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Carcinogenesis Advance Access originally published online on June 15, 2005
Carcinogenesis 2005 26(11):1879-1889; doi:10.1093/carcin/bgi153
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Carcinogenesis vol.26 no.11 © Oxford University Press 2005; all rights reserved.

Differential transcriptional regulation of human telomerase in a cellular model representing important genetic alterations in esophageal squamous carcinogenesis

Michael Quante, Steffen Heeg, Alexander von Werder, Gitta Goessel, Christine Fulda, Michaela Doebele, Hiroshi Nakagawa 1, Roderick Beijersbergen 2, Hubert E. Blum and Oliver G. Opitz *

Department of Medicine and Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany, 1 Gastroenterology Division, University of Pennsylvania, Philadelphia, PA, USA and 2 Netherlands Cancer Institute, Amsterdam, The Netherlands

* To whom correspondence should be addressed at: Department of Medicine II and Institute of Molecular Medicine and Cell Research, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany. Email: opitz{at}med1.ukl.uni-freiburg.de

Telomerase activity is observed in ~90% of human cancer including esophageal squamous cell cancer. Normal somatic cells do not display telomerase activity on a regular basis. The major mechanism to regulate telomerase activity in human cells is the transcriptional control of the catalytic subunit, the human reverse transcriptase gene hTERT. However, the manner in which telomerase activity is regulated during malignant transformation and whether this regulation is influenced by single genetic alterations important in this process are not well understood. In this study we investigated the transcriptional regulation and activity of human telomerase in a cellular model representing important known genetic alterations observed in esophageal cancer. We characterized the respective cells with regard to their telomere biology and telomerase expression, transcriptional regulation using promoter- as well as electrophoretic mobility shift assay-analyses and their promoter methylation status. We could demonstrate that telomerase expression and subsequent activity are differentially regulated in the progression from normal esophageal epithelial cells to genetically defined esophageal cells harboring a specific genetic alteration frequently found in esophageal cancer and compared those changes with esophageal cancer cells. Whereas primary esophageal cells are mainly regulated by Sp1, in cells harboring a genetic alteration as cyclin D1 overexpression other transcription factors like E2F and c-myc as well as promoter methylation influence hTERT transcription. This model demonstrates that the transcriptional regulation of telomerase is influenced by a given genetic alteration important in esophageal cancer, and therefore provides new insight in telomerase regulation during carcinogenesis.


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