The Hippo signaling pathway controls organ size and tumorigenesis
through a kinase cascade that inactivates Yes-associated
protein (YAP). Here, we show that YAP plays a central role in
controlling the progression of cervical cancer. Our results suggest
that YAP expression is associated with a poor prognosis for cervical
cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo
signaling pathway and activate YAP to induce cervical cancer cell
proliferation and migration. Activated YAP allows for up-regulation
of TGF-α, AREG, and EGFR, forming a positive signaling loop to
drive cervical cancer cell proliferation. HPV E6 protein, a major
etiological molecule of cervical cancer, maintains high YAP protein
levels in cervical cancer cells by preventing proteasome-dependent
YAP degradation to drive cervical cancer cell proliferation. Results
from human cervical cancer genomic databases and an accepted
transgenic mouse model strongly support the clinical relevance of
the discovered feed-forward signaling loop. Our study indicates
that combined targeting of the Hippo and the ERBB signaling pathways
represents a novel therapeutic strategy for prevention and
treatment of cervical cancer
