Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning

Nat Med. 2003 Apr;9(4):416-23. doi: 10.1038/nm843. Epub 2003 Mar 17.


Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies. Its high mortality rate is mainly a result of intra-hepatic metastases. We analyzed the expression profiles of HCC samples without or with intra-hepatic metastases. Using a supervised machine-learning algorithm, we generated for the first time a molecular signature that can classify metastatic HCC patients and identified genes that were relevant to metastasis and patient survival. We found that the gene expression signature of primary HCCs with accompanying metastasis was very similar to that of their corresponding metastases, implying that genes favoring metastasis progression were initiated in the primary tumors. Osteopontin, which was identified as a lead gene in the signature, was over-expressed in metastatic HCC; an osteopontin-specific antibody effectively blocked HCC cell invasion in vitro and inhibited pulmonary metastasis of HCC cells in nude mice. Thus, osteopontin acts as both a diagnostic marker and a potential therapeutic target for metastatic HCC.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Algorithms
  • Animals
  • Artificial Intelligence
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / pathology
  • Carcinoma, Hepatocellular* / virology
  • Female
  • Gene Expression Profiling*
  • Hepatitis B virus / isolation & purification
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / pathology
  • Liver Neoplasms* / virology
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neoplasm Metastasis / genetics
  • Osteopontin
  • Sialoglycoproteins / genetics*
  • Sialoglycoproteins / immunology


  • SPP1 protein, human
  • Sialoglycoproteins
  • Spp1 protein, mouse
  • Osteopontin