Identification and validation of SERPINE1 as a prognostic and immunological biomarker in pan-cancer and in ccRCC

Abstract

Background:SERPINE1, a serine protease inhibitor involved in the regulation of the plasminogen activation system, was recently identified as a cancer-related gene. However, its clinical significance and potential mechanisms in pan-cancer remain obscure.Methods: In pan-cancer multi-omics data from public datasets, including The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), and online web tools were used to analyze the expression of SERPINE1 in different cancers and its correlation with prognosis, genetic alteration, DNA promoter methylation, biological processes, immunoregulator expression levels, immune cell infiltration into tumor, tumor mutation burden (TMB), microsatellite instability (MSI), immunotherapy response and drug sensitivity. Further, two single-cell databases, Tumor Immune Single-cell Hub 2 (TISCH2) and CancerSEA, were used to explore the expression and potential roles of SERPINE1 at a single-cell level. The aberrant expression of SERPINE1 was further verified in clear cell renal cell carcinoma (ccRCC) through qRT-PCR of clinical patient samples, validation in independent cohorts using The Gene Expression Omnibus (GEO) database, and proteomic validation using the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database.Results: The expression of SERPINE1 was dysregulated in cancers and enriched in endothelial cells and fibroblasts. Copy number amplification and low DNA promoter methylation could be partly responsible for high SERPINE1 expression. High SERPINE1 expression was associated with poor prognosis in 21 cancers. The results of gene set enrichment analysis (GSEA) indicated SERPINE1 involvement in the immune response and tumor malignancy. SERPINE1 expression was also associated with the expression of several immunoregulators and immune cell infiltration and could play an immunosuppression role. Besides, SERPINE1 was found to be related with TMB, MSI, immunotherapy response and sensitivity to several drugs in cancers. Finally, the high expression of SERPINE1 in ccRCC was verified using qRT-PCR performed on patient samples, six independent GEO cohorts, and proteomic data from the CPTAC database.Conclusion: The findings of the present study revealed that SERPINE1 exhibits aberrant expression in various types of cancers and is associated with cancer immunity and tumor malignancy, providing novel insights for individualized cancer treatment.

Expression of Serpin Family E Member 1 (SERPINE1) Is Associated with Poor Prognosis of Gastric Adenocarcinoma

“…Significantly, from the SERPINE1-related GSEA, it can be seen that TNFA_SIGNALING _VIA_NFKB and INFLAMMATORY_RESPONSE is significantly related to SERPINE1, which implies that SERPINE1 is related to immune signaling pathway. In addition, some published articles have reported significant correlation between SERPINE1 and immunity factor in pan-cancer [42]. cGAS-cGAMP-STING, the three musketeers of cytosolic DNA sensing and signaling [43], initialize the immune process.…”

SERPINE1: Role in Cholangiocarcinoma Progression and a Therapeutic Target in the Desmoplastic Microenvironment

“…In intrahepatic CCA, the TGF-β-specific gene signature includes inflammatory mediators and the potent profibrotic genes SERPINE1 (which encodes plasminogen activator inhibitor-1; PAI-1) and CCN2 [64]. PAI-1 is particularly relevant as this serine protease inhibitor is expressed by tumor cells and endothelial elements in the TME but also, in particular, by the CAF population [49,[65][66][67][68] (Figures 1 and 2). The mechanisms whereby PAI-1 contributes to the progression of malignancy may vary per tumor type and TME complexity.…”