In this study, we found that the general expression pattern of cell aging-related genes is correlated with the malignancy features of gliomas and identified cell aging-related genes that significantly participate in many processes involved in the gradual loss of cellular functions and cell death, which is associated with glioma prognosis. We further built a 14-gene risk signature that not only precisely predicted the unfavorable prognosis of gliomas more effectively than the WHO grade but also perfectly reflected malignancy-correlated clinicopathological features, such as IDH mutation status and WHO grade. Moreover, we systemically analyzed the function of genes that correlated with the signature risk score in gliomas and identified the corresponding functions, biological processes, key signaling pathways, and hallmarks, which might partially explain the malignancy of gliomas and the poor survival of patients in the high-risk group. Our results highlight the role of cell aging-related genes in the survival of patients with further stratified gliomas, and the 14-gene signature has the potential to be a more effective for determining the prognosis of gliomas with further stratification according to the WHO 2016 integrated diagnostic criteria. Furthermore, we also revealed the biological functions of the genes that were associated with risk signature.
The current mainstream view is that cell aging likely promotes glioma occurrence and development because glioma is more common in the elderly, and the median age at diagnosis is ≥ 60 years. At this age, the number of senescent cells is greatly increased in the brain. Moreover, cell aging in gliomas is likely result in posttreatment recurrence. There are two theories as to why cell aging may be the driving factor of residual disease. (A) The combination of temozolomide (TMZ) and radiation therapy, which is usually performed after surgery, induces cell aging in the microenvironment surrounding the tumor. Researchers have observed the presence of aging cells in glioma samples, especially in the tumor microenvironment, where residual glioma cells are also located. Ionizing radiation can cause brain aging in mice, which is believed to cause abnormal function 19, and TMZ causes senescence in astrocytes in vitro 20. Therefore, DNA-damaging antitumor therapies have been shown to induce senescence in healthy cells. (B) Aging brain cells produce and secrete a large number of factors, from extracellular matrix (ECM) components to remodeling factors, some of which can promote tumor survival and invasion. For example, astrocytes from aging primate brains synthesize excess hyaluronic acid, supporting single-cell invasion and NF-κB activation 21; aging astrocytes also produce excessive levels of fibronectin, which may promote cell survival and collective invasion 22; and aging astrocytes express both MMP-2 and MMP-9, which are necessary factors glioma invasion of multiple brain regions 23. It is well known that aging astrocytes and endothelial cells also secrete a large number of cytokines and chemokines. Among them, IL6 and IL8 can activate NF-κB and STAT3 signals in glioma cells to maintain their stemness and promote their invasiveness 22. It has been found that conditioned medium from aging astrocytes in vitro can promote the proliferation of glioma cell lines by increasing c-Myc; more importantly, this conditioned medium can improve the survival of TMZ-treated glioma cells 24. Additionally, although residual glioma cells are very different from the original tumor, they secrete factors that are part of the aging-associated secretory phenotype (SASP), which maintains residual gliomas through therapy and drives drug resistance and recurrence 25. Altogether, these results indicate that cellular senescence is likely to cause gliomas and residual tumors.
We identified a 14-gene risk signature related to cell aging in gliomas. The fourteen genes included in our signature were PRMT6, PML, CDK1, FOXM1, SERPINE1, ID2, TERT, TP63, WNT16, NPM1, PTEN, PDCD4, SIRT1 and TERF2. Among them, nine genes included in our signature were associated with high risk, and patients with high expression of these genes had a poor prognosis. The remaining four genes were associated with low risk. As shown below, nine genes have similar functions and are involved in cell mitosis, proliferation, metastasis and progression of glioma. Some studies found that PRMT6 methylation of the RCC1 signaling axis regulates mitosis, tumorigenicity, and the radiation response of glioblastoma stem cells 26. Furthermore, the PML/Slit axis controls physiological cell migration and cancer invasion in gliomas 27. Studies have suggested that blockade of CDK1 induces synthetic lethality in malignant gliomas 28; moreover, FoxM1 promotes β-catenin nuclear localization and controls Wnt target gene expression and glioma tumorigenesis 29; ID2 promotes the survival of glioblastoma cells during metabolic stress by regulating mitochondrial function 30. A multicenter study revealed that methylation of the TERT promoter in childhood gliomas could be used for risk stratification 31 and NPM1 histone chaperone expression is upregulated in glioblastoma to promote cell survival and maintain nucleolar shape 32. On the other hand, another four genes have functions involved in glioma suppression. Loss of tumor suppressor PTEN function increases immune resistance in gliomas 33. Researchers found that downregulation of Pdcd4 facilitates glioblastoma proliferation in vivo 34, the SIRT1 activator SRT2183 suppresses glioma cell growth 35, and molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells 36.
In summary, our study highlighted the prognostic value of cell aging-related genes in gliomas and revealed a risk signature with 14 cell aging-related genes to further stratify the outcomes of patient with gliomas with definitive WHO subgroups. Clinical characteristics, pathological features, biological processes, significant signaling pathways and hallmarks of gliomas correlated with the risk signature were also identified. These results provide fundamental information for understanding the roles of cellular senescence in gliomas and indicate the potential clinical implications of cell aging-related genes in gliomas.