PT  - JOURNAL ARTICLE
AU  - Sora Enya
AU  - Koichi Kawakami
AU  - Yutaka Suzuki
AU  - Shinpei Kawaoka
TI  - A novel zebrafish intestinal tumor model reveals a role for <em>cyp7a1</em>-dependent tumor-liver crosstalk in tumor's adverse effects on host
AID  - 10.1101/199349
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 199349
4099  - http://biorxiv.org/content/early/2017/10/06/199349.short
4100  - http://biorxiv.org/content/early/2017/10/06/199349.full
AB  - The nature of host organs and genes that underlie tumor-induced physiological disruption on host remains ill-defined. Here, we establish a novel zebrafish intestinal tumor model that is optimized for addressing this issue, and find that hepatic cyp7a1, the rate-limiting factor for synthesizing bile acids (BAs), is such a host gene. Inducing krasG12D by Gal4 specifically expressed in the posterior intestine resulted in formation of an intestinal tumor classified as dysplasia. The local intestinal tumor caused systemic detrimental effects on host including liver inflammation, hepatomegaly, growth defects, and organismal death. Whole-organismal level gene expression analysis and metabolite measurements revealed that the intestinal tumor reduced total BAs levels via down-regulation of hepatic cyp7a1. Genetically rescuing cyp7a1 expression in the liver restored the BAs 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-BAs metabolism, and liver inflammation in tumor-bearing fish. 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.