Department of Biological Sciences, National University of Singapore, 117543, Singapore.
Department of Microbiology, Oregon State University, Corvallis, Oregon, 97331, USA.
Sci Rep. 2017 Jan 24;7:41280. doi: 10.1038/srep41280.
Hepatocellular carcinoma (HCC) is more prevalent in men than women, but the reason for this gender disparity is not well understood. To investigate whether zebrafish could be used to study the gender disparity of HCC, we compared the difference of liver tumorigenesis between female and male fish during early tumorigenesis and long-term tumor progression in our previously established inducible and reversible HCC model - the kras transgenic zebrafish. We found that male fish developed HCC faster than females. The male tumors were more severe from the initiation stage, characteristic of higher proliferation, activation of WNT/β-catenin pathway and loss of cell adhesion. During long-term tumor progression, the male tumors developed into more advanced multi-nodular tumors, whereas the female tumors remain uniform and homogenous. Moreover, regression of male tumors required longer time. We further investigated the role of sex hormones in kras transgenic fish. Estrogen treatment showed tumor suppressing effect during early tumorigenesis through inhibiting cell proliferation, whereas androgen accelerated tumor growth by promoting cell proliferation. Overall, our study presented the zebrafish as a useful animal model for study of gender disparity of HCC.
肝细胞癌（HCC）在男性中比女性更为常见，但这种性别差异的原因尚不清楚。为了研究斑马鱼是否可用于研究 HCC 的性别差异，我们比较了在我们先前建立的可诱导和可逆 HCC 模型 - kras 转基因斑马鱼中，早期肿瘤发生和长期肿瘤进展过程中雌雄鱼肝脏肿瘤发生的差异。我们发现，雄性鱼比雌性鱼更快地发展为 HCC。雄性肿瘤从起始阶段就更严重，具有更高的增殖、WNT/β-catenin 通路激活和细胞黏附丧失的特征。在长期肿瘤进展过程中，雄性肿瘤发展为更先进的多结节肿瘤，而雌性肿瘤保持均匀和同质。此外，雄性肿瘤的消退需要更长的时间。我们进一步研究了性类固醇激素在 kras 转基因鱼中的作用。雌激素治疗在早期肿瘤发生过程中通过抑制细胞增殖表现出肿瘤抑制作用，而雄激素通过促进细胞增殖加速肿瘤生长。总的来说，我们的研究表明斑马鱼是研究 HCC 性别差异的有用动物模型。
