Integrative Analysis Identifies TCIRG1 as a Potential Prognostic and Immunotherapy-Relevant Biomarker Associated with Malignant Cell Migration in Clear Cell Renal Cell Carcinoma

SIMPLE SUMMARY: TCIRG1, also known as V-ATPase-a3, is critical for cellular metabolism, membrane transport, and intracellular signaling through its dependent acidification. In earlier research, TCIRG1 was found to be dysregulated in several cancers and to accelerate the growth of various malignancies. The molecular mechanisms behind TCIRG1 and its possible role in the development of clear cell renal cell carcinoma are still poorly understood. Our research is the first to thoroughly examine TCIRG1’s function in clear cell renal cell carcinoma prognosis, immunity, and treatment. The validity that TCIRG1 can accelerate the development of renal clear cell carcinoma was also confirmed in this work by using certain testable experiments. This establishes the theoretical framework for our future investigation into the occurrence and progression of clear cell renal cell carcinoma. ABSTRACT: Background: TCIRG1, also known as V-ATPase-a3, is critical for cellular life activities through its dependent acidification. Prior to the present research, its relationship with prognostic and tumor immunity in clear cell renal cell carcinoma (ccRCC) had not yet been investigated. Methods: We assessed TCIRG1 expression in normal and tumor tissues using data from TCGA, GEO, GTEX, and IHC. We also analyzed the relationship between TCIRG1 and somatic mutations, TMB, DNA methylation, cancer stemness, and immune infiltration. We evaluated the relevance of TCIRG1 to immunotherapy and potential drugs. Finally, we explored the effect of TCIRG1 knockdown on tumor cells. Results: TCIRG1 was overexpressed in tumor tissue and predicted a significantly unfavorable clinical outcome. High TCIRG1 expression may be associated with fewer PBRM1 and more BAP1 mutations and may reduce DNA methylation, thus leading to a poor prognosis. TCIRG1 was strongly associated with CD8+ T-cell, Treg, and CD4+ T-cell infiltration. Moreover, TCIRG1 was positively correlated with TIDE scores and many drug sensitivities. Finally, experiments showed that the knockdown of TCIRG1 inhibited the migration of ccRCC cells. Conclusions: TCIRG1 may have great potential in identifying prognostic and immunomodulatory mechanisms in tumor patients and may provide a new therapeutic strategy for ccRCC.