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 (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.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide [1]
This study identified IL-6 and IL-10 as markers of toll like receptor 4 (TLR4) activation in hepatocellular carcinoma (HCC) and subjects with non-alcoholic fatty liver disease (NAFLD) and obesity as the target population who would benefit from TLR4 inhibition treatment for HCC chemoprevention
Whole-exome sequencing of HCCs and Ingenuity Pathway Analysis identified TLR4 as a candidate target for HCC prevention in HepPten- mice
Summary
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide [1]. In the United States, HCC incidence and mortality rates are rapidly increasing, in part due to the epidemics of obesity and diabetes, leading to non-alcoholic fatty liver disease (NAFLD) [2, 3]. NAFLD is a spectrum of diseases that begins with simple steatosis and eventually progresses to steatohepatitis (NASH), leading to cirrhosis and HCC [4]. Most patients with HCC are diagnosed at an advanced stage when limited treatment options are available, often due to the presence of cirrhosis and poor liver function. The development of novel therapeutic options for the treatment of NASH and prevention of HCC is urgently needed [5, 6]. We performed wholeexome sequencing on tumors and used Ingenuity Pathway www.oncotarget.com
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