The role of signaling pathways in the development and treatment of hepatocellular carcinoma

Oncogene. 2010 Sep 9;29(36):4989-5005. doi: 10.1038/onc.2010.236. Epub 2010 Jul 19.


Hepatocellular carcinoma (HCC) is a highly prevalent, treatment-resistant malignancy with a multifaceted molecular pathogenesis. Current evidence indicates that during hepatocarcinogenesis, two main pathogenic mechanisms prevail: (1) cirrhosis associated with hepatic regeneration after tissue damage caused by hepatitis infection, toxins (for example, alcohol or aflatoxin) or metabolic influences, and (2) mutations occurring in single or multiple oncogenes or tumor suppressor genes. Both mechanisms have been linked with alterations in several important cellular signaling pathways. These pathways are of interest from a therapeutic perspective, because targeting them may help to reverse, delay or prevent tumorigenesis. In this review, we explore some of the major pathways implicated in HCC. These include the RAF/MEK/ERK pathway, phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, WNT/beta-catenin pathway, insulin-like growth factor pathway, hepatocyte growth factor/c-MET pathway and growth factor-regulated angiogenic signaling. We focus on the role of these pathways in hepatocarcinogenesis, how they are altered, and the consequences of these abnormalities. In addition, we also review the latest preclinical and clinical data on the rationally designed targeted agents that are now being directed against these pathways, with early evidence of success.

Publication types

  • Review

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / etiology*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / therapy*
  • ErbB Receptors / genetics
  • ErbB Receptors / physiology
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / physiology
  • Humans
  • Liver Neoplasms / ethnology*
  • Liver Neoplasms / etiology*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Liver Neoplasms / therapy*
  • MAP Kinase Signaling System / physiology
  • Models, Biological
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / physiology
  • Receptors, Vascular Endothelial Growth Factor / genetics
  • Receptors, Vascular Endothelial Growth Factor / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Somatomedins / genetics
  • Somatomedins / physiology


  • HGF protein, human
  • Somatomedins
  • Hepatocyte Growth Factor
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-met
  • Receptors, Vascular Endothelial Growth Factor