MicroRNAs are frequently dysregulated in human
neoplasms, including
gastrointestinal cancers. Nevertheless, the global influence of
microRNA dysregulation on cellular signaling is still unknown. Here we sought to elucidate cellular signaling dysregulation by
microRNAs in
gastrointestinal cancers at the systems biology level followed by experimental validation. Signature dysregulated
microRNAs in gastric, colorectal and
liver cancers were defined based on our previous studies. Targets of signature dysregulated
miRNAs were predicted using multiple computer algorithms followed by gene enrichment analysis to identify biological processes perturbed by dysregulated
microRNAs. Effects of
microRNAs on endocytosis were measured by
epidermal growth factor (
EGF) internalization assay. Our analysis revealed that, aside from well-established
cancer-related signaling pathways, several novel pathways, including axon guidance,
neurotrophin/
nerve growth factor signaling, and endocytosis, were found to be involved in the pathogenesis of
gastrointestinal cancers. The regulation of
EGF receptor (EGFR) endocytosis by two predicted
miRNAs, namely miR-17 and miR-145, was confirmed experimentally. Functionally, miR-145, which blocked EGFR endocytosis, prolonged EGFR membrane signaling and altered responsiveness of
colon cancer cells to EGFR-targeting drugs. In conclusion, our analysis depicts a comprehensive picture of cellular signaling dysregulation, including endocytosis, by
microRNAs in
gastrointestinal cancers.