Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition

Cancer Cell. 2016 Dec 12;30(6):879-890. doi: 10.1016/j.ccell.2016.11.004.


Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention.

Keywords: cancer chemoprevention; gene signature; hepatocellular carcinoma; prognostic prediction; transcriptome.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / prevention & control*
  • Cell Line, Tumor
  • Gene Expression Profiling / methods*
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease
  • Humans
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / genetics*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / prevention & control*
  • Lysophospholipids / biosynthesis*
  • Rats
  • Risk Factors
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Lysophospholipids
  • lysophosphatidic acid