GPX8 regulates pan-apoptosis in gliomas to promote microglial migration and mediate immunotherapy responses

IntroductionGliomas have emerged as the predominant brain tumor type in recent decades, yet the exploration of non-apoptotic cell death regulated by the pan-optosome complex, known as pan-apoptosis, remains largely unexplored in this context. This study aims to illuminate the molecular properties of pan-apoptosis-related genes in glioma patients, classifying them and developing a signature using machine learning techniques.MethodsThe prognostic significance, mutation features, immunological characteristics, and pharmaceutical prediction performance of this signature were comprehensively investigated. Furthermore, GPX8, a gene of interest, was extensively examined for its prognostic value, immunological characteristics, medication prediction performance, and immunotherapy prediction potential. ResultsExperimental techniques such as CCK-8, Transwell, and EdU investigations revealed that GPX8 acts as a tumor accelerator in gliomas. At the single-cell RNA sequencing level, GPX8 appeared to facilitate cell contact between tumor cells and macrophages, potentially enhancing microglial migration. ConclusionsThe incorporation of pan-apoptosis-related features shows promising potential for clinical applications in predicting tumor progression and advancing immunotherapeutic strategies. However, further in vitro and in vivo investigations are necessary to validate the tumorigenic and immunogenic processes associated with GPX8 in gliomas

CircRNA ARFGEF1 functions as a ceRNA to promote oncogenic KSHV-encoded viral interferon regulatory factor induction of cell invasion and angiogenesis by upregulating glutaredoxin 3.

Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs that can decoy other RNAs to inhibit their functions. Kaposi's sarcoma (KS), caused by oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angiogenic and invasive vascular tumor of endothelial origin commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) induces cell invasion, angiogenesis and cellular transformation; however, the role of circRNAs is largely unknown in the context of KSHV vIRF1. Herein, transcriptome analysis identified 22 differentially expressed cellular circRNAs regulated by vIRF1 in an endothelial cell line. Among them, circARFGEF1 was the highest upregulated circRNA. Mechanistically, vIRF1 induced circARFGEF1 transcription by binding to transcription factor lymphoid enhancer binding factor 1 (Lef1). Importantly, upregulation of circARFGEF1 was required for vIRF1-induced cell motility, proliferation and in vivo angiogenesis. circARFGEF1 functioned as a competing endogenous RNAs (ceRNAs) by binding to and inducing degradation of miR-125a-3p. Mass spectrometry analysis demonstrated that glutaredoxin 3 (GLRX3) was a direct target of miR-125a-3p. Knockdown of GLRX3 impaired cell motility, proliferation and angiogenesis induced by vIRF1. Taken together, vIRF1 transcriptionally activates circARFGEF1, potentially by binding to Lef1, to promote cell oncogenic phenotypes via inhibiting miR-125a-3p and inducing GLRX3. These findings define a novel mechanism responsible for vIRF1-induced oncogenesis and establish the scientific basis for targeting these molecules for treating KSHV-associated cancers