Identification of the Prognostic Signatures of Glioma With Different PTEN Status.
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ABSTRACT:
SUBMITTER: Zhang P
PROVIDER: S-EPMC8317988 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Ferroptosis is a newly discovered form of regulated cell death with distinct properties and recognizing functions involved in physical conditions or various diseases, including cancers. However, the relationship between gliomas and ferroptosis-related lncRNAs (FRLs) remains unclear. Methods: We collected a total of 1850 samples from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEX) databases, including 698 tumor and 1,152 normal samples. A list of ferroptosis-related genes was downloaded from the Ferrdb website. Differentially expressed FRLs (DEFRLS) were analyzed using the “limma” package in R software. Subsequently, prognosis-related FRLs were obtained by univariate Cox analysis. Finally, a prognostic model based on the 3 FRLs was constructed using Cox regression analysis with the least absolute shrinkage and selection operator (LASSO) algorithm. The prognostic power of the model was assessed using receiver operating characteristic (ROC) curve analysis and Kaplan-Meier (K-M) survival curve analysis. In addition, we further explored the relationship of the immune landscape and somatic mutations to prognostic model characteristics. Finally, we validated the function of LINC01426 in vitro. Results: We successfully constructed a 3-FRLs signature and classified glioma patients into high-risk and low-risk groups based on the risk score calculated from this signature. Compared with traditional clinicopathological features [age, sex, grade, isocitrate dehydrogenase (IDH) status], the prognostic accuracy of this model is more stable and stronger. Additionally, the model had stable predictive power for overall survival over a 5-year period. In addition, we found significant differences between the two groups in cellular immunity, the numbers of many immune cells, including NK cells, CD4+, CD8+ T-cells, and macrophages, and the expression of many immune-related genes. Finally, the two groups were also significantly different at the level of somatic mutations, especially in glioma prognosis-related genes such as IDH1 and ATRX, with lower mutation rates in the high-risk group leading to poorer prognosis. Finally, we found that the ferroptosis process of glioma cells was inhibited after knocking down the expression of LINC01426. Conclusion: The proposed 3-FRL signature is a promising biomarker for predicting prognostic features in glioma patients.
| S-EPMC9549413 | biostudies-literature
Project description:The aim of the present study was to identify the common molecular mechanisms of multiple glioma subtypes, including astrocytoma, glioblastoma and oligodendroglioma, in addition to the specific mechanisms of different types. The gene expression profile set GSE4290 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) from three types of glioma, relative to non-tumor tissue, were calculated by the t-test method with a linear regression model. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs was performed. GeneVenn online analysis software was used for the comparison of the DEGs between subtypes. A total of 795 DEGs, including 619 up and 176 downregulated DEGs were screened from the astrocytoma expression profiles; these were enriched in the KEGG pathways of 'neuroactive ligand-receptor interaction' (upregulated) and 'Wnt signaling pathway' (downregulated). Protein-protein interaction networks for astrocytoma, glioblastoma and oligodendroglioma were constructed with 1,617, 7,027 and 1,172 pairs, respectively. A total of 595 common DEGs were obtained between the three subtypes, which were enriched in pathways associated with neural signaling. Glioblastoma is a subtype of astrocytoma; there were 195 DEGs common between these subtypes that were not also associated with oligodendroglioma. DEGs unique to astrocytoma, glioblastoma and oligodendroglioma were associated with the development of the nervous system, the cell cycle and cell matrix components, respectively. The screened DEG p53 gene is likely to be critical for glioma development, including via the Wnt and p53 signaling pathways. Brain-derived neurotrophic factor and cyclin-dependent kinase 1 genes were also likely to be important in the mechanism of glioma development, and were associated with the cell cycle and p53 signaling pathways. Immune system-associated and cell matrix component pathways may be unique signaling pathways associated with astrocytoma and oligodendroglioma, respectively.
| S-EPMC5778919 | biostudies-literature
Project description:Current staging systems of cancer are mainly based on the anatomical extent of disease. They need refinement by biological parameters to improve stratification of patients for tumor therapy or surveillance strategies. Thanks to developments in genomic, transcriptomic, and big-data technologies, we are now able to explore molecular characteristics of tumors in detail and determine their clinical relevance. This has led to numerous prognostic and predictive gene expression signatures that have the potential to establish a classification of tumor subgroups by biological determinants. However, only a few gene signatures have reached the stage of clinical implementation so far. In this review article, we summarize the current status, and present and future challenges of prognostic gene signatures in three relevant cancer entities: breast cancer, colorectal cancer, and hepatocellular carcinoma.
| S-EPMC8000474 | biostudies-literature
Project description:BackgroundGliomas are the most common primary tumors of the central nervous system. The complexity and heterogeneity of the tumor makes it difficult to obtain good biomarkers for drug development. In this study, through The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA), we analyze the common diagnostic and prognostic moleculer markers in Caucasian and Asian populations, which can be used as drug targets in the future.MethodsThe RNA-seq data from Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) were analyzed to identify signatures. Based on the signatures, the prognosis index (PI) of every patient was constructed to predict the prognostic risk. Also, gene ontology (GO) functional enrichment analysis and KEGG analysis were conducted to investigate the biological functions of these mRNAs. Glioma patients' data in the CGGA database were introduced to validate the effectiveness of the signatures among Chinese populations. Excluding the previously reported prognostic markers of gliomas from this study, the expression of HSPA5 and MTPN were examined by qRT-PCR and immunohistochemical assay.ResultsIn total, 20 mRNAs were finally selected to build PI for patients from TCGA, including 16 high-risk genes and four low-risk genes. For Chinese patients, the log-rank test p values of PI were both less than 0.0001 in two independent datasets. And the AUCs were 0.831 and 0.907 for 3 years of two datasets, respectively. Moreover, among these 20 mRNAs, 10 and 15 mRNAs also had a significant predictive effect via univariate COX analysis in CGGA_693 and CGGA_325, respectively. qRT-PCR and Immunohistochemistry assay indicated that HSPA5 and MTPN over-expressed in Glioma samples compared to normal samples.ConclusionThe 20-gene signature can forecast the risk of Glioma in TCGA effectively, moreover it can also predict the risks of Chinese patients through validation in the CGGA database. HSPA5 and MTPN are possible biomarkers of gliomas suitable for all populations to improve the prognosis of these patients.
| S-EPMC8121073 | biostudies-literature
Project description:Glioblastoma (GBM) is the most common aggressive form of brain cancer with overall dismal prognosis (10-12 months) despite all current multimodal treatments. Previously we identified adipocyte enhancer binding protein 1 (AEBP1) as a differentially regulated gene in GBM. On probing the role of AEBP1 over expression in glioblastoma, we found that both cellular proliferation and survival were affected upon AEBP1 silencing in glioma cells, resulting in cell death. In the present study we report that the classical caspase pathway components are not activated in cell death induced by AEBP1 down regulation in PTEN-deficient (U87MG and U138MG) cells. PARP-1 was not cleaved but over-activated under AEBP1 down regulation which leads to the synthesis of PAR in the nucleus triggering the release of AIF from the mitochondria. Subsequently, AIF translocates to the nucleus along with MIF causing chromatinolysis. AEBP1 positively regulates PI3KinaseCβ by the binding to AE-1 binding element in the PI3KinaseCβ promoter. Loss of PI3KinaseCβ expression under AEBP1 depleted condition leads to excessive DNA damage and activation of PARP-1. Furthermore, over expression of PIK3CB (in trans) in U138MG cells prevents DNA damage in these AEBP1 depleted cells. On the contrary, AEBP1 down regulation induces caspase-dependent cell death in PTEN-proficient (LN18 and LN229) cells. Ectopic expression of wild-type PTEN in PTEN-deficient U138MG cells results in the activation of canonical caspase and Akt dependent cell death. Collectively, our findings define AEBP1 as a potential oncogenic driver in glioma, with potential implications for therapeutic intervention.
| S-EPMC6787275 | biostudies-literature
Project description:Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. In addition, this data set has also been used to identify a common prognostic gene signature in human AML (Li Z. et al., unpublished). 93 human AML samples bearing various cytogenetic and molecular abnormalities are used to identify miR-181 target genes and a common prognostic gene signature.
2012-04-03 | E-GEOD-30285 | biostudies-arrayexpress
Project description:Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. In addition, this data set has also been used to identify a common prognostic gene signature in human AML (Li Z. et al., unpublished).
2012-04-04 | GSE30285 | GEO
Project description:WHO 2/3 glioma is a common intracranial tumor that seriously affects the quality of life and survival time of patients. Previous studies have shown that the tricarboxylic acid (TCA) cycle is closely related to the occurrence and development of glioma, while recent studies have shown that cuproptosis, a novel programmed death pathway, is closely related to the inhibition of the TCA cycle. In our study, eight of ten cuproptosis-related genes (CRGs) were found to be differentially expressed between normal and WHO 2/3 glioma tissues. Through the LASSO algorithm, the cuproptosis-associated risk signatures (CARSs) were constructed, which can effectively predict the prognosis of WHO 2/3 glioma patients and are closely related to clinicopathological features. We analyzed the relationship between risk score and immune cell infiltration through Xcell, ssGSEA, TIMER database, and immune checkpoint molecules. In addition, the relationship between risk score and chemotherapeutic drug sensitivity was also investigated. The prognosis-related independent risk factors FDX1 and CDKN2A identified from CARSs are considered potential prognostic biomarkers for WHO 2/3 glioma. The clinical prognosis model based on cuproptosis is expected to provide an effective reference for the diagnosis and treatment of clinical WHO 2/3 glioma patients.
| S-EPMC9434124 | biostudies-literature
Project description:Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) has frequently been observed in human gliomas, conferring AKT activation and resistance to ionizing radiation (IR) and drug treatments. Recent reports have shown that PTEN loss or AKT activation induces premature senescence, but many details regarding this effect remain obscure. In this study, we tested whether the status of PTEN determined fate of the cell by examining PTEN-deficient U87, U251, and U373, and PTEN-proficient LN18 and LN428 glioma cells after exposure to IR. These cells exhibited different cellular responses, senescence or apoptosis, depending on the PTEN status. We further observed that PTEN-deficient U87 cells with high levels of both AKT activation and intracellular reactive oxygen species (ROS) underwent senescence, whereas PTEN-proficient LN18 cells entered apoptosis. ROS were indispensable for inducing senescence in PTEN-deficient cells, but not for apoptosis in PTEN-proficient cells. Furthermore, transfection with wild-type (wt) PTEN or AKT small interfering RNA induced a change from premature senescence to apoptosis and depletion of p53 or p21 prevented IR-induced premature senescence in U87 cells. Our data indicate that PTEN acts as a pivotal determinant of cell fate, regarding senescence and apoptosis in IR-exposed glioma cells. We conclude that premature senescence could have a compensatory role for apoptosis in the absence of the tumor suppressor PTEN through the AKT/ROS/p53/p21 signaling pathway.
| S-EPMC3131905 | biostudies-literature
Project description:The concept that solid tumors are maintained by a productive interplay between neoplastic and non-neoplastic elements has gained traction with the demonstration that stromal fibroblasts and immune system cells dictate cancer development and progression. While less studied, brain tumor (glioma) biology is likewise influenced by non-neoplastic immune system cells (macrophages and microglia) which interact with neoplastic glioma cells to create a unique physiological state (glioma ecosystem) distinct from that found in the normal tissue. To explore this neoplastic ground state, we leveraged several preclinical mouse models of neurofibromatosis type 1 (NF1) optic glioma, a low-grade astrocytoma whose formation and maintenance requires productive interactions between non-neoplastic and neoplastic cells, and employed whole tumor RNA-sequencing and mathematical deconvolution strategies to characterize this low-grade glioma ecosystem as an aggregate of cellular and acellular elements. Using this approach, we demonstrate that optic gliomas generated by altering the germline Nf1 gene mutation, the glioma cell of origin, or the presence of co-existing genetic alterations represent molecularly-distinct tumors. However, these optic glioma tumors share a 25-gene core signature, not found in normal optic nerve, that is normalized by microglia inhibition (minocycline), but not conventional (carboplatin) or molecularly-targeted (rapamycin) chemotherapy. Lastly, we identify a genetic signature conferred by Pten reduction and corrected by PI3K inhibition. This signature predicts progression-free survival in patients with either low-grade or high-grade glioma. Collectively, these findings support the concept that gliomas are composite ecological systems whose biology and response to therapy may be best defined by examining the tumor as a whole.
| S-EPMC5581044 | biostudies-literature