Virology, Nebraska Center for


Document Type


Date of this Version



EMBO Molecular Medicine Vol 7 No 11 2015


Copyright 2015 The Authors.


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.