Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis
| العنوان: | Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis |
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| المؤلفون: | Sanjoy K. Khan, Young Eun Kim, Wantae Kim, Hanjun Kim, Eek-hoon Jho, Tohru Ishitani, Jason Dahlman, Ogyi Park, Yingzi Yang, Jelena Gvozdenovic-Jeremic, Bin Gao |
| المصدر: | Journal of Clinical Investigation. 127:137-152 |
| بيانات النشر: | American Society for Clinical Investigation, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | STAT3 Transcription Factor, 0301 basic medicine, medicine.medical_specialty, Cell signaling, Carcinoma, Hepatocellular, Notch signaling pathway, Cell Cycle Proteins, Tumor initiation, Protein Serine-Threonine Kinases, Serine-Threonine Kinase 3, WW domain, Mice, 03 medical and health sciences, Liver Neoplasms, Experimental, Proto-Oncogene Proteins, Internal medicine, medicine, Animals, Hippo Signaling Pathway, Wnt Signaling Pathway, beta Catenin, Adaptor Proteins, Signal Transducing, Mice, Knockout, Hippo signaling pathway, Receptors, Notch, biology, Hepatocyte Growth Factor, Wnt signaling pathway, YAP-Signaling Proteins, General Medicine, Phosphoproteins, 030104 developmental biology, Endocrinology, Hippo signaling, Catenin, biology.protein, Cancer research, Research Article |
| الوصف: | Malignant tumors develop through multiple steps of initiation and progression, and tumor initiation is of singular importance in tumor prevention, diagnosis, and treatment. However, the molecular mechanism whereby a signaling network of interacting pathways restrains proliferation in normal cells and prevents tumor initiation is still poorly understood. Here, we have reported that the Hippo, Wnt/β-catenin, and Notch pathways form an interacting network to maintain liver size and suppress hepatocellular carcinoma (HCC). Ablation of the mammalian Hippo kinases Mst1 and Mst2 in liver led to rapid HCC formation and activated Yes-associated protein/WW domain containing transcription regulator 1 (YAP/TAZ), STAT3, Wnt/β-catenin, and Notch signaling. Previous work has shown that abnormal activation of these downstream pathways can lead to HCC. Rigorous genetic experiments revealed that Notch signaling forms a positive feedback loop with the Hippo signaling effector YAP/TAZ to promote severe hepatomegaly and rapid HCC initiation and progression. Surprisingly, we found that Wnt/β-catenin signaling activation suppressed HCC formation by inhibiting the positive feedback loop between YAP/TAZ and Notch signaling. Furthermore, we found that STAT3 in hepatocytes is dispensable for HCC formation when mammalian sterile 20-like kinase 1 and 2 (Mst1 and Mst2) were removed. The molecular network we have identified provides insights into HCC molecular classifications and therapeutic developments for the treatment of liver tumors caused by distinct genetic mutations. |
| تدمد: | 1558-8238 0021-9738 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::34fa608a4332c91ab959a74ed9fba49d https://doi.org/10.1172/jci88486 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....34fa608a4332c91ab959a74ed9fba49d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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