Department of Medicine, Stanford University, Stanford, California 94305, USA.
J Biol Chem. 2011 May 20;286(20):18301-10. doi: 10.1074/jbc.M110.215707. Epub 2011 Mar 26.
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.
前梯度同源物 2（AGR2）在正常肠道和大多数人类腺癌中表达，包括来自食管、胰腺、肺、乳腺、卵巢和前列腺的腺癌。先前在裸鼠中的人类腺癌细胞系异种移植物表明，AGR2 支持肿瘤生长。此外，AGR2 能够在成纤维细胞和上皮细胞系中诱导体外转化表型。AGR2 促进生长的作用机制尚不清楚。本研究表明，AGR2 诱导 Amphiregulin（AREG）的表达，AREG 是一种促进 EGFR 配体的表达。在腺癌细胞中诱导 AREG 表达能够挽救当 AGR2 表达减少时丧失的转化表型。进一步的实验表明，AGR2 通过激活 Hippo 信号通路共激活因子 YAP1 诱导 AREG 的表达。因此，AGR2 通过调节 Hippo 和 EGF 受体信号通路促进生长。
