Monday, July 28, 2025
Increasing evidence indicates that the dysregulation of ATP6V0A4 is linked to aggressive behaviors in various types of cancer, including oral squamous cell carcinoma (OSCC). This study integrated data from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database to identify key molecular mechanisms. Using univariate Cox regression and LASSO regression, a prognostic model was constructed, complemented by random forest algorithms to identify core genes. A multi-omics analysis strategy was employed, including pan-cancer expression profiling, protein atlas validation, GO/KEGG enrichment, and clinicopathological feature correlation analysis, as well as tumor immune microenvironment assessment and immunotherapy response prediction models. Experimental validation involved RT-qPCR to measure ATP6V0A4 expression in OSCC cell lines and plasmid transfection to establish overexpression models. The study found that low ATP6V0A4 expression is significantly associated with poor prognosis in OSCC patients, with the expression level showing a close correlation with clinical T staging. Additionally, the expression status of ATP6V0A4 is linked to the distribution and function of various immune cells in the tumor microenvironment. In vitro experiments demonstrated that overexpression of ATP6V0A4 suppresses tumor cell proliferation, migration, and invasion. OSCC patients with low ATP6V0A4 expression exhibit higher sensitivity to drugs like GDC0810, GSK591, and MK8776. This discovery provides new insights and potential therapeutic strategies for combination therapy in OSCC. Oral squamous cell carcinoma (OSCC) remains one of the most aggressive malignancies with a 5-year survival rate of 55–60% [1], significantly lower than other cancers like breast (89%) and colorectal (65%). With an aging population, its burden is projected to exceed 500,000 cases by 2035. Current protocols include surgical resection, radiotherapy, and chemotherapy, but postoperative complications are severe. Targeted immunotherapies against EGFR and PD-1/PD-L1 pathways have shown preliminary efficacy, but only 15–20% of patients benefit. Therefore, identifying specific molecular markers and mechanisms is needed for precision medicine in OSCC. V-ATPase is a multisubunit complex with a cytosolic catalytic domain (V1) and a transmembrane proton channel domain (V0). The V0 domain contains four a-subunit isoforms that regulate enzyme localization in different cellular membranes. ATP6V0A4, encoding the a4 isoform, exhibits tissue-specific expression, mainly in the kidney and epididymis. It mediates the polarized localization of V-ATPase in plasma membrane of renal α-intercalated cells, contributing to H⁺ secretion in renal tubules [7]. Recent studies show ATP6V0A4 not only acidifies acidic organelles like lysosomes and endosomes but also plays roles in vital processes such as transport, protein processing, and cotransport, as well as physiological functions like urinary acidification and bone metabolism regulation [9]. Emerging evidence highlights dual functions of ATP6V0A4 in tumor progression. In breast cancer models, high ATP6V0A4 expression was observed in invasive MDA-MB-231 cells, while siRNA-mediated gene silencing suppressed their invasive capacity [7]. Treatment with specific V-ATPase inhibitors also inhibited invasive phenotype in these cells [10]. Mechanistic studies in metastatic hepatocellular carcinoma showed that downregulation of ATP6V0A4 suppressed proton pump activity and extracellular acidification rate, leading to dual suppression of tumor growth and metastasis [11]. Notably, ATP6V0A4 expression in renal cell carcinoma suggests heterogeneous regulatory patterns across tumor types. These discrepancies may be due to factors like pH homeostasis in the tumor microenvironment, activation of invasion signaling pathways, and reprogramming of cellular energy metabolism. However, the mechanism and role of ATP6V0A4 in OSCC remain poorly understood. This study aims to clarify the role of ATP6V0A4 in OSCC and its underlying mechanisms to provide novel therapeutic targets for this disease. The corresponding clinicopathological characteristics and prognostic information of OSCC patients, including gender, age, and stage, were downloaded from the TCGA GDC database. Samples with primary sites "lip", "hard palate", "gingiva", "base of tongue", "floor of mouth", "other and ill-defined sites in lip, oral cavity and pharynx", "other and ill-defined sites of tongue", and "other and unspecified sites in oral cavity" were selected for analysis. Among them, 32 normal and 397 cancer samples were used. OSCC sequencing data were downloaded from GSE25099, a GPL5175 platform with 79 samples. The R package "limma" was used for DEG analysis. The study found that low ATP6V0A4 expression is significantly associated with poor prognosis, with the expression level showing a close correlation with clinical T staging. The expression status of ATP6V0A4 is linked to the function and distribution of various immune cells in the tumor microenvironment. In vitro experiments indicated that overexpression of ATP6V0A4 suppresses tumor cell proliferation, migration, and invasion. Patients with low ATP6V0A4 expression have higher sensitivity to drugs like GDC0810, GSK591, and MK8776. This discovery provides novel insights and potential therapeutic strategies for combination therapy in OSCC. Oral squamous cell carcinoma (OSCC) remains one of the most aggressive malignancies with a 5-year survival rate of 55–60% [1], significantly lower than other cancers like breast (89%) and colorectal (65%). With an aging population, its burden is projected to exceed 500,000 cases by 2035. Current standard treatment protocols include surgical resection, radiotherapy, and chemotherapy, but postoperative complications are severe. Targeted immunotherapies against EGFR and PD-1/PD-L1 pathways have shown preliminary efficacy, but only 15–20% of patients benefit. Therefore, identifying specific molecular markers and mechanisms is needed for precision medicine in OSCC.
Reference: ATP6V0A4 as a novel prognostic biomarker and potential therapeutic target in oral squamous cell carcinomaLabels: BMC Oral Health
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