YAP Accelerates Notch-Driven Cholangiocarcinogenesis via mTORC1 in Mice
| العنوان: | YAP Accelerates Notch-Driven Cholangiocarcinogenesis via mTORC1 in Mice |
|---|---|
| المؤلفون: | Biao Fan, Ge Chen, Xin Chen, Cindy Ament, Hongwei Xu, Silvia Ribback, Rajesh Pal, Jesus M. Banales, Mario G. Pes, Pedro M. Rodrigues, Diego F. Calvisi, Baogang Peng, Jingxiao Wang, Matthias Evert, Xinjun Lu |
| المصدر: | Am J Pathol The American journal of pathology, vol 191, iss 9 |
| بيانات النشر: | American Society for Investigative Pathology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Liver Cancer, 0301 basic medicine, Intracellular domain, Adult, Male, 2019-20 coronavirus outbreak, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mTORC1, Mechanistic Target of Rapamycin Complex 1, Medical and Health Sciences, Proto-Oncogene Mas, Pathology and Forensic Medicine, Cholangiocarcinoma, 03 medical and health sciences, Mice, Rare Diseases, 0302 clinical medicine, Pathology, 2.1 Biological and endogenous factors, Animals, Humans, Aetiology, Receptor, Notch1, Cancer, Adaptor Proteins, Signal Transducing, Aged, chemistry.chemical_classification, Notch1, Liver Disease, Signal Transducing, Adaptor Proteins, Transporter, Regular Article, YAP-Signaling Proteins, Middle Aged, Amino acid, Long latency, 030104 developmental biology, chemistry, Bile Duct Neoplasms, 030220 oncology & carcinogenesis, Cancer research, Female, biological phenomena, cell phenomena, and immunity, Signal transduction, Digestive Diseases, Receptor, Transcription Factors |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ea27c816593537935223f3055907b896 https://europepmc.org/articles/PMC8420864/ |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ea27c816593537935223f3055907b896 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |