Toll-like receptor 4: a target for chemoprevention of hepatocellular carcinoma in obesity and steatohepatitis

Citations Over TimeTop 14% of 2018 papers

Abstract

// Jennifer Nguyen 1 , Jingjing Jiao 1 , Kristin Smoot 1 , Gordon P. Watt 1, 2 , Chen Zhao 1 , Xingzhi Song 3 , Heather L. Stevenson 4 , Joseph B. McCormick 2 , Susan P. Fisher-Hoch 2 , Jianhua Zhang 3 , P. Andrew Futreal 3 and Laura Beretta 1 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 University of Texas Health Science Center at Houston, School of Public Health in Brownsville, Brownsville, TX, USA 3 Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA Correspondence to: Laura Beretta, email: lberetta@mdanderson.org Keywords: toll-like receptor 4; chemoprevention; NAFLD; hepatocellular carcinoma; mouse model Received: April 07, 2018      Accepted: June 13, 2018      Published: June 29, 2018 ABSTRACT The incidence of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) is rapidly increasing. We aimed to elucidate the genetic basis of NAFLD-associated HCC and identify candidate targets for chemoprevention. Twenty HCC tumors, distant liver and matched tails from mice with hepatocyte-deletion of Pten (Hep Pten - ) were subjected to whole-exome sequencing. A total of 162 genes with somatic non-synonymous single nucleotide variants or exonic small insertions and deletions in tumors were identified. Ingenuity Pathway Analysis of these 162 genes, further identified Toll-like receptor (TLR) 4, a key mediator of proinflammatory responses, and resatorvid, a TLR4 inhibitor, as the main causal networks of this dataset. Resatorvid treatment strongly prevented HCC development in these mice ( p < 0.001). Remarkably, HCC patients with high tumoral TLR4 mRNA expression were more likely to be diagnosed with NAFLD and obese. TLR4 mRNA expression positively correlated with IL-6 and IL-10 mRNA expression in HCC tumors and the correlation was stronger in obese HCC patients. We have identified tumor mutation signatures and associated causal networks in NAFLD-associated HCC in Hep Pten - mice and further demonstrated the important role of TLR4 in promoting HCC development. This study also identified IL-6 and IL-10 as markers of TLR4 activation in HCC and subjects with NAFLD and obesity as the target population who would benefit from TLR4 inhibition treatment for HCC chemoprevention.

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