Enya, S., Kawakami, K., Suzuki, Y., Kawaoka, S. (2018) A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor-liver crosstalk in causing adverse effects on the host.. Disease models & mechanisms. 11(8).
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.