A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor–liver crosstalk in causing adverse effects on the host
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 bi...
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The Company of Biologists
2018-08-01
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doaj-49ecf0fd3ee4478abf83741a202e15212020-11-24T21:23:02ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-08-0111810.1242/dmm.032383032383A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor–liver crosstalk in causing adverse effects on the hostSora Enya0Koichi Kawakami1Yutaka Suzuki2Shinpei Kawaoka3Almut SchulzeMariia Yuneva Advanced Telecommunications Research Institute International (ATR), The Thomas N. Sato BioMEC-X Laboratories, Kyoto 619-0288, Japan Division of Molecular and Developmental Biology, National Institute of Genetics, and Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), Mishima, Shizuoka 411-8540, Japan The University of Tokyo, Graduate School of Frontier Science, Kashiwa 277-8651, Japan Advanced Telecommunications Research Institute International (ATR), The Thomas N. Sato BioMEC-X Laboratories, Kyoto 619-0288, Japan 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.http://dmm.biologists.org/content/11/8/dmm032383Intestinal tumorHepatomegalyLiver inflammationGrowth defectcyp7a1Cholesterol metabolism |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sora Enya Koichi Kawakami Yutaka Suzuki Shinpei Kawaoka Almut Schulze Mariia Yuneva |
spellingShingle |
Sora Enya Koichi Kawakami Yutaka Suzuki Shinpei Kawaoka Almut Schulze Mariia Yuneva 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 Intestinal tumor Hepatomegaly Liver inflammation Growth defect cyp7a1 Cholesterol metabolism |
author_facet |
Sora Enya Koichi Kawakami Yutaka Suzuki Shinpei Kawaoka Almut Schulze Mariia Yuneva |
author_sort |
Sora Enya |
title |
A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor–liver crosstalk in causing adverse effects on the host |
title_short |
A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor–liver crosstalk in causing adverse effects on the host |
title_full |
A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor–liver crosstalk in causing adverse effects on the host |
title_fullStr |
A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor–liver crosstalk in causing adverse effects on the host |
title_full_unstemmed |
A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor–liver crosstalk in causing adverse effects on the host |
title_sort |
novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor–liver crosstalk in causing adverse effects on the host |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2018-08-01 |
description |
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. |
topic |
Intestinal tumor Hepatomegaly Liver inflammation Growth defect cyp7a1 Cholesterol metabolism |
url |
http://dmm.biologists.org/content/11/8/dmm032383 |
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