Author:
Cigliano Antonio,Zhang Shanshan,Ribback Silvia,Steinmann Sara,Sini Marcella,Ament Cindy E.,Utpatel Kirsten,Song Xinhua,Wang Jingxiao,Pilo Maria G.,Berger Fabian,Wang Haichuan,Tao Junyan,Li Xiaolei,Pes Giovanni M.,Mancarella Serena,Giannelli Gianluigi,Dombrowski Frank,Evert Matthias,Calvisi Diego F.,Chen Xin,Evert Katja
Abstract
Abstract
Background
Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined.
Methods
We established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP.
Results
Overexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis.
Conclusions
Overall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesis
Funder
National Institutes of Health
Liver Center, University of California, San Francisco
Associazione Italiana per la Ricerca sul Cancro
Universitätsklinikum Regensburg
Publisher
Springer Science and Business Media LLC
Cited by
11 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献