MYC-regulated genes involved in liver cell dysplasia identified in a transgenic model of liver cancer.
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.
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.
Danele
D
Hunecke
Reinhard
R
Spanel
Florian
F
Länger
Suk Woo
SW
Nam
Juergen
J
Borlak
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020518:Focal Nodular Hyperplasia / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055106:Genome-Wide Association Study; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D017228:Hepatocyte Growth Factor