Hepatocellular carcinoma results from chronic cyclin D1 overexpression in transgenic mice.
Hepatocellular carcinoma results from chronic cyclin D1 overexpression in transgenic mice.
复制标题
DOI：
--
复制
发表时间：
2001-07
期刊：
影响因子：
11.2
通讯作者：
N. Deane;M. Parker;R. Aramandla;Lisa Diehl;Woo-Jung Lee;M. K. Washington;L. Nanney;Y. Shyr;R. Beauchamp
中科院分区：
文献类型：
--
作者：
N. Deane;M. Parker;R. Aramandla;Lisa Diehl;Woo-Jung Lee;M. K. Washington;L. Nanney;Y. Shyr;R. Beauchamp
Cyclin D1 是一种已知的癌基因，也是细胞周期进程的关键调节因子。细胞周期蛋白 D1 基因的扩增及其过度表达与人类肝细胞癌 (HCC) 的侵袭性相关。在这项研究中，已经产生了两个独立的转基因小鼠品系，它们在大鼠肝脏脂肪酸结合蛋白启动子的控制下表达细胞周期蛋白D1。该转基因特异性指导肝脏和肠道中的表达。 RNA 和蛋白质分析表明，与野生型同胞相比，肝脏和肠道中细胞周期蛋白 D1 基因产物的表达增加。两种转基因品系均出现进行性肝病。肝脏和肠道的 H&E 染色切片检查显示 3 个月大时肝脏出现增生性变化。到6个月大时，转基因小鼠出现明显的肝脏肿大和肝脏发育不良的组织学证据。与雌性动物相比，雄性动物的这些早期变化明显更为显着。 9 个月大时出现肝脏腺瘤，并在随后的 6 个月内进展为 HCC。到 15-17 个月大时，87% 的雄性和 69% 的雌性动物患有腺瘤结节或 HCC。到 17 个月大时，31% 的雄性和雌性动物患有已进展为 HCC 的疾病。这些动物代表了人类肝癌研究的独特且重要的新模型。这项研究表明，cyclin D1 的过度表达足以引发肝细胞癌变。
Cyclin D1 is a known oncogene and a key regulator of cell cycle progression. Amplification of the cyclin D1 gene and its overexpression have been associated with aggressive forms of human hepatocellular carcinoma (HCC). In this study, two independent lines of transgenic mice have been generated that express cyclin D1 under the control of the rat liver fatty acid binding protein promoter. This transgene specifically directs expression in the liver and the intestines. RNA and protein analysis demonstrated increased expression of the cyclin D1 gene product in the liver and bowel when compared with wild-type siblings. Both transgenic lines developed progressive liver disease. Examination of H&E stained sections of the liver and bowel revealed hyperplastic changes in the liver by 3 months of age. By 6 months of age, transgenic mice had obvious hepatomegaly and histological evidence of dysplasia in the liver. These early changes were significantly more dramatic in male animals when compared with female animals. By 9 months of age adenomas of the liver appeared, progressing to HCC over the ensuing 6-month period. By 15-17 months of age, 87% of male and 69% of female animals had either adenomatous nodules or HCCs. By 17 months of age, 31% of male and female animals had disease that had progressed to HCC. These animals represent a unique and significant new model for the study of human HCC. This study demonstrates that overexpression of cyclin D1 is sufficient to initiate hepatocellular carcinogenesis.