Toll-like receptor 4: a target for chemoprevention of hepatocellular carcinoma in obesity and steatohepatitis
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Jennifer Nguyen1, Jingjing Jiao1, Kristin Smoot1, Gordon P. Watt1,2, Chen Zhao1, Xingzhi Song3, Heather L. Stevenson4, Joseph B. McCormick2, Susan P. Fisher-Hoch2, Jianhua Zhang3, P. Andrew Futreal3 and Laura Beretta1
1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2University of Texas Health Science Center at Houston, School of Public Health in Brownsville, Brownsville, TX, USA
3Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA
Laura Beretta, email: [email protected]
Keywords: toll-like receptor 4; chemoprevention; NAFLD; hepatocellular carcinoma; mouse model
Received: April 07, 2018 Accepted: June 13, 2018 Published: June 29, 2018
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 (HepPten-) 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 HepPten- 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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