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.
Highlights
Lung cancer is currently a leading cause of death in both men and women worldwide, and the combined lung cancer-related death rate exceeds that of the three most common incident cancers combined
To identify hub smoking-related genes (SRGs) that might contribute to lung cancer development, we evaluated the expression of these 83 SRGs in lung cancers, using data from the Cancer Genome Atlas (TCGA)
We identified 27 hub SRGs that were significantly correlated with lung cancer development through our integrated analysis of the 83 SRGs and the differentially expressed genes identified from TCGA (Figure 2F)
Summary
Lung cancer is currently a leading cause of death in both men and women worldwide, and the combined lung cancer-related death rate exceeds that of the three most common incident cancers (colon, breast and pancreatic) combined. The status of lung cancer as one of the most common causes of cancer death persists, despite an understanding of the major etiology. Epidemiological studies have identified cigarette smoking as the most important risk factor for lung cancer, and 80% and 50% of lung cancers in male and female patients, respectively, are associated with cigarette smoking. The vast majority of lung cancers occur in people aged >50 years with a history of cigarette smoking [5], whereas only 10–15% of cases involve non-smokers [6]. Lung cancer is the leading cause of cancer-related mortality worldwide. 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
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