Bénédicte Delire1, Peter Stärkel1,2. 1. Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Catholic University of Louvain, Brussels, Belgium. 2. Department of Gastroenterology, Saint-Luc Academic Hospital and Institute of Clinical Research, Catholic University of Louvain, Brussels, Belgium.
Abstract
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.
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 humanhepatocarcinogenesis 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.
Authors: Li Che; Maria G Pilo; Antonio Cigliano; Gavinella Latte; Maria M Simile; Silvia Ribback; Frank Dombrowski; Matthias Evert; Xin Chen; Diego F Calvisi Journal: Cell Cycle Date: 2017-01-24 Impact factor: 4.534
Authors: Julia Weber; Rupert Öllinger; Mathias Friedrich; Ursula Ehmer; Maxim Barenboim; Katja Steiger; Irina Heid; Sebastian Mueller; Roman Maresch; Thomas Engleitner; Nina Gross; Ulf Geumann; Beiyuan Fu; Angela Segler; Detian Yuan; Sebastian Lange; Alexander Strong; Jorge de la Rosa; Irene Esposito; Pentao Liu; Juan Cadiñanos; George S Vassiliou; Roland M Schmid; Günter Schneider; Kristian Unger; Fengtang Yang; Rickmer Braren; Mathias Heikenwälder; Ignacio Varela; Dieter Saur; Allan Bradley; Roland Rad Journal: Proc Natl Acad Sci U S A Date: 2015-10-27 Impact factor: 11.205