دورية أكاديمية
أعرض في EDS

p53R245W Mutation Fuels Cancer Initiation and Metastases in NASH-driven Liver Tumorigenesis.

التفاصيل البيبلوغرافية
العنوان: p53R245W Mutation Fuels Cancer Initiation and Metastases in NASH-driven Liver Tumorigenesis.
المؤلفون: Dibra D; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Gagea M; Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Qi Y; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Chau GP; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Su X; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lozano G; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
المصدر: Cancer research communications [Cancer Res Commun] 2023 Dec 29; Vol. 3 (12), pp. 2640-2652.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 9918281580506676 Publication Model: Print Cited Medium: Internet ISSN: 2767-9764 (Electronic) Linking ISSN: 27679764 NLM ISO Abbreviation: Cancer Res Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Philadelphia, Pennsylvania] : American Association for Cancer Research, [2021]-
مواضيع طبية MeSH: Non-alcoholic Fatty Liver Disease*/genetics , Carcinoma, Hepatocellular*/genetics , Liver Neoplasms*/genetics, Mice ; Animals ; Tumor Suppressor Protein p53/genetics ; Carcinogenesis/genetics ; Mutation ; Disease Models, Animal ; Obesity/complications
مستخلص: Obesity is a significant global health concern. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are common risk factors for hepatocellular carcinoma (HCC) and are closely associated with metabolic comorbidities, including obesity and diabetes. The TP53 tumor suppressor is the most frequently mutated gene in liver cancers, with half of these alterations being missense mutations. These mutations produce highly abundant proteins in cancer cells which have both inhibitory effects on wildtype (WT) p53, and gain-of-function (GOF) activities that contribute to tumor progression. A Western diet increases p53 activity in the liver. To elucidate the functional consequences of Trp53 mutations in a NASH-driven liver tumorigenesis model, we generated somatic mouse models with Trp53 deletion or the missense hotspot mutant p53R245W only in hepatocytes and placed mice on a high-fat, choline-deficient diet. p53R245W in the presence of diet increased fatty liver, compensatory proliferation in the liver parenchyma, and enriched genes of tumor-promoting pathways such as KRAS signaling, MYC, and epithelial-mesenchymal transition when compared with controls in the premalignant liver. Moreover, p53R245W suppressed transcriptional activity of WT p53 in the liver in vivo under metabolic challenges, and shortened survival and doubling of HCC incidence as compared with control heterozygous mice. Complete loss of Trp53 also significantly accelerated liver tumor incidence and lowered time-to-tumor development compared with WT controls. p53R245W GOF properties increased carcinoma initiation, fueled mixed hepatocholangial carcinoma incidence, and tripled metastatic disease. Collectively, our in vivo studies indicate that p53R245W has stronger tumor promoting activities than Trp53 loss in the context of NASH.
Significance: Using somatic NASH-driven mouse models with p53 deletion or mutant p53R245W only in hepatocytes, we discovered that p53R245W increased carcinoma initiation, fueled hepatocholangial carcinoma incidence, and tripled metastases.
(© 2023 The Authors; Published by the American Association for Cancer Research.)
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معلومات مُعتمدة: P30 CA016672 United States CA NCI NIH HHS; P50 CA217674 United States CA NCI NIH HHS; R01 CA082577 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Tumor Suppressor Protein p53)
تواريخ الأحداث: Date Created: 20231204 Date Completed: 20240101 Latest Revision: 20240313
رمز التحديث: 20240314
مُعرف محوري في PubMed: PMC10761659
DOI: 10.1158/2767-9764.CRC-23-0218
PMID: 38047594
قاعدة البيانات: MEDLINE
الوصف
تدمد:2767-9764
DOI:10.1158/2767-9764.CRC-23-0218