0.694, respectively. Patients in the low-risk group had a better prognosis, stronger immune function activity, and more immune cell infiltration. In contrast, enrichment analysis revealed that the malignant phenotype was more prevalent in the high-risk group. In vitro experiments indicated that RP11-131L12.4 increased the tumor proliferation, migration and invasion, but decreased the necroptosis. Moreover, this nrlncRNA was also proved to be negatively associated with patient prognosis.
Conclusion
The signature of nrlncRNAs may aid in the formulation of tailored and precise treatment for individuals with IDH-wild-type GBM. RP11-131L12.4 may play indispensable role in necroptosis suppression.
