Volume 228, Issue 4 p. 520-533
Original Paper

MYC-regulated genes involved in liver cell dysplasia identified in a transgenic model of liver cancer

Danele Hunecke

Danele Hunecke

Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany

Department of Molecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Strasse 1, 30625 Hannover, Germany

Search for more papers by this author
Reinhard Spanel

Reinhard Spanel

Institute of Pathology, Viersen, Germany

Search for more papers by this author
Florian Länger

Florian Länger

Department of Pathology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany

Search for more papers by this author
Suk Woo Nam

Corresponding Author

Suk Woo Nam

Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, Korea

Professor Juergen Borlak, Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. e-mail: [email protected]

Suk Woo Nam, Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail: [email protected]

Search for more papers by this author
Juergen Borlak

Corresponding Author

Juergen Borlak

Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany

Department of Molecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Strasse 1, 30625 Hannover, Germany

Professor Juergen Borlak, Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. e-mail: [email protected]

Suk Woo Nam, Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail: [email protected]

Search for more papers by this author
First published: 31 May 2012
Citations: 29

No conflicts of interest were declared.

Abstract

Foci of liver cell dysplasia (LCD) are distinct morphological entities and may evolve into hepatocellular carcinomas (HCCs). While most HCCs overexpress c-Myc, its role in LCD remains uncertain. Therefore, a c-Myc transgenic model of HCC was investigated to understand the genetic events forcing liver cells into dysplasia and subsequent malignant transformation. Specifically, whole genome scans enabled fingerprinting of genes at different stages of disease, ie LCD and HCC, while laser microdissected LCD lesions were used to validate regulation of candidate genes by quantitative real-time RT-PCR, ie Mybbp1a, Rps7, Rps19, Rpl10a, Skp1a, Tfdp1, Nhp2, and Bola2. EMSA band shift assays confirmed c-Myc DNA binding at regulatory sequences of candidate gene-specific promoters. Additionally, published ChIP-seq data helped to define the candidate genes as c-Myc bona fide targets. Treatment of the human hepatoma cell line HepG2 with hepatic growth factor (Hgf) caused c-Myc protein induction and transcriptional up-regulation of candidate genes, albeit at different levels when individual genes were compared. A significant increase of HepG2 entering the G1-phase was associated with up-regulation of the candidate genes in an Hgf concentration-dependent matter. Finally, we confirmed regulation of candidate genes in patients' samples with low- and high-grade dysplasia and HCC staged T1 to T3, while their expression was unchanged in focal nodular hyperplasia and hepatic adenoma, therefore asserting the diagnostic value and clinical significance of these candidate genes. Overall, novel c-Myc targeted genes were identified and may contribute to hepatocyte transformation by altering cell cycle control, thereby contributing to c-Myc's oncogenic activity. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.