Promotion of Hepatocellular Carcinoma by the Intestinal Microbiota and TLR4

被引：1175

作者：

Dapito, Dianne H. ^{[1
,2
]}

Mencin, Ali ^{[3
]}

Gwak, Geum-Youn ^{[1
,7
]}

Pradere, Jean-Philippe ^{[1
]}

Jang, Myoung-Kuk ^{[1
]}

Mederacke, Ingmar ^{[1
]}

Caviglia, Jorge M. ^{[1
]}

Khiabanian, Hossein ^{[4
,5
]}

Adeyemi, Adebowale ^{[3
]}

Bataller, Ramon ^{[8
]}

Lefkowitch, Jay H. ^{[6
]}

Bower, Maureen ^{[9
]}

Friedman, Richard ^{[4
,5
]}

Sartor, R. Balfour ^{[9
]}

Rabadan, Raul ^{[4
,5
]}

Schwabe, Robert F. ^{[1
,2
,4
]}

机构：

[1] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY 10032 USA

[2] Columbia Univ, Inst Human Nutr, New York, NY 10032 USA

[3] Columbia Univ, Dept Pediat, New York, NY 10032 USA

[4] Columbia Univ, Herbert Irving Canc Ctr, New York, NY 10032 USA

[5] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA

[6] Columbia Univ, Dept Pathol, New York, NY 10032 USA

[7] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Med, Seoul 135710, South Korea

[8] Inst Invest Biomed August Pi & Sunyer, Hosp Clin, Liver Unit, Barcelona 08036, Spain

[9] Univ N Carolina, Div Gastroenterol & Hepatol, Dept Med, Chapel Hill, NC 27599 USA

来源：

CANCER CELL | 2012年 / 21卷 / 04期

关键词：

NF-KAPPA-B; HEPATOCYTE GROWTH-FACTOR; BACTERIAL TRANSLOCATION; HEPATIC-FIBROSIS; LIVER-CANCER; CIRRHOSIS; ACTIVATION; INFLAMMATION; TUMORIGENESIS; ENDOTOXIN;

D O I：

10.1016/j.ccr.2012.02.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma (HCC), a long-term consequence of chronic liver injury, inflammation, and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in non-bone-marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.

引用

页码：504 / 516

页数：13

共 48 条

[21] Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis [J].

Inokuchi, Sayaka ;

Aoyama, Tomonori ;

Miura, Kouichi ;

Oesterreicher, Christoph H. ;

Kodama, Yuzo ;

Miyai, Katsumi ;

Akira, Shizuo ;

Brenner, David A. ;

Seki, Ekihiro .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (02) :844-849

[22] Modulation of Hepatic Fibrosis by c-Jun-N-Terminal Kinase Inhibition [J].

Kluwe, Johannes ;

Pradere, Jean-Philippe ;

Gwak, Geum-Youn ;

Mencin, Ali ;

De Minicis, Samuele ;

Oesterreicher, Christoph H. ;

Colmenero, Jordi ;

Bataller, Ramon ;

Schwabe, Robert F. .

GASTROENTEROLOGY, 2010, 138 (01) :347-359

[23] ERK activation drives intestinal tumorigenesis in Apcmin/+ mice [J].

Lee, Sung Hee ;

Hu, Li-Li ;

Gonzalez-Navajas, Jose ;

Seo, Geom Seog ;

Shen, Carol ;

Brick, Jonathan ;

Herdman, Scott ;

Varki, Nissi ;

Corr, Maripat ;

Lee, Jongdae ;

Raz, Eyal .

NATURE MEDICINE, 2010, 16 (06) :665-U65

[24] Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling [J].

Levental, Kandice R. ;

Yu, Hongmei ;

Kass, Laura ;

Lakins, Johnathon N. ;

Egeblad, Mikala ;

Erler, Janine T. ;

Fong, Sheri F. T. ;

Csiszar, Katalin ;

Giaccia, Amato ;

Weninger, Wolfgang ;

Yamauchi, Mitsuo ;

Gasser, David L. ;

Weaver, Valerie M. .

CELL, 2009, 139 (05) :891-906

[25] ENDOTOXEMIA IN PATIENTS WITH CHRONIC LIVER-DISEASES - RELATIONSHIP TO SEVERITY OF LIVER-DISEASES, PRESENCE OF ESOPHAGEAL-VARICES, AND HYPERDYNAMIC CIRCULATION [J].

LIN, RS ;

LEE, FY ;

LEE, SD ;

TSAI, YT ;

LIN, HC ;

LU, RH ;

HSU, WC ;

HUANG, CC ;

WANG, SS ;

LO, KJ .

JOURNAL OF HEPATOLOGY, 1995, 22 (02) :165-172

[26] Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma [J].

Luedde, Tom ;

Beraza, Naiara ;

Kotsikoris, Vasileios ;

van Loo, Geert ;

Nenci, Arianna ;

De Vos, Rita ;

Roskams, Tania ;

Trautwein, Christian ;

Pasparakis, Manolis .

CANCER CELL, 2007, 11 (02) :119-132

[27] NF-κB in the liver-linking injury, fibrosis and hepatocellular carcinoma [J].

Luedde, Tom ;

Schwabe, Robert F. .

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, 2011, 8 (02) :108-118

[28] Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog [J].

Machida, Keigo ;

Tsukamoto, Hidekazu ;

Mkrtchyan, Hasmik ;

Duan, Lewei ;

Dynnyk, Alla ;

Liu, Helene Minyi ;

Asahina, Kinji ;

Govindarajan, Sugantha ;

Raye, Ratna ;

Ou, Jing-hsiung James ;

Seki, Ekihiro ;

Deshaies, Raymond ;

Miyake, Kensuke ;

Lai, Michael M. -C. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (05) :1548-1553

[29] IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis [J].

Maeda, S ;

Kamata, H ;

Luo, JL ;

Leffert, H ;

Karin, M .

CELL, 2005, 121 (07) :977-990

[30] Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production [J].

Naugler, Willscott E. ;

Sakurai, Toshiharu ;

Kim, Sunhwa ;

Maeda, Shin ;

Kim, KyoungHyun ;

Elsharkawy, Ahmed M. ;

Karin, Michael .

SCIENCE, 2007, 317 (5834) :121-124

← 1 2 3 4 5 →