Endotoxin Accumulation Prevents Carcinogen-Induced... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Endotoxin Accumulation Prevents Carcinogen-Induced Apoptosis and Promotes Liver Tumorigenesis in Rodents

Yu, Le-Xing1,**; Yan, He-Xin1,**; Liu, Qiong1; Yang, Wen1; Wu, Hong-Ping1; Dong, Wei1; Tang, Liang1; Lin, Yan1; He, Ya-Qin1; Zou, Shan-Shan1; Wang, Chao1; Zhang, Hui-Lu1; Cao, Guang-Wen1,3; Wu, Meng-Chao1; Wang, Hong-Yang1,2,*

1_International Cooperation Laboratory on Signal Transduction, Liver Centre of SMMU, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China_

2_National Laboratory for Oncogene and Related Genes, Cancer Institute of Shanghai Jiao Tong University, Shanghai, China_

3_Department of Epidemiology, Second Military Medical University, Shanghai, China_

*Address reprint requests to: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China. E-mail:[email protected]; fax: 86 21 6556 6851

Received 9 March 2010; accepted 5 June 2010

Supported by National Natural Science Foundation of China grant no. (30871293, 30921006). Chinese National Programs for High Technology Research and Development grant no. (2007AA02Z166). Chinese National Key Project grant no. (2008ZX10002). Shanghai Young Scholars grant Grant number: 07QA14070; Grant number 07SG45; Grant number 08400701000.

**These authors contributed equally to this work.

View this article online atwileyonlinelibrary.com.

Additional Supporting Information may be found in the online version of this article.

Abstract

Increasing evidence suggests that the presence of endotoxemia is of substantial clinical relevance to patients with cirrhosis, but it is unclear whether and how gut-derived LPS amplifies the tumorigenic response of the liver. We found that the circulating levels of LPS were elevated in animal models of carcinogen-induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor Toll-like receptor 4 (TLR4) in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen-induced toxicity via blocking NF-κB activation and sensitizing the liver to reactive oxygen species (ROS)-induced toxicity, but lessens inflammation-mediated compensatory proliferation. Reconstitution of TLR4 -expressing myeloid cells in TLR4 -deficient mice restored diethylnitrosamine (DEN)-induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. Meanwhile, deletion of gut-derived endotoxin suppressed DEN-induced cytokine production and compensatory proliferation, whereas in vivo LPS pre-challenge promotes hepatocyte proliferation.

Conclusion:

Our data indicate that sustained LPS accumulation represents a pathological mediator of inflammation-associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in patients with cirrhosis who are at risk of developing HCC. (Hepatology 2010.)