Effect of mutant β-catenin on liver growth homeostasis and hepatocarcinogenesis in transgenic mice
| Autor: | Eric P. Sandgren, Adam Jochem, Katie E. Holmes, Timothy J. Stein |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Regulation of gene expression
Genetically modified mouse medicine.medical_specialty Beta-catenin Hepatology biology Adenomatous polyposis coli Transgene Mutant medicine.disease medicine.anatomical_structure Endocrinology Hepatocyte Internal medicine medicine biology.protein Cancer research Liver cancer |
| Zdroj: | Liver International. 31:303-312 |
| ISSN: | 1478-3223 |
| Popis: | Protein-stabilizing point mutations or deletions of β-catenin, an intracellular messenger in the Wnt signalling pathway, have been reported in up to 50% of human and mouse hepatocellular carcinomas (HCC) (1–10). Several investigators have used transgenic mouse models to confirm the association of β-catenin mutations with liver growth abnormalities. Diffuse hepatocyte-directed expression of mutant β-catenin initiated in fetal liver causes hepatomegaly and loss of animal condition within 5 weeks after birth (11, 12). Diffuse expression initiated in adult liver causes hepatomegaly within 3 weeks of onset (12). Focal expression initiated in adults has no apparent effect on liver growth, and is not associated with altered hepatocyte foci or HCC (12). Mutant β-catenin only promotes cancer when combined with other carcinogenic alterations, including the focal expression of mutant Hras (13), loss of the serine/threonine kinase Lkb1 (14) or administration of diethylnitrosamine (15). β-Catenin also plays a role in the metabolic zonation of the liver (16, 17). Several enzymes are expressed exclusively in perivenous hepatocytes. Membranous immunohistochemical staining of wild-type β-catenin protein in hepatocytes is most intense in the perivenous region (17). The expression of the adenomatous polyposis coli protein, a negative regulator of β-catenin, is strongest in periportal hepatocytes, where no β-catenin staining is noted. Benhamouche and colleagues inactivated adenomatous polyposis coli throughout mouse liver. Both β-catenin and perivenous-restricted genes were now expressed diffusely in the liver, indicating a loss of normal hepatic metabolic zonation (17). Furthermore, two-thirds of these mice also developed HCC (16). This report describes a novel transgenic mouse model that extends our understanding of the effects of oncogenic β-catenin on liver growth homeostasis, including cancer. Our model provides the ability to regulate organ-specific transgene expression in a temporal fashion, and allows us to quantify the influence of β-catenin on hepatocyte growth in vivo. We first describe model validation. We then use this model to address several questions that previous studies could not answer: (i) are β-catenin-induced lesions reversible? (ii) Are the effects of β-catenin cell autonomous or non-cell autonomous? And (iii) can we establish a model in which mutant β-catenin by itself induces mouse hepatic neoplasms in vivo? |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|