The dynamic alteration of transcriptional regulation by crucial TFs during tumorigenesis of gastric cancer

Background: The mechanisms of Gastric cancer (GC) initiation and progression are complicated, at least partly owing to the dynamic changes of gene regulation during carcinogenesis. Thus, investigations on the changes in regulatory networks can improve the understanding of cancer development and provide novel insights into the molecular mechanisms of cancer.

Methods: Differential co-expression analysis (DCEA), differential gene regulation network (GRN) modeling and differential regulation analysis (DRA) were integrated to detect differential transcriptional regulation events between gastric normal mucosa and cancer samples based on GSE54129 dataset. Cytological experiments and IHC staining assays were used to validate the dynamic changes of CREB1 regulated targets in different stages.

Results: A total of 1955 differentially regulated genes (DRGs) were identified and prioritized in a quantitative way. Among the top 1% DRGs, 14 out of 19 genes have been reported to be GC relevant. The four transcription factors (TFs) among the top 1% DRGs, including CREB1, BPTF, GATA6 and CEBPA, were regarded as crucial TFs relevant to GC progression. The differentially regulated links (DRLs) around the four crucial TFs were then prioritized to generate testable hypotheses on the differential regulation mechanisms of gastric carcinogenesis. To validate the dynamic alterations of gene regulation patterns of crucial TFs during GC progression, we took CREB1 as an example to screen its differentially regulated targets by using cytological and IHC staining assays. Eventually, TCEAL2 and MBNL1 were proved to be differentially regulated by CREB1 during tumorigenesis of gastric cancer.

Conclusions: By combining differential networking information and molecular cell experiments verification, testable hypotheses on the regulation mechanisms of GC around the core TFs and their top ranked DRLs were generated. Since TCEAL2 and MBNL1 have been reported to be potential therapeutic targets in SCLC and breast cancer respectively, their translation values in GC are worthy of further investigation.