Correlation of PIK3R1 overexpression with CD73+ FOXP3+ regulatory T cell infiltration and its role in tumor progression and prognosis prediction in gastric cancer

Abstract

Abstract Background Biomarkers are crucially required to predict the prognosis of patients with gastric cancer (GC) and especially to identify those who may have intrinsic antitumor immune responses to immunotherapeutic strategies. Methods The publicly available databases, our cohort and the vitro experiments were used to identify the biological behavior mediated by PIK3R1 overexpression in GC. We evaluated the relationships between PIK3R1 expression levels and immune cell infiltration by immunohistochemistry, mRNA-seq data and single-cell sequencing data. Furthermore, both The Cancer Genome Atlas (TCGA) stomach adenocarcinoma data and cell lines were utilized to detect the function and mechanism of PIK3R1 in GC. Finally, the prognostic value of PIK3R1 was evaluated using an integrated nomogram. Results PIK3R1 expression levels were reduced in many human cancers, while they significantly increased in GC. High PIK3R1 expression levels were associated with disease progression and poor overall survival (OS). In vitro experiments, up-regulated PIK3R1 expression promoted the proliferation, invasion, and metastasis of GC cells. Further, PIK3R1 expression was closely correlated with regulatory T cell infiltration and its related biomarkers (such as FOXP3 and CD73). PIK3R1 overexpression was positively correlated with activated TGF-β/SMAD signaling in the TCGA cohort and the GC cell lines. Analysis of single-cell sequencing data demonstrated that PIK3R1 had an increasing trend during the transformation of benign cells into malignant cells and had a synchronous expression pattern with CD73 and several immunosuppressive molecules (such as FOXP3, LAG3, PDL1, GZMB, and GZMK) that play a role in T cell development. An easy-to use nomogram based on PIK3R1 and CD73 expression levels and several clinicopathological factors outperformed TNM staging at prognosis. Conclusions These findings inferred that PIK3R1 acts as a prognostic factor to predict the OS of patients with GC and implied the importance of developing novel immunotherapeutic strategies.