Identification of hub pathways and drug candidates in gastric cancer through systems biology

Abstract

Gastric cancer is the fourth cause of cancer death globally, and gastric adenocarcinoma is its most common type. Efforts for the treatment of gastric cancer have increased its median survival rate by only seven months. Due to the relatively low response of gastric cancer to surgery and adjuvant therapy, as well as the complex role of risk factors in its incidences, such as protein-pomp inhibitors (PPIs) and viral and bacterial infections, we aimed to study the pathological pathways involved in gastric cancer development and investigate possible medications by systems biology and bioinformatics tools. In this study, the protein–protein interaction network was analyzed based on microarray data, and possible effective compounds were discovered. Non-coding RNA versus coding RNA interaction network and gene-disease network were also reconstructed to better understand the underlying mechanisms. It was found that compounds such as amiloride, imatinib, omeprazole, troglitazone, pantoprazole, and fostamatinib might be effective in gastric cancer treatment. In a gene-disease network, it was indicated that diseases such as liver carcinoma, breast carcinoma, liver fibrosis, prostate cancer, ovarian carcinoma, and lung cancer were correlated with gastric adenocarcinoma through specific genes, including hgf, mt2a, mmp2, fbn1, col1a1, and col1a2. It was shown that signaling pathways such as cell cycle, cell division, and extracellular matrix organization were overexpressed, while digestion and ion transport pathways were underexpressed. Based on a multilevel systems biology analysis, hub genes in gastric adenocarcinoma showed participation in the pathways such as focal adhesion, platelet activation, gastric acid secretion, HPV infection, and cell cycle. PPIs are hypothesized to have a therapeutic effect on patients with gastric cancer. Fostamatinib seems a potential therapeutic drug in gastric cancer due to its inhibitory effect on two survival genes. However, these findings should be confirmed through experimental investigations.

Transforming RNA-Seq gene expression to track cancer progression in the multi-stage early to advanced-stage cancer development

“…The turquoise module was the largest module comprising 139 genes and also identified pathways that were related to other cancers such as breast cancer, gastric cancer, and retinoblastoma. Gastric adenocarcinoma has been reported to be correlated to the investigated cancers including liver carcinoma and lung cancer through specific genes [ 42 ]. It was noted that some genes were shared between the detected cancer pathways, this included the AURKA gene, which was involved in the gastric and breast cancer pathways.…”

A systems biology approach to pathogenesis of gastric cancer: gene network modeling and pathway analysis

“…In their study, overexpression of signaling pathways, including extracellular matrix organization, cell division, and cell cycle, as well as downregulation of ion transport and digestion pathways were also indicated. They also reported that their identified hub genes in gastric adenocarcinoma participated in platelet activation, focal adhesion, gastric acid secretion, cell cycle and HPV infection pathways [ 66 ]. In 2018, Saberi Anvar et al used a systems biology approach for GC biomarkers and found that cell cycle, neutropin signaling pathway and nucleotide excision are the most enriched signals.…”

Genetic variations in relation to bleeding and pharmacodynamics of dabigatran in Chinese patients with nonvalvular atrial fibrillation: A nationwide multicentre prospective cohort study

“…45 FBN1 gene involvement in the pathways of platelet activation was discovered in a recent work focused on a multilayer systems biology investigation of gastric cancer. 46 Besides, activated fibrinolysis, thrombin and platelet dysfunction are less well known but are indeed important features of Marfan syndrome. 47 The above information may provide us preliminary insight into exploring the effect of FBN2 gene on bleeding of drugs.…”

“…It might mediate cell adhesion by interacting with the cell surface receptors integrins ITGAV:ITGB3 and ITGA5:ITGB1, 43,44 and subsequently bind heparin, resulting in assembly of microfibrils 45 . FBN1 gene involvement in the pathways of platelet activation was discovered in a recent work focused on a multilayer systems biology investigation of gastric cancer 46 . Besides, activated fibrinolysis, thrombin and platelet dysfunction are less well known but are indeed important features of Marfan syndrome 47 .…”