YAP/TAZ initiates gastric tumorigenesis via upregulation of MYC

YAP and TAZ play oncogenic roles in various organs, but the role of YAP/TAZ in gastric cancer remains unclear. Here we show that YAP/TAZ activation initiates gastric tumorigenesis in vivo and verify its significance in human gastric cancer. In mice, YAP/TAZ activation in the pyloric stem cell led to step-wise tumorigenesis. RNA sequencing identified MYC as a decisive target of YAP, which controls MYC at transcriptional and post-transcriptional levels. These mechanisms tightly regulated MYC in homeostatic conditions, but YAP activation altered this balance by impeding miRNA processing, causing a shift towards MYC upregulation. Pharmacological inhibition of MYC suppressed YAP-dependent phenotypes in vitro and in vivo, verifying its functional role as a key mediator. Human gastric cancer samples also displayed a significant correlation between YAP and MYC. We re-analyzed human transcriptome data to verify enrichment of YAP signatures in a subpopulation of gastric cancers and found that our model closely reflected the molecular pattern of patients with high YAP activity. Overall, these results provide genetic evidence of YAP/TAZ as oncogenic initiators and drivers for gastric tumors with MYC as the key downstream mediator. These findings are also evident in human gastric cancer, emphasizing the significance of YAP/TAZ signaling in gastric carcinogenesis.

https://ift.tt/2qHwnXu