Overexpression of Yes-associated protein confers doxorubicin resistance in hepatocellullar carcinoma
Overexpression of Yes-associated protein confers doxorubicin resistance in hepatocellullar carcinoma
复制标题
Yes相关蛋白的过度表达导致肝细胞癌对阿霉素产生耐药性
DOI：
10.3892/or.2012.2176
复制
发表时间：
2013-02-01
期刊：
影响因子：
4.2
通讯作者：
Chen, Jinfei
中科院分区：
文献类型：
--
作者：
Huo, Xinying;Zhang, Qi;Chen, Jinfei
肝细胞癌（HCC）是世界范围内最具侵袭性的恶性肿瘤之一，对化疗具有高度耐药性。是相关蛋白（雅普）是Hippo信号通路的下游效应子，其在许多类型的癌症中经常过表达。肝细胞癌中雅普基因的扩增和雅普的过表达与肝细胞恶性转化和肿瘤进展有关。本研究旨在探讨雅普在肝癌化疗耐药中的潜在作用。过表达雅普导致对阿霉素诱导的肝癌细胞凋亡的抵抗，而通过RNA干扰抑制内源性雅普表达则表现出相反的效果。Western印迹显示，暴露于阿霉素后，与载体对照相比，YAP过表达细胞表现出切割的PARP减少，Akt和ERK 1/2磷酸化增加，Bcl-xL表达升高。抑制雅普表达可使HCC细胞对阿霉素敏感，表现为PARP裂解增加，磷酸化Akt、磷酸化ERK 1/2和Bcl-xL表达水平降低。此外，预处理与MEK 1/2抑制剂U 0126，而不是PI 3-K抑制剂LY 294002显着增强阿霉素诱导的细胞凋亡，并降低Bcl-xL的表达在YAP过表达的肝癌细胞。我们的数据提供的证据表明，过表达的雅普发挥了重要作用，赋予阿霉素耐药HCC，这是至少部分介导的YAP诱导的激活MAP激酶途径。靶向雅普可能是克服HCC多柔比星耐药的一种有前景的辅助治疗。
Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies worldwide and is highly resistant to chemotherapy. Yes-associated protein (YAP) is the downstream effector of the Hippo signaling pathway, which is frequently overexpressed in many types of cancers. Amplification of the YAP gene and overexpression of YAP in HCC have previously been reported to contribute to hepatocyte malignant transformation and tumor progression. In this study, we aimed to investigate the potential role of YAP in HCC chemoresistance. Overexpression of YAP resulted in resistance against doxorubicin-induced apoptosis in HCC cell lines, whereas suppression of the endogenous YAP expression by RNA interference demonstrated the reverse effect. Western blotting revealed that, following exposure to doxorubicin, YAP-overexpressing cells exhibited decreased cleaved PARP, increased phosphorylation of Akt and ERK1/2, and elevated Bcl-xL expression in comparison to the vector control. Inhibition of YAP expression sensitized HCC cells to doxorubicin, by exhibiting increased cleaved PARP, decreased levels of phosphorylated Akt, phosphorylated ERK1/2 and Bcl-xL expression. In addition, pretreatment with the MEK1/2 inhibitor U0126 but not the PI3-K inhibitor LY294002 significantly enhanced doxorubicin-induced apoptosis and decreased Bcl-xL expression in YAP-overexpressing HCC cells. Our data provide evidence that overexpression of YAP plays an important role in conferring doxorubicin resistance to HCC, which is at least partially mediated by YAP-induced activation of the MAP kinase pathway. Targeting YAP may be a promising adjunct for overcoming doxorubicin resistance in HCC.