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10.1158/1078-0432.CCR-14-2191

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suck abstract from ncbi


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pmid25739674
      Clin+Cancer+Res 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]
  • |Animals [MESH]
  • |Cell Line, Tumor [MESH]
  • |Cell Proliferation/drug effects [MESH]
  • |Drug Resistance, Neoplasm/genetics [MESH]
  • |Epithelial Cells/pathology [MESH]
  • |ErbB Receptors/antagonists & inhibitors/*biosynthesis/genetics [MESH]
  • |Esophageal Neoplasms/drug therapy/*genetics/pathology [MESH]
  • |Gene Expression Regulation, Neoplastic/drug effects [MESH]
  • |Hippo Signaling Pathway [MESH]
  • |Humans [MESH]
  • |Mice [MESH]
  • |Phosphoproteins/*biosynthesis/genetics [MESH]
  • |Porphyrins/administration & dosage [MESH]
  • |Primary Cell Culture [MESH]
  • |Prognosis [MESH]
  • |Protein Serine-Threonine Kinases/biosynthesis/genetics [MESH]
  • |Transcription Factors [MESH]
  • |Transcriptional Activation/*genetics [MESH]
  • |Verteporfin [MESH]


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