YAP promotes tumirogenesis via activation of EGFR

The Hippo-YAP pathway has emerged as a major driver of tumorigenesis in many human cancers. YAP is a transcriptional co-activator and while details of YAP regulation are quickly emerging, it remains unknown what downstream targets are critical for YAP's oncogenic functions. To determine the mechanisms involved and identify disease-relevant targets, we examined YAP's role in neurofibromatosis type 2 (NF2) using cell and animal models. We found that YAP function is required for NF2-null Schwann cell survival, proliferation and tumor growth in vivo. Moreover, YAP promotes transcription of several targets including PTGS2, which codes for COX-2, a key enzyme in prostaglandin biosynthesis, and AREG, which codes for the EGFR ligand, amphiregulin. Both AREG and prostaglandin E2 converge to activate signaling through EGFR. Importantly, treatment with the COX-2 inhibitor Celecoxib significantly inhibited the growth of NF2-null Schwann cells and tumor growth in a mouse model of NF2.

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