Department of Biological Sciences, National University of Singapore, Singapore.
Genome Institute of Singapore, Singapore.
Biochem Biophys Res Commun. 2019 Mar 19;510(4):558-564. doi: 10.1016/j.bbrc.2019.02.008. Epub 2019 Feb 7.
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is mainly due to genetic changes in hepatocytes. However, molecular expression in hepatocytes during hepatocarcinogenesis has not been characterized. In this study, using an inducible kras transgenic zebrafish models for HCC, transcriptomic profiles of oncogenic hepatocytes from larvae, male and female adult fish following a brief induction of oncogenic kras were investigated. We found that oncogenic hepatocytes from all the three sources possess most of the cancer hallmarks at molecular level, including Sustaining proliferative signaling, Evading growth suppressors, Resisting cell death, Avoiding immune destruction, Inflammation, Reprogramming of energy metabolism, Angiogenesis, and Activating invasion and metastasis, suggesting the malignant transformation at molecular level could occur at the early stage of hepatocarcinogensis and can be captured in hepatocytes. However, each group of oncogenic hepatocytes also had their own characteristics. Larval oncogenic hepatocytes have cancer stem cell features. Female oncogenic hepatocytes showed resemblance to a mild human HCC subtype while male oncogenic hepatocytes resembled a severe HCC subtype, consistent with the observed sex disparity of HCC in both zebrafish and human. Finally, the two adult groups were more similar to each other than to the larval group, indicating an overwhelming effect of development over the gender.
肝细胞癌（HCC）是原发性肝癌中最常见的类型，主要归因于肝细胞中的遗传改变。然而，在肝癌发生过程中，肝细胞中的分子表达尚未得到表征。在这项研究中，我们使用诱导型 Kras 转基因斑马鱼模型来研究 HCC，研究了短暂诱导致癌性 Kras 后，来自幼虫、雄性和雌性成年鱼的致癌性肝细胞的转录组谱。我们发现，来自所有三个来源的致癌性肝细胞在分子水平上都具有大多数癌症特征，包括维持增殖信号、逃避生长抑制物、抵抗细胞死亡、避免免疫破坏、炎症、能量代谢重编程、血管生成和激活侵袭和转移，表明恶性转化可能在肝癌发生的早期阶段发生，并且可以在肝细胞中捕获。然而，每一组致癌性肝细胞也有其自身的特点。幼虫致癌性肝细胞具有癌症干细胞特征。雌性致癌性肝细胞表现出类似于轻度人类 HCC 亚型的特征，而雄性致癌性肝细胞则类似于严重的 HCC 亚型，这与在斑马鱼和人类中观察到的 HCC 性别差异一致。最后，两个成年组彼此之间比幼虫组更相似，这表明发育对性别具有压倒性影响。
