Differential regulation analysis reveals dysfunctional regulatory mechanism involving transcription factors and microRNAs in gastric carcinogenesis

Gastric cancer (GC) is one of the most incident malignancies in the world. Although lots of featured genes and microRNAs (miRNAs) have been identified to be associated with gastric carcinogenesis, underlying regulatory mechanisms still remain unclear. In order to explore the dysfunctional mechanisms of GC, we developed a novel approach to identify carcinogenesis relevant regulatory relationships, which is characterized by quantifying the difference of regulatory relationships between stages. Firstly, we applied the strategy of differential coexpression analysis (DCEA) to transcriptomic datasets including paired mRNA and miRNA of gastric samples to identify a set of genes/miRNAs related to gastric cancer progression. Based on these genes/miRNAs, we constructed conditional combinatorial gene regulatory networks (cGRNs) involving both transcription factors (TFs) and miRNAs. Enrichment of known cancer genes/miRNAs and predicted prognostic genes/miRNAs was observed in each cGRN. Then we designed a quantitative method to measure differential regulation level of every regulatory relationship between normal and cancer, and the known cancer genes/miRNAs proved to be ranked significantly higher. Meanwhile, we defined differentially regulated link (DRL) by combining differential regulation, differential expression and the regulation contribution of the regulator to the target. By integrating survival analysis and DRL identification, three master regulators TCF7L1, TCF4, and MEIS1 were identified and testable hypotheses of dysfunctional mechanisms underlying gastric carcinogenesis related to them were generated. The fine-tuning effects of miRNAs were also observed. We propose that this differential regulation network analysis framework is feasible to gain insights into dysregulated mechanisms underlying tumorigenesis and other phenotypic changes.