The Human Adenocarcinoma-associated Gene, AGR2, Induces Expression of Amphiregulin through Hippo Pathway Co-activator YAP1 Activation
The Human Adenocarcinoma-associated Gene, AGR2, Induces Expression of Amphiregulin through Hippo Pathway Co-activator YAP1 Activation
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DOI：
10.1074/jbc.m110.215707
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发表时间：
2011-05-20
影响因子：
4.8
通讯作者：
Lowe, Anson W.
中科院分区：
文献类型：
--
作者：
Dong, Aiwen;Gupta, Aparna;Lowe, Anson W.
前梯度同源基因2(AGR2)在正常肠道和大多数人类腺癌中表达，包括来自食道、胰腺、肺、乳腺、卵巢和前列腺的腺癌。此前在裸鼠体内移植的人腺癌细胞株证明AGR2支持肿瘤生长。此外，AGR2还能在体外诱导成纤维细胞和上皮细胞转化表型。AGR2促进生长的机制尚不清楚。本研究表明，AGR2可诱导促生长因子EGFR配体--双调节蛋白(AREG)的表达。在腺癌细胞中诱导AREG的表达能够挽救当AGR2表达降低时丢失的转化表型。更多的实验表明，AGR2对AREG的诱导是通过激活河马信号通路共激活子YAP1介导的。因此，AGR2通过调节河马和EGF受体信号通路促进生长。
Anterior Gradient Homolog 2 (AGR2) is expressed by the normal intestine and by most human adenocarcinomas, including those derived from the esophagus, pancreas, lung, breast, ovary, and prostate. Xenografts of human adenocarcinoma cell lines in nude mice previously demonstrated that AGR2 supports tumor growth. In addition, AGR2 is able to induce in vitro a transformed phenotype in fibroblast and epithelial cell lines. The mechanism underlying the growth promoting effects of AGR2 is unknown. The present study shows that AGR2 induces expression of amphiregulin (AREG), a growth promoting EGFR ligand. Induced AREG expression in adenocarcinoma cells is able to rescue the transformed phenotype that is lost when AGR2 expression is reduced. Additional experiments demonstrate that AGR2 induction of AREG is mediated by activation of the Hippo signaling pathway co-activator, YAP1. Thus AGR2 promotes growth by regulating the Hippo and EGF receptor signaling pathways.