Global gene profiling of spontaneous hepatocellular carcinoma in B6C3F1 mice: similarities in the molecular landscape with human liver cancer.
Global gene profiling of spontaneous hepatocellular carcinoma in B6C3F1 mice: similarities in the molecular landscape with human liver cancer.
复制标题
DOI：
10.1177/0192623311407213
复制
发表时间：
2011-06
影响因子：
1.5
通讯作者：
Sills RC
中科院分区：
文献类型：
--
作者：
Hoenerhoff MJ;Pandiri AR;Lahousse SA;Hong HH;Ton TV;Masinde T;Auerbach SS;Gerrish K;Bushel PR;Shockley KR;Peddada SD;Sills RC
肝细胞癌（HCC）是全世界发病和死亡的重要原因。尽管人类肝癌的危险因素众所周知，但这种疾病的分子发病机制很复杂，而且总的来说，治疗选择仍然很差。使用啮齿动物模型来研究人类癌症已被广泛追求，包括通过基因工程啮齿动物和用于致癌性和毒理学研究的啮齿动物模型。特别是，国家毒理学计划（NTP）两年生物测定中使用的B6C3F1小鼠已用于评估环境和职业化学品以及其他化合物的致癌作用。 B6C3F1 小鼠自发性 HCC 的高发病率在与人类疾病的相关性方面对其作为化学诱导 HCC 模型的使用提出了挑战。利用全局基因表达谱，我们确定了人类肝癌中几种类似改变的介质的失调，包括胎儿癌基因的重新表达、原癌基因的上调、抑癌基因的下调以及细胞周期介质、生长因子、凋亡调节因子以及血管生成和细胞外基质重塑因子的异常表达。尽管人类和小鼠 HCC 之间在病因学和发病机制方面仍存在重大差异，但小鼠和人类 HCC 的整体基因表达和分子通路失调存在重要相似之处。这些数据为该模型在具有人类潜在致癌风险的化合物的危害识别中的应用提供了进一步的支持，并可能有助于更好地理解NTP两年致癌性生物测定中化学暴露引起的肿瘤发生机制。
Hepatocellular carcinoma (HCC) is an important cause of morbidity and mortality worldwide. Although the risk factors of human HCC are well known, the molecular pathogenesis of this disease is complex, and in general, treatment options remain poor. The use of rodent models to study human cancer has been extensively pursued, both through genetically engineered rodents and rodent models used in carcinogenicity and toxicology studies. In particular, the B6C3F1 mouse used in the National Toxicology Program (NTP) two-year bioassay has been used to evaluate the carcinogenic effects of environmental and occupational chemicals, and other compounds. The high incidence of spontaneous HCC in the B6C3F1 mouse has challenged its use as a model for chemically induced HCC in terms of relevance to the human disease. Using global gene expression profiling, we identify the dysregulation of several mediators similarly altered in human HCC, including re-expression of fetal oncogenes, upregulation of protooncogenes, downregulation of tumor suppressor genes, and abnormal expression of cell cycle mediators, growth factors, apoptosis regulators, and angiogenesis and extracellular matrix remodeling factors. Although major differences in etiology and pathogenesis remain between human and mouse HCC, there are important similarities in global gene expression and molecular pathways dysregulated in mouse and human HCC. These data provide further support for the use of this model in hazard identification of compounds with potential human carcinogenicity risk, and may help in better understanding the mechanisms of tumorigenesis resulting from chemical exposure in the NTP two-year carcinogenicity bioassay.