Gut flora disequilibrium promotes the initiation of liver cancer by modulating tryptophan metabolism and up-regulating SREBP2

被引：61

作者：

Chen, Wen ^{[1
,2
,3
]}

Wen, Liang ^{[1
,2
,3
,4
]}

Bao, Yingying ^{[1
,2
,3
]}

Tang, Zengwei ^{[1
,2
,3
]}

Zhao, Jianhui ^{[1
,2
,3
]}

Zhang, Xiaozhen ^{[1
,2
,3
]}

Wei, Tao ^{[1
,2
,3
,4
]}

Zhang, Jian ^{[1
,2
,3
,4
]}

Ma, Tao ^{[1
,2
,3
,4
]}

Zhang, Qi ^{[1
,2
,3
,4
]}

Zhi, Xiao ^{[1
,2
,3
,4
]}

Li, Jin ^{[1
,2
,3
]}

Zhang, Cheng ^{[1
,2
,3
]}

Ni, Lei ^{[1
,3
]}

Li, Muchun ^{[1
,3
]}

Liang, Tingbo ^{[1
,2
,3
,4
]}

机构：

[1] Zhejiang Univ, Affiliated Hosp 1, Zhejiang Prov Key Lab Pancreat Dis, Sch Med, Hangzhou 310003, Zhejiang, Peoples R China

[2] Zhejiang Clin Res Ctr Hepatobiliary & Pancreat Dis, Hangzhou 310009, Zhejiang, Peoples R China

[3] Zhejiang Univ, Canc Ctr, Hangzhou 310014, Zhejiang, Peoples R China

[4] Zhejiang Univ, Affiliated Hosp 1, Sch Med, Dept Hepatobiliary & Pancreat Surg, Hangzhou 310003, Zhejiang, Peoples R China

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2022年 / 119卷 / 52期

基金：

中国国家自然科学基金;

关键词：

gut microbiota; liver tumorigenesis; SREBP2; tryptophan metabolism; AhR; ARYL-HYDROCARBON RECEPTOR; INTESTINAL MICROBIOTA; INFLAMMATION; MECHANISMS; CELL;

D O I：

10.1073/pnas.2203894119

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri, which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2.

引用

页数：13

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