Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice.
Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice.
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发表时间：
2003-08
期刊：
影响因子：
11.2
通讯作者：
P. Bertolino;W. Tong;P. Herrera;H. Cassé;Chang X. Zhang;Zhao-Qi Wang
中科院分区：
文献类型：
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作者：
P. Bertolino;W. Tong;P. Herrera;H. Cassé;Chang X. Zhang;Zhao-Qi Wang
易感基因对多发性内分泌瘤1型（MEN 1）综合征的作用在很大程度上仍不清楚。先前的研究表明，Men 1基因的无效突变导致小鼠妊娠中期死亡，而杂合Men 1基因敲除小鼠在生命后期发展为多发性内分泌肿瘤。为了寻找menin在抑制肿瘤发展中的因果作用的直接证据，我们产生了Men 1基因在胰腺β细胞中被特异性破坏的小鼠。这些小鼠早在2月龄时就开始出现增生性胰岛，6月龄时出现胰岛素瘤。胰岛病变表现出多阶段肿瘤进展的特征，包括β细胞去分化、血管生成和E-钙粘蛋白和β-连环蛋白的表达改变。此外，血液胰岛素和葡萄糖水平的紊乱与肿瘤发展相关，模拟人类MEN 1症状。我们的数据表明，这种小鼠品系为研究与MEN 1疾病相关的肿瘤发生机制提供了有力的工具。
The function of the predisposition gene to multiple endocrine neoplasia type 1 (MEN1) syndrome remains largely unknown. Previous studies demonstrated that null mutation of the Men1 gene caused mid-gestation lethality in mice, whereas heterozygous Men1 knockout mice developed multiple endocrine tumors late in life. To seek direct evidence on the causal role of menin in suppressing tumor development, we generated mice in which the Men1 gene was disrupted specifically in pancreatic beta cells. These mice began to develop hyperplastic islets at as early as 2 months of age and insulinomas at 6 months of age. The islet lesions exhibited features of multistage tumor progression, including beta-cell dedifferentiation, angiogenesis, and altered expression of both E-cadherin and beta-catenin. Additionally, disturbance of blood insulin and glucose levels correlated with tumor development, mimicking human MEN1 symptoms. Our data indicate that this strain of mice provides a powerful tool for the study of the mechanisms of tumorigenesis related to MEN1 disease.