Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
Am J Pathol. 2020 Jun;190(6):1175-1187. doi: 10.1016/j.ajpath.2020.01.020. Epub 2020 Mar 20.
Hepatocellular carcinoma (HCC) is the most common form of liver tumors. Although HCC is associated with chronic viral infections, alcoholic cirrhosis, and nonalcoholic fatty liver disease, genetic factors that contribute to the HCC risk remain unknown. The BRCA2 DNA repair associated (BRCA2) and cyclin-dependent kinase inhibitor 1A (CDKN1A) interacting protein, known as BCCIP, are essential for cell viability and maintenance of genomic stability. In this study, we established a new genetically engineered mouse model with Bccip deficiency. Mosaic or heterozygous Bccip deletion conferred an increased risk of spontaneous liver tumorigenesis and B-cell lymphoma development at old age. These abnormalities are accompanied with chronic inflammation, histologic features of nonalcoholic steatohepatitis, keratin and ubiquitin aggregates within cytoplasmic Mallory-Denk bodies, and changes of the intracellular distribution of high-mobility group box 1 protein. Our study suggests BCCIP dysregulation as a risk factor for HCC and offers a novel mouse model for future investigations of nonviral or nonalcoholic causes of HCC development.
肝细胞癌 (HCC) 是最常见的肝脏肿瘤形式。尽管 HCC 与慢性病毒感染、酒精性肝硬化和非酒精性脂肪性肝病有关，但导致 HCC 风险的遗传因素仍不清楚。BRCA2 相关的 DNA 修复 (BRCA2) 和细胞周期蛋白依赖性激酶抑制剂 1A (CDKN1A) 相互作用蛋白，称为 BCCIP，是细胞活力和基因组稳定性所必需的。在这项研究中，我们建立了一种具有 Bccip 缺陷的新型基因工程小鼠模型。镶嵌或杂合 Bccip 缺失会增加自发性肝肿瘤发生和老年时 B 细胞淋巴瘤发展的风险。这些异常伴随着慢性炎症、非酒精性脂肪性肝炎的组织学特征、细胞质 Mallory-Denk 体中的角蛋白和泛素聚集物，以及高迁移率族框 1 蛋白的细胞内分布的变化。我们的研究表明 BCCIP 失调是 HCC 的一个危险因素，并为未来研究非病毒性或非酒精性 HCC 发展的原因提供了一种新型小鼠模型。
