Identification of the prognostic and immunological roles of aquaporin 4: A potential target for survival and immunotherapy in glioma patients

Abstract

Recent studies have revealed the critical role of AQP4 in the occurrence and development of gliomas. However, the role of AQP4 in immune regulation has not yet been reported. Many recent reports have identified the lymphatic system’s occurrence within the central nervous system (CNS) and the vital role of immune regulation in treating brain tumors. Therefore, the present study aimed to explore the role of AQP4 in the immune regulation of glioma. We used bioinformatics analysis to investigate the immunoregulatory function of AQP4, including its correlation with immunity, anti-tumor immune processes, immunotherapy, immune infiltration, tumor mutational burden (TMB), stemness, mutation, and pan-cancer. The results revealed that AQP4 was significantly associated with the expression of multiple immune checkpoints, immune cells, as well as multiple immune cell effector genes, and antigen presentation and processing abilities. Although no significant correlation was found between the AQP4 gene and IDH mutation and MGMT, AQP4 demonstrated substantial expression differences in different immunophenotypes and molecular types. Using the TTD database, we discovered that EGFR, ABAT, and PDGFRA are strongly associated with AQP4 expression in the glioblastoma (GBM) classification, and these factors could be the potential AQP4-related immunotherapy targets. Afterward, we screened the differential genes in the high and low AQP4 gene expression group, the high and low immune score group, and the high and low matrix score group and took the intersection as the candidate factor. Finally, univariate Cox analysis was used to find eight prognostic variables with significant differences across the candidate genes. After lasso dimensionality reduction, three genes built the model (RARRES1, SOCS3, and TTYH1). The scoring model generated by the three genes was eventually obtained after the multi-factor screening of the three genes. Finally, combined with clinical information and cox regression analysis, it was further confirmed that the model score could be used as an independent prognostic factor.

AQP4-independent TRPV4 modulation of plasma membrane water permeability

“…Reduced AQPs expression has been reported under pathological conditions ( Markou et al, 2022 ), including brain edema after stroke or trauma ( Papadopoulos et al, 2002 ; Clément et al, 2020 ; Dadgostar et al, 2022 ), neurological diseases ( Yang et al, 2011 ; Alvestad et al, 2013 ; Li et al, 2022 ), cancer progression and metastasis ( Lan et al, 2022 ), and inflammation. Of note, AQP1 and AQP4 are reported to be downregulated in the choroid plexus and the ependyma, respectively, of spontaneously hypertensive rat, as a putative compensatory mechanism to reduce the cerebrospinal fluid (CSF) production and volume ( Carnero Contentti and Correale, 2021 ; González-Marrero et al, 2022 ).…”

Deciphering Glioblastoma: Fundamental and Novel Insights into the Biology and Therapeutic Strategies of Gliomas

“…Additionally, a separate study identified a strong association between AQP4 expression and the expressions of epidermal growth factor receptor (EGFR), 4-aminobutyrate aminotransferase (ABAT), and platelet-derived growth factor receptor alpha (PDGFRA) in the classification of GBM. These factors have been proposed as potential targets for AQP4-related immunotherapy strategies [ 164 ]. Tan et al documented a negative correlation between the apparent diffusion coefficient and the expression of Aquaporin 4 (AQP4) mRNA in AS [ 165 ].…”

Peritumoral Edema in Gliomas: A Review of Mechanisms and Management

“…Moreover, it has been shown to improve cerebral edema in animal studies [101,102]. While these findings are encouraging, more comprehensive studies evaluating their effect on peritumoral edema are urgently needed to establish their potential as therapeutic agents for peritumoral edema [103].…”