The Hippo Coactivator YAP1 Mediates EGFR Overexpression and Confers Chemoresistance in Esophageal Cancer.
The Hippo Coactivator YAP1 Mediates EGFR Overexpression and Confers Chemoresistance in Esophageal Cancer.
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DOI：
10.1158/1078-0432.ccr-14-2191
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发表时间：
2015-06-01
期刊：
影响因子：
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通讯作者：
Ajani JA
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文献类型：
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作者：
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
食管癌（EC）是一种侵袭性恶性肿瘤，通常对治疗有抵抗性。表皮生长因子受体（EGFR）的过度表达与食管癌患者的不良预后相关。然而，使用EGFR抑制剂的临床试验并未给食管癌患者带来益处。EGFR抑制失败可能是由于与其他致癌途径的串扰。
在这项研究中，通过免疫组织化学方法检测了食管腺癌耐药肿瘤组织与敏感组织中YAP1和EGFR的表达。进行了蛋白质印迹、免疫荧光、实时定量PCR、启动子分析、定点诱变以及体外和体内功能测定，以阐明YAP1介导的EGFR表达和转录以及与食管癌化疗耐药性的关系。
我们证明Hippo通路共激活因子YAP1可在多种细胞系统中诱导EGFR表达和转录。与敏感的食管癌组织相比，YAP1和EGFR在耐药的食管癌组织中均过度表达。此外，我们发现YAP1在转录水平上增加EGFR表达，这需要EGFR启动子中完整的TEAD结合位点。最重要的是，外源性诱导YAP1会诱导对5 - 氟尿嘧啶和多西他赛的耐药性，而敲低YAP1会使食管癌细胞对这些细胞毒性药物敏感。维替泊芬，一种YAP1抑制剂，可有效抑制YAP1和EGFR的表达，并使细胞对细胞毒性药物敏感。
我们的数据提供了证据，表明YAP1对EGFR的上调在赋予食管癌细胞治疗抗性方面起着重要作用。在食管癌中，靶向YAP1 - EGFR轴可能比单独靶向EGFR更有效。
Esophageal cancer (EC) is an aggressive malignancy and often resistant to therapy. Overexpression of EGFR has been associated with poor prognosis of EC patients. However, clinical trials using EGFR inhibitors have not provided benefit for EC patients. Failure of EGFR inhibition may be due to crosstalk with other oncogenic pathways. In this study, expression of YAP1 and EGFR were examined in EAC resistant tumor tissues vs sensitive tissues by immunohistochemistry. Western blot, immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis and in vitro and in vivo functional assays were performed to elucidate the YAP1 mediate EGFR expression and transcription and the relationship with chemoresistance in esophageal cancer. 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 EC tissues compared to sensitive EC tissues. Further, 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-FU and docetaxcel, while knockdown of YAP sensitizes EC cells to these cytotoxics. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics. Our data provide evidence that YAP1 up-regulation of EGFR plays an important role in conferring therapy resistance in EC cells. Targeting YAP1-EGFR axis may be more efficacious than targeting EGFR alone in EC.