Hippo transducer TAZ promotes epithelial mesenchymal transition and supports pancreatic cancer progression.
Hippo transducer TAZ promotes epithelial mesenchymal transition and supports pancreatic cancer progression.
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Hippo 传感器 TAZ 促进上皮间质转化并支持胰腺癌进展
DOI：
10.18632/oncotarget.5772
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发表时间：
2015-11-03
期刊：
影响因子：
--
通讯作者：
Quan M
中科院分区：
文献类型：
--
作者：
Xie D;Cui J;Xia T;Jia Z;Wang L;Wei W;Zhu A;Gao Y;Xie K;Quan M
具有PDZ结合基序的转录共激活子（TAZ）是Hippo通路的一个换能器，促进癌症的发生和进展。在本研究中，我们试图确定TAZ的表达和激活在胰腺癌发生和进展中的作用和潜在机制。通过细胞培养、分子生物学和小鼠模型研究了TAZ和Hippo信号在促进胰腺癌发生和进展中的机制作用。我们的实验和机制发现的相关性通过人类胰腺肿瘤标本得到验证。我们发现TAZ在胰腺肿瘤中的表达明显高于正常胰腺组织。进一步分析TAZ表达与组织微阵列临床病理参数的相关性，发现其表达与肿瘤分化呈正相关。TAZ在胰腺癌细胞系中的表达高于胰腺导管上皮细胞。TAZ在胰腺癌细胞中的激活促进了癌细胞的增殖、迁移、侵袭和上皮-间质转化。进一步的机制研究表明，TAZ在胰腺癌细胞中的异常表达和激活是由于Hippo通路上游的正调节因子Merlin的表达受到抑制，TAZ在胰腺癌细胞中的致癌功能是由TEA/ATTS结构域转录因子介导的。因此，TAZ作为一种致癌基因，促进胰腺癌上皮-间质转化和进展。因此，TAZ可能是胰腺癌有效治疗策略的靶点。
Transcriptional co-activator with PDZ binding motif (TAZ) is a transducer of the Hippo pathway and promotes cancer development and progression. In the present study, we sought to determine the roles and underlying mechanisms of elevated expression and activation of TAZ in pancreatic cancer development and progression. The mechanistic role of TAZ and Hippo signaling in promotion of pancreatic cancer development and progression was examined using cell culture, molecular biology, and mouse models. The relevance of our experimental and mechanistic findings was validated using human pancreatic tumor specimens. We found that TAZ expression was markedly higher in pancreatic tumors than in normal pancreatic tissue. Further analysis of the correlation of TAZ expression with tissue microarray clinicopathologic parameters revealed that this expression was positively associated with tumor differentiation. Also, TAZ expression was higher in pancreatic cancer cell lines than in pancreatic ductal epithelial cells. TAZ activation in pancreatic cancer cells promoted their proliferation, migration, invasion, and epithelial-mesenchymal transition. Further mechanistic studies demonstrated that aberrant expression and activation of TAZ in pancreatic cancer cells resulted from suppression of the expression of Merlin, a positive regulator upstream of the Hippo pathway, and that the oncogenic function of TAZ in pancreatic cancer cells was mediated by TEA/ATTS domain transcription factors. Therefore, TAZ functioned as an oncogene and promoted pancreatic cancer epithelial-mesenchymal transition and progression. TAZ thus may be a target for effective therapeutic strategies for pancreatic cancer.