The Multifaceted Role of lncRNA GAS5: A Pan-Cancer Analysis of Its Diagnostic, Prognostic, and Therapeutic Potential.

introductionCancer is a significant global health problem characterized by increased incidence and large disparities in outcomes. There is a compelling need to identify novel biomarkers to enhance early detection, prognosis, and tailored therapies. Growth arrest-specific transcript 5 (GAS5) is a long noncoding RNA (lncRNA) with potential as a tumor suppressor in a subset of cancers. Its roles in the diagnosis, prognosis, and therapy across cancer types remain underexplored.

methodsIn this study, a pan-cancer comprehensive analysis of the expression status of GAS5 was conducted using various bioinformatics tools and genomic datasets, including Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN), and Gene Expression Omnibus (GEO). The expression of GAS5 in different types of cancers was determined and then evaluated for its correlation with clinicopathological parameters, immune cell infiltration, survival outcome, and the methylation status of its promoter. Additionally, the Kaplan-Meier plotter (KMP) was used for overall survival assessment, and the cBioPortal tool was applied for genetic alteration and radiation therapy response assessment. Functional analyses were performed using data from the Long Noncoding RNA Cancer Arrays (lnCAR) database, which included coexpression networks, competing endogenous RNA (ceRNA) interactions, and pathway enrichment.

resultsOur analysis, based on three large datasets, showed that GAS5 was significantly upregulated mainly in cholangiocarcinoma (CHOL), kidney renal clear cell carcinoma (KIRC), and liver hepatocellular carcinoma (LIHC) (p < 0.05). On the contrary, it was downregulated in breast invasive carcinoma (BRCA), kidney chromophobe (KICH), and uterine corpus endometrial carcinoma (UCEC). High GAS5 expression was associated with poor overall survival in LIHC and KIRC (p < 0.05). Promoter hypomethylation was identified as a key regulatory mechanism in CHOL, KIRC, and LIHC (p < 0.05). GAS5 expression exhibited positive correlations with immune cell infiltration (e.g., CD4+ T cells, CD8+ T cells, and macrophages) in LIHC and negative correlations (e.g., B cells, dendritic cells) in KIRC. Our network analysis has established GAS5 as a ceRNA that interacts with 36 miRNAs and 95 protein-coding genes, affecting pathways like metabolism, mitogen-activated protein kinase (MAPK) signaling, and cytokine-cytokine receptor interactions in LIHC (p < 0.05). The genetic alterations may have an impact on GAS5 expression levels and how it functions during radiation treatment. Furthermore, the epigenetic control of GAS5 by DNA methylation suggests possible targets for personalized treatment methods.

conclusionThis comprehensive analysis across various cancers offers a significant foundation for GAS5 as a potential diagnostic and prognostic biomarker, especially prominent in LIHC, with additional relevance in KIRC. Identification of tissue-specific regulatory mechanisms and correlations with immune cells opens new perspectives into the context-dependent functionality of GAS5. These findings highlight the potential of GAS5 for developing targeted therapies and advancing personalized medicine, paving the way for future research into GAS5-based treatment strategies in cancer.