Landscape of Alternative Splicing Events Related to Prognosis and Immune Infiltration in Glioma: A Data Analysis and Basic Verification

Abstract

Background. Glioma is a prevalent primary brain cancer with high invasiveness and typical local diffuse infiltration. Alternative splicing (AS), as a pervasive transcriptional regulatory mechanism, amplifies the coding capacity of the genome and promotes the progression of malignancies. This study was aimed at identifying AS events and novel biomarkers associated with survival for glioma. Methods. RNA splicing patterns were collected from The Cancer Genome Atlas SpliceSeq database, followed by calculating the percentage of splicing index. Expression profiles and related clinical information of glioma were integrated based on the UCSC Xena database. The AS events in glioma were further analyzed, and glioma prognosis-related splicing factors were identified with the use of bioinformatics analysis and laboratory techniques. Further immune infiltration analysis was performed. Results. Altogether, 9028 AS events were discovered. Upon univariate Cox analysis, 425 AS events were found to be related to the survival of patients with glioma, and 42 AS events were further screened to construct the final prognostic model ( area under the curve = 0.974 ). Additionally, decreased expression of the splicing factors including Neuro-Oncological Ventral Antigen 1 (NOVA1), heterogeneous nuclear ribonucleoprotein C (HNRNPC), heterogeneous nuclear ribonucleoprotein L-like protein (HNRNPLL), and RNA-Binding Motif Protein 4 (RBM4) contributed to the poor survival in glioma. The immune infiltration analysis demonstrated that AS events were related to the proportion of immune cells infiltrating in glioma. Conclusions. It is of great value for comprehensive consideration of AS events, splicing networks, and related molecular subtype clusters in revealing the underlying mechanism and immune microenvironment remodeling for glioma, which provides clues for the further verification of related therapeutic targets.

HNRNPLL is a Prognostic Biomarker Associated with Hepatocellular Carcinoma Immune Infiltration and Related to Migration of Hepatocellular Carcinoma Cells

“…As a member of the hnRNPS family, studies on HNRNPLL have focused on the role of alternative splicing. HNRNPLL has been shown to be involved in immune in ltration related to alternative splicing in gliomas (32), and it has been shown to regulate stem cell renewal and replacement through alternative splicing (33). Other studies have suggested that HNRNPLL regulates the secretion of immunoglobulins in plasma cells by binding to proteins (34), and HNRNPLL has been demonstrated to regulate hepatic glucose metabolism through the lncLGR long non-coding RNA (35).…”

Targeting alternative splicing in cancer immunotherapy

“…Mis-splicing can remodel the immune microenvironment in tumors. Studies have shown that AS-derived neoantigens can participate in immune reprogramming and directly influence the formation of the tumor microenvironment (TME) ( Zhang Y. et al, 2021 ), suggesting that patients who harbor different splicing substrates may respond differently to the same immunotherapy ( Zhang Y. et al, 2021 ; Su et al, 2022 ). Another study has validated this hypothesis in lung adenocarcinoma.…”