Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Neumann, JHL.
Characterisation of Subtypes of Hepatocellular Carcinoma on the Basis of Gene-Expression Profiles.
[ Dissertation ] Medical University of Graz; 2004. pp.101.
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Lackner Karoline
- Mischinger Hans-Jörg
- Zatloukal Kurt
- Altmetrics:
- Abstract:
- Hepatocellular Carcinoma (HCC) is one of the most common human malignant neoplasms causing worldwide more than 400.000 deaths per year. Geographical variations in incidence and mortality correlate to different levels of exposure to risk factors. The main causes of HCC include chronic infection with hepatitis B or C viruses, chronic alcohol abuse and ingestion of aflatoxin B1. Mallory Bodies (MB) and Intracellular Hyaline Bodies (IHB) are cytoplasmatic inclusions in hepatocytes associated with a variety of neoplastic and non-neoplastic liver diseases. MB and IHB were found in almost 10.30% of investigated HCC. In addition to these morphological studies several immunohistochemical and molecular studies indicate that these cancers differ in their mechanisms of hepatocarcinogenesis. In our aim to identify molecular mechanisms underlying the pathogenesis of liver cancer and to identify new subgroups of HCC, we generated subtractive suppressive hypridization (SSH) cDNA libraries, highly enriched with clones representing genes both up- and down-regulated in diseased tissue. These libraries were generated from HCCs with different aetiologies and from a pool of non-neoplastic liver tissue. In addition to SSH clones, an exhaustive literature search was performed to identify genes known or suspected to be involved in carcinogenesis in general, and corresponding cDNA (IMAGE) clones were purchased. Inserts from 2,400 SSH and 2,125 IMAGE cDNAs were amplified and printed onto glass slides produce a focused HCC cDNA microarray. Cy5-labled cDNA from 8 HCC without inclusions, 2 HCC showing MB and 2 HCC showing IHB was compared with Cy3-labled cDNA from normal liver by competitive hybridization. About 410 genes consistently deregulated in these liver diseases were identified. Clustering analysis of these expression data led to the identification of 27 genes differentially expressed between HCC with and without inclusion bodies. Thus, HCC showing distinct morphological features such as inclusion bodies could be distinguished as a separate molecular entity on the basis of gene expression profiles. We could demonstrate that the presence of inclusion bodies in HCC is associated with various changes mainly in liver cell metabolism and detoxification. Moreover, it can be concluded that glucocorticoids may play a certain role in carcinogenesis of HCC with inclusion bodies. Even though the survival analysis did not show a difference in the subgroup our data indicate that these patients may show a diverse response to drugs metabolized by members of the CYP3A subfamily.