Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors
| العنوان: | Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors |
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| المؤلفون: | Lewis R. Roberts, Robert Hullsiek, Lindsey A. Lee, Wendy A. Hudson, Barbara R. Tschida, Timothy P. Kuka, Michael A. Linden, Vincent W. Keng, Sandra Wagner, David A. Largaespada, Rachel A. Heuer, Pauline J. Beckmann, Nuri A. Temiz, Khalid Amin, Jesse D. Riordan, Joseph H. Nadeau, Ju Dong Yang, Adam J. Dupuy, Carlos A. Tierrablanca, Aaron L. Sarver |
| المصدر: | Cancer Research. 77:6576-6588 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Pathology, medicine.medical_specialty, Molecular pathology, Fatty liver, Cancer, Context (language use), Biology, medicine.disease, Article, digestive system diseases, Insertional mutagenesis, 03 medical and health sciences, 030104 developmental biology, Oncology, Hepatocellular carcinoma, medicine, Cancer research, Steatosis, neoplasms, Genetic screen |
| الوصف: | Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the N-acetyltransferase NAT10, which we found to be overexpressed in human steatosis–associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance. Cancer Res; 77(23); 6576–88. ©2017 AACR. |
| تدمد: | 1538-7445 0008-5472 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::37cd0ca90ca0a637f8e3963106308c88Test https://doi.org/10.1158/0008-5472.can-17-2281Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....37cd0ca90ca0a637f8e3963106308c88 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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