Low expression of CHRDL1 and SPARCL1 predicts poor prognosis of lung adenocarcinoma based on comprehensive analysis and immunohistochemical validation

Abstract

Purpose Exploring the molecular mechanisms of lung adenocarcinoma (LUAD) is beneficial for developing new therapeutic strategies and predicting prognosis. This study was performed to select core genes related to LUAD and to analyze their prognostic value. Methods Microarray datasets from the GEO (GSE75037) and TCGA-LUAD datasets were analyzed to identify differentially coexpressed genes in LUAD using weighted gene coexpression network analysis (WGCNA) and differential gene expression analysis. Functional enrichment analysis was conducted, and a protein–protein interaction (PPI) network was established. Subsequently, hub genes were identified using the CytoHubba plug-in. Overall survival (OS) analyses of hub genes were performed. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas (THPA) databases were used to validate our findings. Gene set enrichment analysis (GSEA) of survival-related hub genes were conducted. Immunohistochemistry (IHC) was carried out to validate our findings. Results We identified 486 differentially coexpressed genes. Functional enrichment analysis suggested these genes were primarily enriched in the regulation of epithelial cell proliferation, collagen-containing extracellular matrix, transforming growth factor beta binding, and signaling pathways regulating the pluripotency of stem cells. Ten hub genes were detected using the maximal clique centrality (MCC) algorithm, and four genes were closely associated with OS. The CPTAC and THPA databases revealed that CHRDL1 and SPARCL1 were downregulated at the mRNA and protein expression levels in LUAD, whereas SPP1 was upregulated. GSEA demonstrated that DNA-dependent DNA replication and catalytic activity acting on RNA were correlated with CHRDL1 and SPARCL1 expression, respectively. The IHC results suggested that CHRDL1 and SPARCL1 were significantly downregulated in LUAD. Conclusions Our study revealed that survival-related hub genes closely correlated with the initiation and progression of LUAD. Furthermore, CHRDL1 and SPARCL1 are potential therapeutic and prognostic indicators of LUAD.