ALDH18A1 regulates glutamine metabolism and tumor microenvironment in the attenuation of clear cell renal cell carcinoma

OBJECTIVES: To assess the potential role of glutamine metabolism-related genes (GMRGs) in the progression, prognosis, and immune microenvironment of clear cell renal cell carcinoma (ccRCC). METHODS: Publicly available single-cell RNA sequencing dataset was obtained, and differential gene expression analysis across tumors were performed. A cross scale disease driver gene validation chain and spatial transcriptome analysis with glutamine metabolism was further analyzed. 17 gene sets (M10295) correlated with glutamine metabolism were derived. The prognostic model of ccRCC constructed according to the differentially expressed GMRGs (DEGMRGs). GO and KEGG data were applied and the "GSVA" R package was used to analyze the characteristics of immune cells infiltration. In vitro validation study was performed in various RCC cell lines. Two shRNA plasmids were independently transfected into cells and examined by Transwell migration assay, proliferation assays and colony information tests. Glutamine levels and its related metabolism genes were also detected. RESULTS: ALDH18A1 may serve as a tumor-specific glutamine metabolic marker in epithelial-derived malignancies, and spatial transcriptome analysis reveals enhanced glutamine metabolic activity in the tumor boundary region. The DEGMRGs-based prognostic model tailored for ccRCC delineated a stark contrast in the prognosis of high-risk group and low-risk group. Patients exhibiting high ALDH18A1 TPM demonstrating poorer prognosis compared to those with low levels. The in vitro study validated the high expression of ALDH18A1 in RCC cell lines. ALDH18A1 could significantly inhibit the proliferation and migration of RCC cells, suppress the glutamine metabolism in RCC cells. Additionally, subcutaneous tumor experiments in mice further confirmed the oncogenic-promoting effects of ALDH18A1 on RCC with the crosstalk of M2 macrophages. CONCLUSIONS: ALDH18A1 could serve as a crucial role in precise classification, treatment response, and prognosis of patients with ccRCC by suppressing the proliferation and glutamine metabolisms in tumor cells and constructing tumor microenvironment.