Genetics and Epigenetics of Hepatocellular Cancers
Evin Özen-İşcan, Post-Doc
Umur Keleş, DVM, PhD Student
Umut Ekin, PhD Student
Aybike Erdoğan, PhD Student
Tuğçe Batur, PhD Student
Özden Öz, PhD Student
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.
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.
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).
|AWARDS AND RECOGNITION
• Gold Muller Honor Award (2016), by Journal of Pharmacist.
• Koç Award for Health Sciences (2004) to the Department of Molecular Biology and Genetics of Bilkent University, Turkey.
• Member of TWAS (Academy of Sciences for the Developing World), since 1996
• Member of EMBO (European Molecular Biology Organization), since 1994
• Member of TUBA (Turkish Academy of Sciences), since 1995
• TÜBİTAK-TWAS Science Award (1995), Turkey
Full list and citations: Google Scholar: Mehmet Ozturk
• Cevik D, Yildiz G, Ozturk M. Common telomerase reverse transcriptase promoter mutations in hepatocellular carcinomas from different geographical locations. World Journal of Gastroenterology 21:311, 2015
• Yildiz G, Arslan-Ergul A, Bagislar S, Konu O, Yuzugullu H, Gursoy- Yuzugullu O, Ozturk N, Ozen C, Ozdag H, Erdal E, Karademir S, Sagol O, Mizrak D, Bozkaya H, Ilk HG, Ilk O, Bilen B, Cetin-Atalay R, Akar N, Ozturk M. Genome-Wide Transcriptional Reorganization Associated with Senescence-to-Immortality Switch during Human Hepatocellular Carcinogenesis. PLoS One 8: e64016, 2013.
• Ceran C, Cokol M, Cingoz, Tasan I, Ozturk M, Yagci T. Novel anti- HER2 monoclonal antibodies: synergy and antagonism with tumor necrosis factor-α. BMC Cancer 12:450, 2012.
• Gursoy-Yuzugullu O, Yuzugullu H, Yilmaz M, Ozturk M. Aflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activation. Liver International 31:561-571, 2011.
• Mumcuoglu M, Bagislar S, Yuzugullu H, Alotaibi H, Senturk S, Telkoparan P, Gur-Dedeoglu B, Cingoz B, Bozkurt B, Tazebay senescent progeny as a mechanism underlying breast cancer cell heterogeneity. PLOS ONE 5(6) :e11288, 2010.
• Senturk S, Mumcuoglu M, Gursos-Yuzugullu O, Cingoz B, Akcalı KC, Ozturk M. Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth.
• Alotaibi H, Ricciardone MD and Ozturk M. Homozygosity at variant MLH1 can lead to secondary mutation in NF1, Neurofibromatosis Type I and Early Onset Leukemia. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 637:209-214, 2008.
• Ozturk N, Erdal E, Mumcuoglu M, Akcali KC, Yalcin O, Senturk S, Arslan-Ergul A, Gur B, Yulug I, Cetin-Atalay R, Yakicier C, Yagci T, Tez M, Ozturk M. Reprogramming of replicative senescence in hepatocellular carcinoma-derived cells. Proceedings of National Academy of Sciences USA 103:2178-2183, 2006.
|PATENT (last 5 years)
• PATENT PENDING PCT/EP2014/058293. Methods for diagnosis and monitoring the response to treatment of hepatocellular carcinoma. B element (Rennes, FR), C Coulouarn (Rennes, FR), M Ozturk (Grenoble, FR). European Patent Office.