The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications

Eur J Clin Invest. 2015 Jun;45(6):609-23. doi: 10.1111/eci.12441. Epub 2015 May 11.


Background: Hepatocellular carcinoma (HCC) is still a major health problem, often diagnosed at an advanced stage. The multikinase inhibitor sorafenib is to date the sole approved systemic therapy. Several signalling pathways are implicated in tumour development and progression. Among these pathways, the Ras/MAPK pathway is activated in 50-100% of human HCCs and is correlated with a poor prognosis. The aim of this work was to review the main intracellular mechanisms leading to aberrant Ras pathway activation in HCC and the potential therapeutic implications.

Materials and methods: This review is based on the material found on PubMed up to December 2014. 'Ras signaling, Ras dysregulation, Ras inhibition, MAPK pathway, cancer, hepatocarcinoma and liver cancer' alone or in combination were the main terms used for online research.

Results: Multiple mechanisms lead to the deregulation of the Ras pathway in liver cancer. Ras and Raf gene mutations are rare events in human hepatocarcinogenesis in contrast to experimental models in rodents. Downregulation of several Ras/MAPK pathway inhibitors such as GAPs, RASSF proteins, DUSP1, Sprouty and Spred proteins is largely implicated in the aberrant activation of this pathway in the context of wild-type Ras and Raf genes. Epigenetic or post-transcriptional mechanisms lead to the downregulation of these tumour suppressor genes.

Conclusion: Ras/MAPK pathway effectors may be considered as potential therapeutic targets in the field of HCC. In particular after the arrival of sorafenib, more Ras/MAPK inhibitors have emerged and are still in preclinical or clinical investigation for HCC therapy.

Keywords: Hepatocarcinogenesis; Ras dysregulation; Ras inhibitors; Ras signaling; human; liver cancer.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Apoptosis Regulatory Proteins
  • Carcinogenesis / metabolism
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / etiology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / physiology
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / etiology*
  • MAP Kinase Signaling System / physiology*
  • Membrane Proteins / physiology
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Monomeric GTP-Binding Proteins / physiology
  • Mutation / genetics
  • Niacinamide / analogs & derivatives
  • Niacinamide / therapeutic use
  • Phenylurea Compounds / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use
  • Rats
  • Sorafenib
  • Tumor Suppressor Proteins / physiology
  • raf Kinases / metabolism
  • ras GTPase-Activating Proteins / antagonists & inhibitors
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • RASSF1 protein, human
  • RASSF5 protein, human
  • SPRED1 protein, human
  • Tumor Suppressor Proteins
  • ras GTPase-Activating Proteins
  • Niacinamide
  • Sorafenib
  • raf Kinases
  • Mitogen-Activated Protein Kinases
  • Monomeric GTP-Binding Proteins
  • ras Proteins