Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma

Sun, Chao; Xiao, Liming; Zhao, Yuliang; Shi, Jiankuan; Yuan, Yuan; Gu, Yu; Zhang, Feng; Gao, Xing; Yang, Ying; Yang, Risheng; Qin, Junhui; Zhang, Jin; Wang, Chao; Wang, Yingmei; Wang, Zhe; Hu, Peizhen; Chang, Ting; Wang, Liang; Wang, Gang; Chen, Huangtao; Li, Zhuyi; Ye, Jing

doi:10.1016/j.tranon.2020.100758

Cited by 18 publications

(17 citation statements)

References 42 publications

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“…Additionally, a low serum lymphocyte count is an independent risk factor for HGG. Numerous studies have also demonstrated that IDH mutations play an important role in diagnosing, evaluating medication effectiveness, predicting survival, and reducing the invasiveness of biomarkers associated with glioma, and are widely deemed the most significant genetic alteration ( 13 – 16 ). Then, we further performed a correlation analysis between serum lymphocyte count and IDH1 mutation or 1p19q codeletion.…”

Section: Discussionmentioning

confidence: 99%

“…The isocitrate dehydrogenase (IDH) gene encodes an enzyme that is involved in the control of cellular metabolism, epigenetic regulation, redox states, and DNA repair ( 12 ). The IDH mutation is critical for diagnosis, treatment efficacy evaluation, survival prediction, and reduced invasiveness of biomarkers associated with glioma, and is widely deemed the most significant genetic alteration ( 13 , 14 ). It is associated with better outcomes in IDH1-mutant patients than in IDH1 wild-type patients ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

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Based on clinical Ki-67 expression and serum infiltrating lymphocytes related nomogram for predicting the diagnosis of glioma-grading

Zhang

et al. 2022

Front. Oncol.

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BackgroundCompelling evidence indicates that elevated peripheral serum lymphocytes are associated with a favorable prognosis in various cancers. However, the association between serum lymphocytes and glioma is contradictory. In this study, a nomogram was established to predict the diagnosis of glioma-grading through Ki-67 expression and serum lymphocytes.MethodsWe performed a retrospective analysis of 239 patients diagnosed with LGG and 178 patients with HGG. Immunohistochemistry was used to determine the Ki-67 expression. Following multivariate logistic regression analysis, a nomogram was established and used to identify the most related factors associated with HGG. The consistency index (C-index), decision curve analysis (DCA), and a calibration curve were used to validate the model.ResultsThe number of LGG patients with more IDH1/2 mutations and 1p19q co-deletion was greater than that of HGG patients. The multivariate logistic analysis identified Ki-67 expression, serum lymphocyte count, and serum albumin (ALU) as independent risk factors associated with HGG, and these factors were included in a nomogram in the training cohort. In the validation cohort, the nomogram demonstrated good calibration and high consistency (C-index = 0.794). The Spearman correlation analysis revealed a significant association between HGG and serum lymphocyte count (r = −0.238, P <0.001), ALU (r = −0.232, P <0.001), and Ki-67 expression (r = 0.457, P <0.001). Furthermore, the Ki-67 expression was negatively correlated with the serum lymphocyte count (r = −0.244, P <0.05). LGG patients had lower Ki-67 expression and higher serum lymphocytes compared with HGG patients, and a combination of these two variables was significantly higher in HGG patients.ConclusionThe constructed nomogram is capable of predicting the diagnosis of glioma-grade. A decrease in the level of serum lymphocyte count and increased Ki-67 expression in HGG patients indicate that their immunological function is diminished and the tumor is more aggressive.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Based on clinical Ki-67 expression and serum infiltrating lymphocytes related nomogram for predicting the diagnosis of glioma-grading

Zhang

et al. 2022

Front. Oncol.

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“…In addition, the genes have been associated with high levels of wild-type IDH and high malignancy. 36,37 Moreover, ROC curves suggested they are promising diagnostic biomarkers and independent prognostic predictors, and could be used as therapeutic targets for glioma. DiseaseMeth 3.0 showed that NCAPH, CDCA8, and DLGAP5 were hypomethylated, while CCNB2 was hypermethylated in glioma samples.…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes and biological pathways in glioma via integrated bioinformatics analysis

Chen

Sun

et al. 2022

J Int Med Res

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Objective Glioma is the most common intracranial primary malignancy, but its pathogenesis remains unclear. Methods We integrated four eligible glioma microarray datasets from the gene expression omnibus database using the robust rank aggregation method to identify a group of significantly differently expressed genes (DEGs) between glioma and normal samples. We used these DEGs to explore key genes closely associated with glioma survival through weighted gene co-expression network analysis. We then constructed validations of prognosis and survival analyses for the key genes via multiple databases. We also explored their potential biological functions using gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). Results We selected DLGAP5, CDCA8, NCAPH, and CCNB2, as four genes that were abnormally up-regulated in glioma samples, for verification. They showed high levels of isocitrate dehydrogenase gene mutation and tumor grades, as well as good prognostic and diagnostic value for glioma. Their methylation levels were generally lower in glioma samples. GSEA and GSVA analyses suggested the genes were closely involved with glioma proliferation. Conclusion These findings provide new insights into the pathogenesis of glioma. The hub genes have the potential to be used as diagnostic and therapeutic markers.

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“…Indeed, a recent study by Su et al highlighted that IDH1 wt (not the mutated form IDH1 R132C ) promotes cell proliferation, invasion and migration in iCCA cell lines by regulation of αKG and NADPH levels [138]. These results are not surprising because over recent years it has emerged that an aberrant expression of non-mutated IDH1 in numerous cancers (e.g., non-small cell lung carcinoma, squamous cell lung cancer, pancreatic ductal adenocarcinoma, primary glioblastoma) [139][140][141][142] correlates with therapy resistance, an aggressive phenotype and poor prognosis [141,[143][144][145]. The biological consequences of IDH1 up-regulation are ascribable to the central role of this enzyme in the regulation of both metabolic and epigenetic processes.…”

Section: Future Perspectives Of Idh1 Inhibitors Use In Intrahepatic Cmentioning

confidence: 99%

IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives

et al. 2020

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Cholangiocarcinoma is a primary malignancy of the biliary tract characterized by late and unspecific symptoms, unfavorable prognosis, and few treatment options. The advent of next-generation sequencing has revealed potential targetable or actionable molecular alterations in biliary tumors. Among several identified genetic alterations, the IDH1 mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some IDH1 point mutations induce widespread epigenetic alterations by means of a gain-of-function of the enzyme, which becomes able to produce the oncometabolite 2-hydroxyglutarate, with inhibitory activity on α-ketoglutarate-dependent enzymes, such as DNA and histone demethylases. Thus, its accumulation produces changes in the expression of several key genes involved in cell differentiation and survival. At present, small-molecule inhibitors of IDH1 mutated enzyme are under investigation in preclinical and clinical phases as promising innovative treatments for IDH1-mutated intrahepatic cholangiocarcinomas. This review examines the molecular rationale and the results of preclinical and early-phase studies on novel pharmacological agents targeting mutant IDH1 in cholangiocarcinoma patients. Contextually, it will offer a starting point for discussion on combined therapies with metabolic and epigenetic drugs, to provide molecular support to target the interplay between metabolism and epigenetics, two hallmarks of cancer onset and progression.

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Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma

Cited by 18 publications

References 42 publications

Based on clinical Ki-67 expression and serum infiltrating lymphocytes related nomogram for predicting the diagnosis of glioma-grading

Based on clinical Ki-67 expression and serum infiltrating lymphocytes related nomogram for predicting the diagnosis of glioma-grading

Identification of hub genes and biological pathways in glioma via integrated bioinformatics analysis

IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives

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