LPCAT3 regulates the immune infiltration and prognosis of ccRCC patients by mediating ferroptosis and endoplasmic reticulum stress.

backgroundClear cell renal cell carcinoma (ccRCC) accounts for 70% of renal cell carcinoma (RCC) cases. Although surgery remains the mainstay treatment, renal injury and high metastasis rates after nephrectomy dramatically reduce patient quality of life. Drugs that stimulate the immune system by targeting checkpoint pathways improve overall survival in patients with RCC. Here, we investigated the applicability of lysophosphatidylcholine acyltransferase 3 (LPCAT3) as a target for immunotherapy.

methodsIn the present study, high LPCAT3 expression in ccRCC was identified using The Cancer Genome Atlas (TCGA) data and validated in two external cohorts from the Gene Expression Omnibus (GEO) database. qRT-PCR was performed to identify the mRNA level of LPCAT3 in tumors and adjacent normal tissues. And immunohistochemistry was used to evaluate the protein level of LPCAT3 between two groups of samples. Furthermore, gene set enrichment analysis was performed to explore the biological processes and pathways related to LPCAT3 expression. Key gene expression and correlation analyses were performed to determine the crosstalk among LPCAT3 expression, ferroptosis, and endoplasmic reticulum stress (ERS). Subsequently, CIBERSORT was used to analyze the immune infiltration status of patients with high and low LPCAT3 expression.

resultsTCGA and GEO data revealed that LPCAT3 expression in ccRCC tumor tissues was higher than that in adjacent normal tissues; moreover, patients with high LPCAT3 expression had better survival outcomes. qRT-PCR and immunohistochemistry verified the high LPCAT3 expression in tumor tissue. Pathways related to ferroptosis and ERS were upregulated in patients with high LPCAT3 expression. Univariate and multivariate regression analyses revealed that low LPCAT3 levels represent an independent risk factor for ccRCC. LPCAT3 expression was positively correlated with M2 macrophage infiltration levels but negatively correlated with the memory B cell, CD8+ T cell, follicular helper T cell, regulatory T cell, activated natural killer cell, and activated memory CD4+ T cell infiltration levels.

conclusionsLPCAT3was identified as a ccRCC biomarker and may regulate immune infiltration and prognosis in ccRCC by mediating ferroptosis and ERS. Thus, it has potential for exploitation as a prognostic and immune therapeutic target for patients with ccRCC.