Role of N-cadherin in proliferation, migration, and invasion of germ cell tumours
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Felix Bremmer1,*, Simon Schallenberg1,*, Hubertus Jarry2, Stefan Küffer1, Silke Kaulfuss3, Peter Burfeind3, Arne Strauß4, Paul Thelen4, Heinz Joachim Radzun1, Philipp Ströbel1, Friedemann Honecker5,6, Carl Ludwig Behnes1
1Institute of Pathology, University of Göttingen, Göttingen, Germany
2Department of Endocrinology, University Medical Center Göttingen, Göttingen, Germany
3Department of Human Genetics, University of Göttingen, Göttingen, Germany
4Department of Urology, University of Göttingen, Göttingen, Germany
5Department of Oncology, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
6Tumour and Breast Center ZeTuP, St. Gallen, Switzerland
*These authors have contributed equally to this work
Felix Bremmer, e-mail: [email protected]
Keywords: N-cadherin, cisplatin resistance, germ cell tumours, GCT-cell lines
Received: July 07, 2015 Accepted: September 22, 2015 Published: October 02, 2015
Germ cell tumors (GCTs) are the most common malignancies in young men. Most patients with GCT can be cured with cisplatin-based combination chemotherapy, even in metastatic disease. In case of therapy resistance, prognosis is usually poor. We investigated the potential of N-cadherin inhibition as a therapeutic strategy. We analyzed the GCT cell lines NCCIT, NTERA-2, TCam-2, and the cisplatin-resistant sublines NCCIT-R and NTERA-2R. Effects of a blocking antibody or siRNA against N-cadherin on proliferation, migration, and invasion were investigated. Mouse xenografts of GCT cell lines were analyzed by immunohistochemistry for N-cadherin expression. All investigated GCT cell lines were found to express N-cadherin protein in vitro and in vivo. Downregulation of N-cadherin in vitro leads to a significant inhibition of proliferation, migration, and invasion. N-cadherin-downregulation leads to a significantly higher level of pERK. N-cadherin-inhibition resulted in significantly higher rates of apoptotic cells in caspase-3 staining. Expression of N-cadherin is preserved in cisplatin-resistant GCT cells, pointing to an important physiological role in cell survival. N-cadherin-downregulation results in a significant decrease of proliferation, migration, and invasion and stimulates apoptosis in cisplatin-naive and resistant GCT cell lines. Therefore, targeting N-cadherin may be a promising therapeutic approach, particularly in cisplatin-resistant, therapy refractory and metastatic GCT.
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