Hepatocellular cancers can be sub-grouped into hepatocellular carcinomas (HCCs) and cholangiocarcinomas that affect mostly adults, and childhood hepatoblastomas. HCCs are the third most common cause of death from cancer, with more than one million patients dying worldwide each year. These tumors show extreme heterogeneity in their genomic aberrations and their epigenetic status is ill-defined. They are naturally resistant to chemotherapy and radiotherapy and the five-year survival rate of affected patients is very low. In order to discover new targets and new anti-tumor drugs, it is important to better characterize molecular mechanisms of hepatocellular cancers.RESEARCH INTERESTS
Our primary goal is to discover novel disease markers, genetic and epigenetic targets and to develop targeted therapies for hepatocellular cancers by exploring their genetic, epigenetic and phenotypic features. Currently, our major research interests are:
1- Mechanisms of escape from senescence-based growth control: we are using cell lines (in vitro and tumors generated in immunodeficient mice), as well as patient-derived material for these studies.
2- Epigenetics: we are using conditional knock-out mouse models for histone variants made available by Stefan Dimitrov (Institute Albert Bonniot, France) combined with “Sleeping Beauty transposon system based liver tumor models (in collaboration with Kasim Diril, iBG-izmir). Selected histone variant genes are deleted specifically in liver cells using a liver-specific promoter associated with 4OH-tamoxifen induction. We will examine the effects of histone variant gene ablations on liver development, regeneration, and carcinogenesis.
3- Cell surface proteins: Proteins that are aberrantly expressed on the surface of hepatocellular cancers will be explored by.RESEARCH HIGHLIGHTS
Our most recent findings concern senescence-related events associated with hepatocellular cancer cell immortalization. We used genome-wide expression analysis to identify sets of genes whose expression is associated with either senescence and cirrhosis or immortality and hepatocellular carcinoma. Surprisingly, a large number of gene sets were affected (Ozturk et al., PNAS 2006, Yildiz et al. PLoS ONE, 2013). We identified a gene signature that allowed us to differentiate HCC from cirrhosis (Yildiz et al. PLoS ONE 2013). More interestingly, we also identified another gene signature with an excellent prediction of patient survival (PATENT PENDING PCT/EP2014/058293).