Autophagy-Dependent Ferroptosis-Related Signature is Closely Associated with the Prognosis and Tumor Immune Escape of Patients with Glioma

Abstract

Background:Ferroptosis is an autophagy-dependent form of cell death, sometimes called "ferritinophagy". Its related pathway has been proven to regulate the programmed death of glioma stem cells. Mining autophagy-dependent ferroptosis-related gene (AD-FRG) signature could facilitate the discovery of mechanisms and therapeutic targets showing drug resistance to chemotherapeutic drugs. Methods: We exhaustively searched HADB, MSigDB and FerrDb datasets and obtained 25 genes confirmed to exist in autophagy and ferroptosis death pathways. Glioma gene expression and clinicopathological data were collected from TCGA and CGGA datasets. Results: Lasso regression and Cox regression analysis were carried out to construct a nine AD-FRGs signature (SIRT1, MTDH, HSPB1, CISD2, HMOX1, ATG7, MTOR, PRKAA2 and EIF2AK4). ROC curve showed that nine genes signature could effectively predict 1-(AUC = 0.869), 3-(AUC = 0.922) and 5-year (AUC = 0.870) survival rates. Immunohistochemical images confirmed the protein expression level of the gene model. The prognostic nomogram of risk score, age, WHO grade, isocitrate dehydrogenase (IDH) wild-type condition, 1p/19q co-deletion state was built. The calibration curve demonstrated that the prediction of the nomogram is highly consistent with the actual results. Moreover, tumor microenvironment analysis showed that the high-risk group was associated with high immune infiltration status and high tumor purity. Correlation analysis showed that the expression of SIRT1, CISD2 and HSPB1 might be related to macrophage infiltration and immunotolerance in glioma tissues. Conclusion: Based on autophagy-dependent ferroptosis-related genes, we established gene signature and nomogram that maybe effectively predict the overall survival rate of glioma and correlate with the immunosuppressive tumor microenvironment (TME).

A Novel Prognostic Signature Based on Glioma Essential Ferroptosis-Related Genes Predicts Clinical Outcomes and Indicates Treatment in Glioma

“…In terms of somatic mutation, we found that the frequency of the IDH1 mutation was greater in the low-risk group, in contrast to the higher mutation rates seen in both PTEN and EGFR in the high-risk group (Figures 6A, B), suggesting that the mutation frequencies in those genes may have different effects on ferroptosis. Previous studies have shown that IDH-mut glioma patients had a better prognosis than those with wild-type IDH, across all WHO grades (11,40), that EGFR amplification was correlated with poor prognosis (59), and that PTEN mutations could promote the infiltration of immunosuppressive tumor-associated 8A-C). Indeed, the high degree of DNA damage and poor repair capacity seen in glioma cells is a trademark feature of cancer and is a determining factor in the growth of tumor cell populations.…”

“…Gene signatures have been constructed from the investigation of 60-80 candidate genes (9,38,39) identified by previous publications. When Zhou and Sun downloaded 173 and 303 FRGs, respectively, from the ferrDB database (40,41), the overall number of candidate genes was relatively small. The numbers and functional classification of FRGs in the ferrDB are constantly updated as new information becomes available, and new analyses of ferroptosis signatures for glioma have become more necessary.…”

Numb Promotes Autophagy through p53 Pathway in Acute Kidney Injury Induced by Cisplatin

“…Beclin-1-mediated autophagy is reported positively related to better prognosis in uveal melanoma [ 36 ], while ATG7 involved in autophagy correlated with increased survival in malignant pleural mesothelioma [ 37 ]. Autophagy accompanied with immune escape is also related to many human diseases including cancers, such as glioma [ 38 ] and lung adenocarcinoma [ 39 ]. Moreover, the side effects of chemotherapy drugs for cancers always induced organ damage including AKI.…”

Ferroptosis in Glioma Immune Microenvironment: Opportunity and Challenge

“…Sun et al. confirmed that autophagy-dependent ferroptosis-related signature is closely associated with the prognosis and tumor immune escape of patients with glioma ( 72 ). Therefore, we recognize autophagy should be one of the hubs between ferroptosis and immunity in glioma.…”