Denda Ayumi, Kitayama Wakashi, Kishida Hideki, Murata Nao, Tsutsumi Masahiro, Tsujiuchi Toshifumi, Nakae Dai, Konishi Yoichi
Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Nara 634-8521, Japan.
Jpn J Cancer Res. 2002 Feb;93(2):125-32. doi: 10.1111/j.1349-7006.2002.tb01250.x.
Development of hepatocellular carcinomas in rats caused by a choline-deficient, L-amino acid-defined (CDAA) diet, usually associated with fatty liver, fibrosis, cirrhosis and oxidative DNA damage, has been recognized as a useful model of hepatocarcinogenesis caused by endogenous factors. In the present study, in order to further explore involved factors and genes, we established an equivalent model in spontaneous liver tumor-resistant C57BL/6J mice. Six-week-old males and females were continuously fed the CDAA diet and histological liver lesions and oxidative DNA damage due to 8-hydroxydeoxyguanosine (8-OHdG) were examined after 22, 65 and 84 weeks. In male mice, fatty change and fibrosis were evident at 22 weeks, and preneoplastic foci of altered hepatocytes were seen at an incidence of 8/8 (100%) and a multiplicity of 6.6 +/- 4.0 per mouse at 65 weeks. Hepatocellular adenomas and carcinomas developed at incidences of 16/24 (66.7%) and 5/24 (20.8%), and multiplicities of 1.42 +/- 1.32 and 0.29 +/- 0.62, respectively, at 84 weeks. The female mice exhibited resistance to development of these lesions. The CDAA diet also increased 8-OHdG levels in male but not female mice. These results indicate that a CDAA diet causes hepatocellular preneoplastic foci, adenomas and carcinomas associated with fibrosis and oxidative DNA damage in mice, as in rats, providing a hepatocarcinogenesis model caused by endogenous factors in mice.
由胆碱缺乏、L-氨基酸限定（CDAA）饮食引起的大鼠肝细胞癌的发展，通常与脂肪肝、纤维化、肝硬化和氧化性DNA损伤有关，已被认为是内源性因素导致肝癌发生的有用模型。在本研究中，为了进一步探索相关因素和基因，我们在自发肝脏肿瘤抗性C57BL/6J小鼠中建立了一个等效模型。六周龄的雄性和雌性小鼠持续喂食CDAA饮食，并在22周、65周和84周后检查肝脏组织学病变以及由8-羟基脱氧鸟苷（8-OHdG）导致的氧化性DNA损伤。在雄性小鼠中，22周时出现脂肪变性和纤维化，65周时可见改变的肝细胞的癌前病灶，发生率为8/8（100%），每只小鼠的病灶数为6.6±4.0。84周时肝细胞腺瘤和癌的发生率分别为16/24（66.7%）和5/24（20.8%），病灶数分别为1.42±1.32和0.29±0.62。雌性小鼠对这些病变的发展具有抗性。CDAA饮食也增加了雄性小鼠而非雌性小鼠的8-OHdG水平。这些结果表明，CDAA饮食会导致小鼠肝细胞癌前病灶、腺瘤和癌，伴有纤维化和氧化性DNA损伤，与大鼠情况相同，为小鼠内源性因素导致的肝癌发生提供了一个模型。
