Lu, Xinjun and Peng, Baogang and Chen, Ge and Pes, Mario G. and Ribback, Silvia and Ament, Cindy and Xu, Hongwei and Pal, Rajesh and Rodrigues, Pedro M. and Banales, Jesus M. and Evert, Matthias and Calvisi, Diego F. and Chen, Xin and Fan, Biao and Wang, Jingxiao (2021) YAP Accelerates Notch-Driven Cholangiocarcinogenesis via mTORC1 in Mice. AMERICAN JOURNAL OF PATHOLOGY, 191 (9). pp. 1651-1667. ISSN 0002-9440, 1525-2191
Full text not available from this repository. (Request a copy)Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignant neoplasm with limited therapeutic options. Previous studies have found that Notch1 overexpression alone suffices to induce iCCA in the mouse, albeit after long latency. The current study found that activation of the Yes-associated protein (Yap) proto-oncogene occurs during Notch1-driven iCCA progression. After co-expressing activated Notch1 intracellular domain (Nicd) and Yap (YapS127A) in the mouse liver, rapid iCCA formation and progression occurred in Nicd/Yap mice. Mechanistically, an increased expression of amino acid transporters and activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway was detected in Nicd/Yap mouse liver tumors. Significantly, the genetic deletion of Raptor, the major mTORC1 component, completely suppressed iCCA development in Nicd/Yap mice. Elevated expression of Notch1, YAP, amino acid transporters, and members of the mTORC1 pathway was also detected ubiquitously in a collection of human iCCA specimens. Their levels were associated with a poor patient outcome. This study demonstrates that Notch and YAP concomitant activation is frequent in human cholangiocarcinogenesis. Notch and YAP synergize to promote iCCA formation by activating the mTORC1 pathway. (Am J Pathol 2021, 191: 1651e1667; https://doi.org/10.1016/j.ajpath.2021.05.017)
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INTRAHEPATIC CHOLANGIOCARCINOMA; HEPATOCELLULAR-CARCINOMA; PATHWAY; YAP/TAZ; CANCER; HEPATOCARCINOGENESIS; CLASSIFICATION; EXPRESSION; ROLES; AKT; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Sep 2022 07:00 |
| Last Modified: | 27 Sep 2022 07:00 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48008 |
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