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

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Delire, Bénédicte [UCL] Starkel, Peter [UCL]

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.

Document type Article de périodique (Journal article) – Synthèse de littérature
Access type Accès restreint
Publication date 2015
Language Anglais
Journal information "European Journal of Clinical Investigation" - Vol. 45, no. 6, p. 609-623 (2015)
Peer reviewed yes
Publisher Wiley-Blackwell Publishing Ltd. ((United Kingdom) Oxford)
issn 0014-2972
e-issn 1365-2362
Publication status Publié
Affiliations UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie
UCL - (SLuc) Service d'hépato-gastro-entérologie
Links
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Bibliographic reference Delire, Bénédicte ; Starkel, Peter. The Ras/MAPK pathway and hepatocarcinoma: Pathogenesis and therapeutic implications. In: European Journal of Clinical Investigation, Vol. 45, no. 6, p. 609-623 (2015)
Permanent URL http://hdl.handle.net/2078.1/164412