Abstract
Non-small-cell lung cancer (NSCLC) is the predominant type of lung cancer in the world. Lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC) are subtypes of NSCLC. We usually regard them as different disease due to their unique molecular characteristics, distinct cells of origin and dissimilar clinical response. However, the differences of genetic and epigenetic progression mechanism between LADC and LSCC are complicated to analyze. Therefore, we applied systems biology approaches and big databases mining to construct genetic and epigenetic networks (GENs) with next-generation sequencing data of LADC and LSCC. In order to obtain the real GENs, system identification and system order detection are conducted on gene regulatory networks (GRNs) and protein-protein interaction networks (PPINs) for each stage of LADC and LSCC. The core GENs were extracted via principal network projection (PNP). Based on the ranking of projection values, we got the core pathways in respect of KEGG pathway. Compared with the core pathways, we found significant differences between microenvironments, dysregulations of miRNAs, epigenetic modifications on certain signaling transduction proteins and target genes in each stage of LADC and LSCC. Finally, we proposed six genetic and epigenetic multiple-molecule drugs to target essential biomarkers in each progression stage of LADC and LSCC, respectively.
Highlights
Lung cancer is the most common malignancy resulting in the largest number of cancer-related deaths worldwide [1, 2]
Based on the principal network projection (PNP) method, we considered the projection value (i.e., DL(k) and DR(t) at equation (38) in the Supplementary Materials) and extracted the core genetic and epigenetic networks (GENs) shown in Supplementary Figures 3, 4 from the real GENs for each stage of Lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC), respectively
Our results show that the dysregulation of tensin 1 (TNS1), IGF-1R and ITGB1 signaling pathways, which are affected by the altered microenvironment, may be involved in the progression from early stage to middle stage LSCC, and the dysfunctions of miRNA regulation, DNA methylation, and epigenetic modification can cause early stage LSCC to progress to middle stage LSCC
Summary
Lung cancer is the most common malignancy resulting in the largest number of cancer-related deaths worldwide [1, 2]. Lung cancers are classified by histological types which have something to do with important implications for the clinical management and prognosis of the disease. There are two main histological groups of lung cancer which are non-small-cell lung cancer (NSCLC) and small-cell lung cancer. NSCLCs are subdivided broadly into three major histological subtypes: lung adenocarcinoma (LADC), lung squamous cell carcinoma (LSCC), called epidermoid carcinoma, and lung large-cell carcinoma (LLCC). Both LADC and LSCC are the predominant form of lung cancer accounting for the 40% and 33% majority of cancer deaths worldwide, respectively [5, 6]
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