Department of Pathology, Harbor-UCLA Medical Center, Torrance, CA, USA.
Exp Mol Pathol. 2011 Dec;91(3):653-9. doi: 10.1016/j.yexmp.2011.07.004. Epub 2011 Jul 28.
Innate immunity factors such as conversion of the 26S proteasome to form the immunoproteasome and the Toll-like receptor signaling pathways are activated in chronic hepatitis induced by the carcinogenic drug DDC. Over time, preneoplastic hepatocyte phenotypes appear in the liver parenchyma. These changed hepatocytes expand in number because they have a growth advantage over normal hepatocytes when responding to chronic liver injury. The changed hepatocytes can be identified using immunofluorescent antibodies to preneoplastic cells e.g. FAT10/UbD, A2 macroglobulin, glutathione transpeptidase, alpha fetoprotein, glycipan 3, FAS, and gamma glutamyl transpeptidase. The formation of the preneoplastic cells occurs concomitant with activation of the Toll-like receptor signaling pathways and the transformation of the 26S proteasome to form the immunoproteasome. This transformation is in response to interferon stimulating response element on the promoter of the FAT10/UbD gene. NFκB, Erk, p38 and Jnk are also up regulated. Specific inhibitors block these responses in vitro in a mouse tumor cell line exposed to interferon gamma. Mallory-Denk bodies form in these preneoplastic cells, because of the depletion of the 26S proteasome due to formation of the immunoproteasome. Thus, MDB forming cells are also markers of the preneoplastic hepatocytes. The UbD positive preneoplastic cells regress when the liver injury induced chronic hepatitis subsides. When the drug DDC is refed to mice and chronic hepatitis is activated, the preneoplastic cell population expands and Mallory-Denk bodies rapidly reform. This response is remembered by the preneoplastic cells for at least four months indicating that an epigenetic cellular memory has formed in the preneoplastic cells. This proliferative response is prevented by feeding methyl donors such as S-adenosylmethionine or betaine. Drug feeding reduces the methylation of H(3) K4, 9, and 27 and this response is prevented by feeding the methyl donors. After 8 to 15months of drug withdrawal in mice the preneoplastic liver cells persist as single or small clusters of cells in the liver lobules. Multiple liver tumors form, some of which are hepatocellular carcinomas. The tumors immunostain positively for the same preneoplastic markers as the preneoplastic cells. Similar cells are identified in human cirrhosis and hepatocellular carcinoma indicating the relevance of the drug model described here to the preneoplastic changes associated with human chronic hepatitis and hepatocellular carcinoma.
先天免疫因子，如 26S 蛋白酶体转化为免疫蛋白酶体和 Toll 样受体信号通路，在致癌药物 DDC 诱导的慢性肝炎中被激活。随着时间的推移，癌前肝细胞表型出现在肝实质中。这些改变的肝细胞数量增加，因为它们在应对慢性肝损伤时比正常肝细胞具有生长优势。可以使用针对癌前细胞的免疫荧光抗体来识别这些改变的肝细胞，例如 FAT10/UbD、A2 巨球蛋白、谷胱甘肽转肽酶、甲胎蛋白、糖基化 3、FAS 和γ-谷氨酰转肽酶。癌前细胞的形成与 Toll 样受体信号通路的激活以及 26S 蛋白酶体转化为免疫蛋白酶体同时发生。这种转化是对 FAT10/UbD 基因启动子上干扰素刺激反应元件的反应。NFκB、Erk、p38 和 Jnk 也被上调。在暴露于干扰素 γ 的小鼠肿瘤细胞系中，特异性抑制剂可阻断体外的这些反应。由于形成免疫蛋白酶体，26S 蛋白酶体耗竭，这些癌前细胞中形成 Mallory-Denk 体。因此，MDB 形成细胞也是癌前肝细胞的标志物。当诱导慢性肝炎的肝损伤消退时，UbD 阳性的癌前细胞会退化。当重新给 DDC 药物并激活慢性肝炎时，癌前细胞群会扩张，Mallory-Denk 体迅速重新形成。这种反应被癌前细胞记住至少四个月，表明癌前细胞中已经形成了表观遗传细胞记忆。通过喂食甲基供体（如 S-腺苷甲硫氨酸或甜菜碱）可以防止这种增殖反应。药物喂养会降低 H(3) K4、9 和 27 的甲基化，而喂食甲基供体可以防止这种反应。在小鼠停药 8-15 个月后，癌前肝细胞作为单个或小簇细胞存在于肝小叶中。形成多个肝肿瘤，其中一些是肝细胞癌。肿瘤免疫染色阳性，与癌前细胞相同的癌前标记物。在人类肝硬化和肝细胞癌中也发现了类似的细胞，表明这里描述的药物模型与人类慢性肝炎和肝细胞癌相关的癌前变化有关。
