TY - JOUR
T1 - Toll-like receptor 4
T2 - A target for chemoprevention of hepatocellular carcinoma in obesity and steatohepatitis
AU - Nguyen, Jennifer
AU - Jiao, Jingjing
AU - Smoot, Kristin
AU - Watt, Gordon P.
AU - Zhao, Chen
AU - Song, Xingzhi
AU - Stevenson, Heather L.
AU - McCormick, Joseph B.
AU - Fisher-Hoch, Susan P.
AU - Zhang, Jianhua
AU - Andrew Futreal, P.
AU - Beretta, Laura
N1 - Funding Information:
We would like to thank Dr. Erika J Thompson and Dr. Hongli Tang from the Sequencing and Microarray Facility and Dr. Xizeng Mao from the Department of Genomic Medicine for their help in sequencing and data analysis. The study was supported by the NIH/NCI under award number P30CA016672 and use of the Sequencing and Microarray Facility, by UTHealth Innovation for Cancer Prevention Research Training Program Post-doctoral Fellowship (Cancer Prevention and Research Institute of Texas grant # RP160015, to J.J), by CPRIT-CURE Summer Undergraduate Program at MD Anderson (to K.S), by a cancer prevention fellowship supported by the National Cancer Institute (grant R25E CA056452, to G.W), by the Trans-Texas HCC Study and a Start-Up fund from The University of Texas MD Anderson Cancer Center (to L.B).
Publisher Copyright:
© Nguyen et al.
PY - 2018/6/29
Y1 - 2018/6/29
N2 - 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 hepatocytedeletion 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.
AB - 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 hepatocytedeletion 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.
KW - Chemoprevention
KW - Hepatocellular carcinoma
KW - Mouse model
KW - NAFLD
KW - Toll-like receptor 4
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U2 - 10.18632/oncotarget.25685
DO - 10.18632/oncotarget.25685
M3 - Article
C2 - 30034633
AN - SCOPUS:85049225215
SN - 1949-2553
VL - 9
SP - 29495
EP - 29507
JO - Oncotarget
JF - Oncotarget
IS - 50
ER -