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The laboratory investigates the role of telomerase in liver regeneration and the molecular pathogenesis of human hepatocellular carcinoma.
Telomeres are specialized high-order chromatin structures that protect chromosome ends against degradation by forming molecular caps. In addition to telomere-stabilizing proteins, telomeres consist of tens of kilo bases of telomeric repeats with the sequence 5'-TTAGGG-3'. In most somatic cells, cellular proliferation is associated with progressive telomere shortening. After a certain number of cell divisions, replication-associated telomere shortening renders telomeric caps unstable and chromosome ends unprotected. Cells with unstable chromosome ends activate their DNA damage response machinery with entry into cell cycle exit and replicative senescence, a post-mitotic and quiescent state. In contrast to somatic cells, human germ cells are capable of undergoing an infinite number of cell divisions. In these cells, the enzyme complex telomerase counterbalances telomere erosion by de novo synthesis of telomeric repeats onto chromosome ends. Telomerase consists of an RNA template for reverse transcription and the rate-limiting catalytic subunit TERT (telomerase reverse transcriptase).
Currently, the laboratory examines the kinetic and dynamic of telomerase regulation during liver regeneration and hepatocarcinogenesis. The highly sensitive RQ-TRAP (real-time quantitative telomeric repeat amplification protocol) allows the necessary monitoring of telomerase activity.
Various studies in epithelial tumours indicate that efficient telomere maintenance represents a prerequisite for the development of cancer from proliferating cells. In this study, we will employ telomerase-immortalized human hepatocytes as non-malignant cell culture model for proliferating liver cells. To study the susceptibility of telomerase-positive clones for malignant transformation and to identify the pathways involved, we will monitor the cells for cytogenetic changes in long-term culture with and without oxidative stress, and employ retroviral insertional mutagenesis to induce genetic alterations. Individual clones will be characterized in comparison to their non-transformed counterparts by molecular and cytogenetic techniques and by proteomics.
OA Dr. med. Henning Wege
hwege@uke.de
Phone 040/42803-5887, paper 149-0247
Building O58, 3rd Floor
Room 304 (laboratory) and 305 (office)
Laboratory: +49-40-7410-52945
Fax: +49-40-7410-59092
1. Wege H, Heim D, Lütgehetmann M, Dierlamm J, Lohse AW, Brümmendorf TH. Forced activation of #-catenin signaling supports the transformation of hTERT-immortalized human fetal hepatocytes. Mol Cancer Res 2011; in press.
2. Sass G, Klinger N, Sirma H, Hashemolhosseini S, Hellerbrand C, Neureiter D, Wege H, Ocker M, Tiegs G. Inhibition of experimental HCC growth in mice by use of the kinase inhibitor DMAT. Int J Oncol 2011; 39: 433-42.
3. Brassat U, Balabanov S, Bali D, Dierlamm J, Braig M, Hartmann U, Sirma H, Günes C, Wege H, Fehse B, Gontarewicz A, Dikomey E, Borgmann K, Brümmendorf TH. Functional p53 is required for effective execution of telomerase inhibition in BCR-ABL positive cells. Exp Hematol 2011; 39: 66-76.
4. Thill M, Berna MJ, Kunst F, Wege H, Strunnikova NV, Gordiyenko N, Grierson R, Richard G, Csaky KG. VEGFR-2 inhibitor SU5416 down-regulates telomerase activity and induces premature senescence in late-outgrowth endothelial progenitor cells from patients with neovascular AMD. Mol Vis 2011; 17: 85-98.
5. Benten D, Keller G, Quaas A, Schrader J, Gontarewicz A, Balabanov S, Braig M, Wege H, Moll J, Lohse AW, Brümmendorf TH. Aurora kinase inhibitor PHA-739358 suppresses growth of hepatocellular carcinoma in vitro and in a xenograft mouse model. Neoplasia 2009; 11: 934-44.
6. Haker B, Fuchs S, Dierlamm J, Brümmendorf TH, Wege H. Absence of oncogenic transformation despite acquisition of cytogenetic aberrations in long-term cultured telomerase-immortalized human fetal hepatocytes. Cancer Lett 2007; 256: 120-127.
7. Wege H, Müller A, Müller L, Petri S, Petersen J, Hillert C. Regeneration in pig livers by compensatory hyperplasia induces high levels of telomerase activity. Comp Hepatol 2007; 6: 6. (Open Access)
8. Shirahashi H, Wu J, Yamamoto N, Catana A, Wege H, Wager B, Okita K, Zern MA. Differentiation of human and mouse embryonic stem cells along a hepatocyte lineage. Cell Transplant 2004; 13: 197-211.
9. Wege H, Chui MS, Le HT, Strom SC, Zern MA. In vitro expansion of human hepatocytes is restricted by telomere-dependent replicative aging. Cell Transplant 2003; 12: 897-906.
10. Wege H, Chui MS, Le HT, Tran JM, Zern MA. SYBR Green real-time telomeric repeat amplification protocol for the rapid quantification of telomerase activity. Nucleic Acids Res 2003; 31: E3. (Open Access)
11. Wege H, Le HT, Chui MS, Liu L, Wu J, Giri R, Malhi H, Sappal BS, Kumaran V, Gupta S, Zern MA. Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential. Gastroenterology 2003; 124: 432-444.
12. Wu J, Lizarzaburu ME, Kurth MJ, Liu L, Wege H, Zern MA, Nantz MH. Cationic lipid polymerization as a novel approach for constructing new DNA delivery agents. Bioconjug Chem 2001; 12: 251-257.
1. Wege H, Brümmendorf TH. Telomere und Telomerase in Zellalterung und Karzinogenese. BioSpektrum 2010; 3:271-3.
2. Keller G, Brassat U, Braig M, Heim D, Wege H, Brümmendorf TH. Telomeres in chronic myeloid leukemia: impact for pathogenesis, disease progression and targeted therapy. Hematol Oncol 2009; 27: 123-9.
3. Heim D, Wege H. Hepatic stem and progenitor cells in liver diseases and hepatocarcinogenesis. Minerva Gastroenterol Dietol 2009; 55: 111-121.
4. Wege H, Brümmendorf TH. Telomerase activation in liver regeneration and hepatocarcinogenesis: Dr. Jekyll or Mr. Hyde? Curr Stem Cell Res Ther 2007; 2: 31-38.
5. Denzer U, Guthoff A, Wege H, Hillert C, Krupski-Berdien G. Das hepatozelluläre Karzinom. Hamburger Ärzteblatt 2006;4:207-213.
6. Wege H, Wu J, Santos RM, Zern MA. Hepatocyte-based therapies for liver diseases - novel strategies and updates. Jornal Português de Gastroenterologia 2001;8:134-142.
Wege H, Brümmendorf TH. Telomerase-Inhibitoren. In: Dempke W (Hrsg.). Molekulare Therapie in der Hämatologie/Onkologie. UNI-MED, Bremen, 2009. Seite 145-153.
WegeH, Wu J, Zern MA. Novel therapeutic modalities for hepatic diseases. In: Okita K (Hrsg.). Frontiers in Hepatology/Liver Cirrhosis. Springer-Verlag, Tokyo, 2001; Seite 17-29.
