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

European Journal of Clinical Investigation - Tập 45 Số 6 - Trang 609-623 - 2015
Bénédicte Delire1, Peter Stärkel2,3
1Laboratory of Hepato‐Gastroenterology Institut de Recherche Expérimentale et Clinique (IREC) Catholic University of Louvain Brussels Belgium
2Department of Gastroenterology Saint‐Luc Academic Hospital and Institute of Clinical Research Catholic University of Louvain Brussels Belgium
3Department of Gastroenterology, Saint-Luc Academic Hospital and Institute of Clinical Research, Catholic University of Louvain, Brussels, Belgium

Tóm tắt

AbstractBackground

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.

Từ khóa


Tài liệu tham khảo

10.1016/S1590-8658(10)60507-5

10.1053/j.gastro.2007.04.061

10.1016/S1535-6108(04)00058-3

10.1016/j.jhep.2011.12.001

10.1056/NEJMoa0708857

10.1016/j.jhep.2009.12.034

10.1002/hep.22506

10.1007/s00204-012-0931-2

10.1002/hep.510270409

10.1053/j.gastro.2006.01.006

10.1006/bbrc.1997.6840

10.1016/j.lab.2005.10.003

10.1111/j.1872-034X.2011.00792.x

10.1007/s00109-014-1177-7

10.1038/sj.onc.1210415

10.1002/hep.27539

10.3390/ijms140510143

10.1016/j.gde.2006.12.004

10.1016/j.bbamcr.2007.01.012

10.1038/sj.onc.1210421

10.4161/sgtp.1.1.12178

10.1038/sj.onc.1207111

10.1016/j.febslet.2014.02.041

10.1128/MCB.20.9.3079-3085.2000

10.1007/s00418-004-0725-6

10.1002/hep.23681

10.1158/0008-5472.CAN-07-6157

10.1016/S0959-440X(02)00007-6

10.1038/nature04869

10.1097/CCO.0000000000000088

10.1016/j.semcancer.2010.10.011

10.1186/1471-230X-3-19

10.1111/j.1478-3231.2004.0940.x

10.1002/hep.510260615

10.1593/neo.05373

10.1016/j.ejso.2011.01.023

10.1016/j.jhep.2010.06.036

10.1177/1947601911411084

10.1093/carcin/18.1.59

10.1007/s00595-012-0462-8

10.1073/pnas.88.3.911

10.1016/0300-483X(95)03112-S

10.1158/0008-5472.CAN-03-2123

10.1073/pnas.87.3.1104

10.1054/bjoc.2000.1675

Froment O, 1994, Mutagenesis of ras proto‐oncogenes in rat liver tumors induced by vinyl chloride, Cancer Res, 54, 5340

Boivin‐Angele S, 2000, Ras gene mutations in vinyl chloride‐induced liver tumours are carcinogen‐specific but vary with cell type and species, Int J Cancer, 85, 223, 10.1002/(SICI)1097-0215(20000115)85:2%3C223::AID-IJC12%3E3.0.CO;2-H

10.1016/j.jbior.2014.04.002

10.1073/pnas.0700153104

10.1038/nrc2960

10.1016/j.jhep.2006.11.012

10.1111/j.1440-1746.2011.07049.x

10.1128/MCB.01090-07

10.1186/1471-230X-10-125

10.1074/jbc.M114.609537

10.1038/sj.onc.1206191

10.1074/jbc.M511837200

10.1186/1471-2407-6-89

10.1093/carcin/bgn170

10.1007/s12072-010-9164-8

10.1038/sj.onc.1206338

10.1186/1471-2407-2-29

10.1155/2012/849874

10.1158/1078-0432.CCR-06-1900

10.1016/j.jhep.2005.12.017

10.1172/JCI31457

10.1007/s11596-009-0309-8

10.1038/sj.onc.1209635

10.1016/j.bbrc.2011.06.068

10.4161/cbt.11.1.14176

10.1007/s10555-014-9497-1

10.1002/jso.22095

10.1158/0008-5472.CAN-05-1072

10.1002/hep.22169

10.1016/j.jhep.2012.04.026

10.1136/gut.52.5.706

10.1038/nature00766

10.1016/j.mrfmmm.2007.08.015

10.1038/sj.onc.1208265

10.1038/cddis.2011.136

10.1016/j.hepres.2004.02.009

10.1002/hep.510270425

10.1615/ForumImmunDisTher.v2.i2.110

10.1053/j.gastro.2006.07.012

Schuierer MM, 2006, Raf kinase inhibitor protein is downregulated in hepatocellular carcinoma, Oncol Rep, 16, 451

10.1186/1756-8722-3-8

10.1038/sj.onc.1202367

10.1002/hep.21551

10.1038/onc.2008.163

10.1002/ijc.24950

10.1158/0008-5472.CAN-09-1482

10.1155/2012/328372

10.1038/labinvest.3700427

10.1074/jbc.M301854200

10.1002/ijc.23720

10.3181/0901-MR-40

10.1016/j.molonc.2014.03.020

10.1002/ijc.23954

10.1002/ijc.27627

10.1042/BST20110609

10.4161/cc.25099

10.1242/jcs.115.6.1189

10.1083/jcb.200109037

10.1016/j.ceb.2003.10.006

10.3390/ijms141020768

10.1158/0008-5472.CAN-06-1377

10.18632/oncotarget.240

10.18632/oncotarget.466

10.1016/j.ejca.2009.04.014

10.1002/mc.20849

10.1186/1476-4598-9-256

10.1038/cddis.2012.200

10.1016/j.ejmech.2013.11.018

10.1002/jcp.24148

10.1007/s00280-013-2269-8

10.1002/ijc.25864

Ravi S, 2014, Regorafenib: an evidence‐based review of its potential in patients with advanced liver cancer, Core Evid, 9, 81

10.1159/000343850

10.1016/j.pharmthera.2013.10.001

10.1158/1535-7163.MCT-06-0436

10.1593/neo.13812

10.1200/JCO.2010.33.9432

10.1158/1535-7163.MCT-07-0162

10.1002/cncr.24863

10.1016/j.jhep.2009.10.008

10.3748/wjg.v19.i37.6144

10.1007/s10620-014-3058-x

10.1111/j.1440-1746.2012.07096.x

10.1016/S1590-8658(10)60515-4

10.1002/cncr.22652

10.1158/1541-7786.MCR-12-0665

10.3892/or.2013.2848

10.1007/s13277-013-1184-2

Thông tin
Thông tin xuất bản

European Journal of Clinical Investigation

Tập 45 Số 6

609-623

Thông tin tác giả