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Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma

Calvisi, Diego Francesco and Ladu, Sara and Gorden, Alexis and Farina, Miriam and Lee, Ju-Seog and Conner, Elizabeth A. and Schroeder, Insa S. and Factor, Valentina M. and Thorgeirsson, Snorri S. (2007) Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. The Journal of Clinical Investigation, Vol. 117 (9), p. 2713-2722. eISSN 1558-8238. Article.

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DOI: 10.1172/JCI31457

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, accounting for an estimated 600,000 deaths annually. Aberrant methylation, consisting of DNA hypomethylation and/or promoter gene CpG hypermethylation, is implicated in the development of a variety of solid tumors, including HCC. We analyzed the global levels of DNA methylation as well as the methylation status of 105 putative tumor suppressor genes and found that the extent of genome-wide hypomethylation and CpG hypermethylation correlates with biological features and clinical outcome of HCC patients. We identified activation of Ras and downstream Ras effectors (ERK, AKT, and RAL) due to epigenetic silencing of inhibitors of the Ras pathway in all HCC. Further, selective inactivation of SPRY1 and -2, DAB2, and SOCS4 and -5 genes and inhibitors of angiogenesis (BNIP3, BNIP3L, IGFBP3, and EGLN2) was associated with poor prognosis. Importantly, several epigenetically silenced putative tumor suppressor genes found in HCC were also inactivated in the nontumorous liver. Our results assign both therapeutic and chemopreventive significance to methylation patterns in human HCC and open the possibility of using molecular targets, including those identified in this study, to effectively inhibit HCC development and progression.

Item Type:Article
ID Code:777
Status:Published
Refereed:Yes
Uncontrolled Keywords:Hepatocellular carcinoma (HCC), Ras, methylation
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:The American Society for Clinical Investigation
eISSN:1558-8238
Publisher Policy:Depositato in conformità con la politica di copyright dell'Editore
Deposited On:18 Aug 2009 10:03

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