A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor-liver crosstalk in causing adverse effects on the host.
A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor-liver crosstalk in causing adverse effects on the host.
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DOI：
10.1242/dmm.032383
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发表时间：
2018-05-03
影响因子：
4.3
通讯作者：
Kawaoka S
中科院分区：
文献类型：
--
作者：
Enya S;Kawakami K;Suzuki Y;Kawaoka S
肿瘤引起的宿主生理破坏的宿主器官和基因的性质仍然不明确。在这里，我们建立了一种适合解决这个问题的新型斑马鱼肠道肿瘤模型，并发现合成胆汁酸的限速因子肝cyp7a1[或者，对于斑马鱼，胆汁醇(BA)]就是这样的宿主基因。 Gal4在后肠中特异性表达，诱导krasG12D导致肠肿瘤的形成。局部肠道肿瘤对宿主造成全身性有害影响，包括肝脏炎症、肝肿大、生长缺陷和机体死亡。整个有机体水平的基因表达分析和代谢物测量表明，肠道肿瘤可能通过改变肝脏 cyp7a1 的表达来降低总 BA 水平。肝脏中基因过度表达 cyp7a1 可恢复 BA 合成并改善肿瘤诱发的肝脏炎症，但不能改善其他肿瘤依赖性表型。因此，我们发现了 cyp7a1 作为宿主基因的一种先前未知的作用，它在荷瘤斑马鱼幼虫中将肠道肿瘤、肝脏胆固醇-BA 代谢和肝脏炎症联系起来。我们的模型为发现负责肿瘤诱导表型的宿主基因以及揭示肿瘤如何不利地影响宿主生物体的机制提供了重要的基础。摘要：作者从基因角度剖析了斑马鱼肠道肿瘤新模型对宿主的不利影响。
The nature of host organs and genes that underlie tumor-induced physiological disruption on the host remains ill-defined. Here, we establish a novel zebrafish intestinal tumor model that is suitable for addressing this issue, and find that hepatic cyp7a1, the rate-limiting factor for synthesizing bile acids [or, in the case of zebrafish, bile alcohol (BA)], is such a host gene. Inducing krasG12D by Gal4 specifically expressed in the posterior intestine resulted in the formation of an intestinal tumor. The local intestinal tumor caused systemic detrimental effects on the host, including liver inflammation, hepatomegaly, growth defects and organismal death. Whole-organism-level gene expression analysis and metabolite measurements revealed that the intestinal tumor reduced total BA levels, possibly via altered expression of hepatic cyp7a1. Genetically overexpressing cyp7a1 in the liver restored BA synthesis and ameliorated tumor-induced liver inflammation, but not other tumor-dependent phenotypes. Thus, we found a previously unknown role of cyp7a1 as the host gene that links the intestinal tumor, hepatic cholesterol–BA metabolism and liver inflammation in tumor-bearing zebrafish larvae. Our model provides an important basis to discover host genes responsible for tumor-induced phenotypes and to uncover mechanisms underlying how tumors adversely affect host organisms. Summary: The authors genetically dissect the adverse effects on the host in a new model of zebrafish intestinal tumor.
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影响因子：
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