Abstract
Epigenetic and microRNA (miRNA) regulation are associated with carcinogenesis and the development of cancer. By using the available omics data, including those from next-generation sequencing, genome-wide methylation profiling, candidate-integrated genetic and epigenetic network (IGEN) analysis, and drug response genome-wide microarray analysis, we constructed an IGEN system based on three coupling regression models that characterize protein-protein interaction networks gene regulatory networks miRNA regulatory networks and epigenetic regulatory networks By applying system identification method and principal genome-wide network projection to IGEN analysis, we identified the core network biomarkers to investigate bladder carcinogenic mechanisms and design multiple drug combinations for treating bladder cancer with minimal side effects. The progression of DNA repair and cell proliferation in stage 1 bladder cancer ultimately results not only in the repression of miR-200a and miR-200b but also in the regulation of the TNF pathway in metastasizing-related genes or proteins, cell proliferation, and DNA repair in stage 4 bladder cancer. We designed a multiple drug combination comprising gefitinib, estradiol, yohimbine, and fulvestrant for treating stage 1 bladder cancer with minimal side effects, and another multiple drug combination comprising gefitinib, estradiol, chlorpromazine, and LY294002 for treating stage 4 bladder cancer with minimal side effects.