Keratin 18-deficiency results in steatohepatitis and liver tumors in old mice: A model of steatohepatitis-associated liver carcinogenesis.
Keratin 18-deficiency results in steatohepatitis and liver tumors in old mice: A model of steatohepatitis-associated liver carcinogenesis.
复制标题
DOI：
10.18632/oncotarget.12325
复制
发表时间：
2016-11-08
期刊：
影响因子：
--
通讯作者：
Haybaeck J
中科院分区：
文献类型：
--
作者：
Bettermann K;Mehta AK;Hofer EM;Wohlrab C;Golob-Schwarzl N;Svendova V;Schimek MG;Stumptner C;Thüringer A;Speicher MR;Lackner C;Zatloukal K;Denk H;Haybaeck J
脂肪性肝炎（Steatohepatitis，SH）相关的肝癌发生是临床医学中日益重要的问题。SH在形态学上以脂肪变性、肝细胞损伤、气球样变、称为Mallory-Denk小体（MDB）的肝细胞胞质内含物、炎症和纤维化为特征。与野生型小鼠相比，17-20个月大的Krt 18 −/−和Krt 18 +/−小鼠自发地出现了与人类SH以及肝脏肿瘤的形态学谱非常相似的肝脏病变。Krt 18 −/−小鼠的病理变化比Krt 18 +/−小鼠更明显。与年龄匹配的Krt 18 +/−和wt小鼠相比，Krt 18 −/−小鼠中雄性占优势的肝脏肿瘤的频率显著更高。与野生型动物相比，Krt 18缺陷型肿瘤显示SH特征，并且通常为多形性形态。肿瘤的aCGH分析显示Krt 18 −/−肝肿瘤中的染色体畸变，影响癌基因和肿瘤抑制基因的位点。通过光学和免疫荧光显微镜以及免疫组织化学分析了3、6、12和17-20月龄的野生型（wt）、Krt 18 +/−和Krt 18 −/−（129 P2/OlaHsd背景）小鼠的肝脏。采用阵列比较基因组杂交（aCGH）技术对老年小鼠肝肿瘤进行了分析。我们的研究结果表明，K18缺乏导致肝细胞脂肪变性，随着年龄的增长，并最终SH。K18缺陷和年龄促进小鼠肝脏肿瘤的发展，通常基于染色体不稳定性，类似于具有干性特征的人类HCC。
Steatohepatitis (SH)-associated liver carcinogenesis is an increasingly important issue in clinical medicine. SH is morphologically characterized by steatosis, hepatocyte injury, ballooning, hepatocytic cytoplasmic inclusions termed Mallory-Denk bodies (MDBs), inflammation and fibrosis. 17-20-months-old Krt18−/− and Krt18+/− mice in contrast to wt mice spontaneously developed liver lesions closely resembling the morphological spectrum of human SH as well as liver tumors. The pathologic alterations were more pronounced in Krt18−/− than in Krt18+/− mice. The frequency of liver tumors with male predominance was significantly higher in Krt18−/− compared to age-matched Krt18+/− and wt mice. Krt18-deficient tumors in contrast to wt animals displayed SH features and often pleomorphic morphology. aCGH analysis of tumors revealed chromosomal aberrations in Krt18−/− liver tumors, affecting loci of oncogenes and tumor suppressor genes. Livers of 3-, 6-, 12- and 17-20-months-old aged wild type (wt), Krt18+/− and Krt18−/− (129P2/OlaHsd background) mice were analyzed by light and immunofluorescence microscopy as well as immunohistochemistry. Liver tumors arising in aged mice were analyzed by array comparative genomic hybridization (aCGH). Our findings show that K18 deficiency of hepatocytes leads to steatosis, increasing with age, and finally to SH. K18 deficiency and age promote liver tumor development in mice, frequently on the basis of chromosomal instability, resembling human HCC with stemness features.