Significance of Tumor Mutation Burden related immune gene PAEP in the progression and prognosis of clear cell renal cell carcinoma

Abstract

Background Clear cell renal cell carcinoma (ccRCC) is a common renal malignant disease with a poor prognosis. Tumor mutation load (TMB) has received much attention in various tumor studies, however, there were limited studies focus on the relationship between TMB and ccRCC. We aimed to investigate the role of TMB-related immune gene progestagen‑associated endometrial protein (PEAP) in ccRCC and the underlying molecular mechanisms. Methods Somatic mutation data of 336 patients with ccRCC were downloaded from the Cancer Genome Atlas (TCGA) database, and the mutational spectrum was analyzed using the "maftools" software package. Based on TCGA -ccRCC cohort, we summarized the status of gene mutations in ccRCC. The TMB was calculated and the samples were divided into high and low TMB groups. Then, we analyzed the relationship between TMB and clinical characteristic. Meanwhile, we identified some TMB-related immune genes through the intersection of TMB-Related differentially expressed genes (DEGs) and immune related genes. Finally, We selected the immune genes most associated with TMB, investigated its expression in renal tissues of ccRCC patients, and further investigated its role and potential molecular mechanisms In-vivo and in-vitro. Results Using bioinformatics we analyzed the most common mutation of Variant Classification, Variant Type, single nucleotide variants (SNV) Class for missense mutations, single nucleotide polymorphism (SNP) and C > T in ccRCC, respectively. we found that higher TMB related to shorter overall survival (OS), lower age and grade. Finally, we identified progesterone associated endometrial protein (PAEP) gene, a novel TMB-related immune gene in ccRCC, which was significantly overexpression in ccRCC tissues and cells with progression and poor survival in ccRCC patients. Furthermore, by constructing 786-O cell model, our results showed that PAEP promoted the invasion, migration, and proliferation of ccRCC cells; meanwhile, PAEP knockdown suppressed the PI3K/Akt/NF-κB signaling pathway. In-vivo studies, we found that after knocking out the PEAP gene, the subcutaneous transplanted tumors in nude mice were smaller and lighter. Mechanistically, we consider that PAEP may regulate the malignant biological phenotype and poor survival prognosis of ccRCC through the PI3K/Akt/NF-κB signaling pathway. Conclusion Our study suggests that PAEP might represents a potential target of antibody immunotherapy for ccRCC patients and also provides a strong theoretical basis for the clinical application of PAEP.