Gene modules and non-coding RNAs involved in pancreatic tumorigenesis through acinar ductal metaplasia
Abstract Background: Acinar ductal metaplasia (ADM) is a recently identified precursor lesion that can progress through pancreatic ductal intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC). However, the genetic alterations and the transcriptional regulators at work during the process of ADM-driven PDAC tumorigenesis are largely unknown. We applied a multidimensional integration strategy to unveil the gene modules and non-coding RNAs that drive the ADM-PanIN-PDAC process. Methods: GSE40895 and the microarray datasets were integrated to unmask the regulators linked to ADM, PanIN and PDAC. Based on the differentially expressed genes and protein–protein interaction (PPI) networks for each stage, overlapping and crosstalk gene modules in ADM-PanIN-PDAC were identified using the search tool for the retrieval of interacting genes (STRING) and Cytoscape. The functions of these modules were elucidated by gene ontology (GO) analysis. The expression levels of hub genes and survival analysis were investigated in human PDAC via gene expression profiling interactive analysis (GEPIA). The MiRDB database was used to predict potential non-coding RNAs (ncRNAs) capable of regulating overlap and crosstalk genes.Results: We found several bridging ADM gene modules (e.g. SMARCA1 and H2AFZ), PanIN gene modules (e.g. HDAC11 and SMARCA2) and PDAC gene modules (e.g. OLFR239 and CLIP3). They were enriched in nucleosome assembly, chromatin organization and G-protein coupled receptor signalling pathways by GO analysis. MicroRNAs (e.g. mmu-miR-335-5p and mmu-miR-669n) and lncRNAs (e.g. H19 and Gm14207) took part in this ample crosstalk by regulating the gene expression. Conclusions: SMARCA1, SMARCA2 and CLIP3 were identified as novel crosstalk genes and potential prognostic biomarkers for ADM-driven PDAC carcinogenesis. After validation in clinical and functional studies, transcriptional regulatory non-coding RNAs targeting crosstalk and overlapping genes could represent effective targets for early PDAC intervention.