Identification of SRXN1 and KRT6A as Key Genes in Smoking-Related Non-Small-Cell Lung Cancer Through Bioinformatics and Functional Analyses

Abstract

BackgroundLung cancer is the leading cause of cancer-related mortality worldwide. Although cigarette smoking is an established risk factor for lung cancer, few reliable smoking-related biomarkers for non-small-cell lung cancer (NSCLC) are available. An improved understanding of these biomarkers would further the development of new biomarker-targeted therapies and lead to improvements in overall patient survival.MethodsWe performed bioinformatic analysis to screened potential target genes, then quantitative PCR, western, siRNA, CCK-8, flow cytometry, tumorigenicity assays in nude mice were performed to validated the function.ResultsIn this study, we identified 83 smoking-related genes (SRGs) based on an integration analysis of two Gene Expression Omnibus (GEO) datasets, and 27 hub SRGs with potential carcinogenic effects by analyzing a dataset of smokers with NSCLC in The Cancer Genome Atlas (TCGA) database. A survival analysis revealed three genes with potential prognostic value, namely SRXN1, KRT6A and JAKMIP3. A univariate Cox analysis revealed significant associations of elevated SRXN1 and KRT6A expression with prognosis. A receiver operating characteristic (ROC) curve analysis indicated the high diagnostic value of SRXN1 and KRT6A for smoking and cancer. Quantitative PCR and western blotting validated the increased expression of SRXN1 and KRT6A mRNA and protein, respectively, in lung cancer cell lines and NSCLC tissues. In patients with NSCLC, SRXN1 and KRT6A expression was associated with the tumor–node–metastasis (TNM) stage, presence of metastasis, history of smoking and daily smoking consumption. Furthermore, inhibition of SRXN1 or KRT6A suppressed viability and enhanced apoptosis in the A549 human lung carcinoma cell line. Tumorigenicity assays in nude mice confirmed that the siRNA-mediated downregulation of SRXN1 and KRT6A expression inhibited tumor growth in vivo.ConclusionsIn summary, SRXN1 and KRT6A act as oncogenes in NSCLC and might be potential biomarkers of smoking exposure and the early diagnosis and prognosis of NSCLC in smokers, which is vital for lung cancer therapy.

A pilot analysis of circulating cfRNA transcripts for the detection of lung cancer

“…The SRXN1 (Sulfiredoxin 1) - another phosphodiesterase 4D anchoring protein, was found to be upregulated in lung cancer cell lines A549 and 95D and 75 NSCLC tissues compared to the adjacent non-tumor tissue. In our study both PDE4DIP and SRXN1 were downregulated in the discovery and validation cohorts[39]. More studies are needed to characterize the directionality associated with clinical characteristics of NSCLC development and progression.…”

A Four-Gene Prognostic Signature Based on the TEAD4 Differential Expression Predicts Overall Survival and Immune Microenvironment Estimation in Lung Adenocarcinoma

“…RHOV has been widely studied to promote LUAD cell growth, metastasis, and therapeutic resistance ( Chen H et al, 2021 ; Zhang et al, 2021 ). In addition, KRT6A has been shown to participate in tumor proliferation, invasion, EMT, and cancer stem cell transformation in lung cancer ( Yang et al, 2020 ; Zhou J et al, 2021 ; Che et al, 2021 ). CPS1 has been reported to be an oncogene that is upregulated and has prognostic significance in LUAD ( Wu et al, 2020 ).…”

A Pilot Analysis of Circulating cfRNA Transcripts for the Detection of Lung Cancer

“…The SRXN1 (Sulfiredoxin 1), another phosphodiesterase 4D anchoring protein, was found to be upregulated in the lung cancer cell lines A549 and 95D and 75 NSCLC tissues compared with the adjacent non-tumor tissue. In our study, both PDE4DIP and SRXN1 were downregulated in the discovery and validation cohorts [ 39 ]. More studies are needed to characterize the directionality associated with the clinical characteristics of NSCLC development and progression.…”