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2015 ; 21
(11
): 2580-90
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The Hippo Coactivator YAP1 Mediates EGFR Overexpression and Confers
Chemoresistance in Esophageal Cancer
#MMPMID25739674
Song S
; Honjo S
; Jin J
; Chang SS
; Scott AW
; Chen Q
; Kalhor N
; Correa AM
; Hofstetter WL
; Albarracin CT
; Wu TT
; Johnson RL
; Hung MC
; Ajani JA
Clin Cancer Res
2015[Jun]; 21
(11
): 2580-90
PMID25739674
show ga
PURPOSE: Esophageal cancer is an aggressive malignancy and often resistant to
therapy. Overexpression of EGFR has been associated with poor prognosis of
patients with esophageal cancer. However, clinical trials using EGFR inhibitors
have not provided benefit for patients with esophageal cancer. Failure of EGFR
inhibition may be due to crosstalk with other oncogenic pathways. EXPERIMENTAL
DESIGN: In this study, expression of YAP1 and EGFR were examined in EAC-resistant
tumor tissues versus sensitive tissues by IHC. Western blot analysis,
immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis,
and in vitro and in vivo functional assays were performed to elucidate the
YAP1-mediated EGFR expression and transcription and the relationship with
chemoresistance in esophageal cancer. RESULTS: We demonstrate that Hippo pathway
coactivator YAP1 can induce EGFR expression and transcription in multiple cell
systems. Both YAP1 and EGFR are overexpressed in resistant esophageal cancer
tissues compared with sensitive esophageal cancer tissues. Furthermore, we found
that YAP1 increases EGFR expression at the level of transcription requiring an
intact TEAD-binding site in the EGFR promoter. Most importantly, exogenous
induction of YAP1 induces resistance to 5-fluorouracil and docetaxcel, whereas
knockdown of YAP1 sensitizes esophageal cancer cells to these cytotoxics.
Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression
and sensitizes cells to cytotoxics. CONCLUSIONS: Our data provide evidence that
YAP1 upregulation of EGFR plays an important role in conferring therapy
resistance in esophageal cancer cells. Targeting YAP1-EGFR axis may be more
efficacious than targeting EGFR alone in esophageal cancer.
|Adaptor Proteins, Signal Transducing/*biosynthesis/genetics
[MESH]