Role of N-cadherin in proliferation, migration, and invasion of germ cell tumours

// Felix Bremmer 1, * , Simon Schallenberg 1, * , Hubertus Jarry 2 , Stefan Küffer 1 , Silke Kaulfuss 3 , Peter Burfeind 3 , Arne Strauß 4 , Paul Thelen 4 , Heinz Joachim Radzun 1 , Philipp Ströbel 1 , Friedemann Honecker 5, 6 , Carl Ludwig Behnes 1 1 Institute of Pathology, University of Göttingen, Göttingen, Germany 2 Department of Endocrinology, University Medical Center Göttingen, Göttingen, Germany 3 Department of Human Genetics, University of Göttingen, Göttingen, Germany 4 Department of Urology, University of Göttingen, Göttingen, Germany 5 Department of Oncology, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany 6 Tumour and Breast Center ZeTuP, St. Gallen, Switzerland * These authors have contributed equally to this work Correspondence to: Felix Bremmer, e-mail: felix.bremmer@med.uni-goettingen.de Keywords: N-cadherin, cisplatin resistance, germ cell tumours, GCT-cell lines Received: July 07, 2015 Accepted: September 22, 2015 Published: October 02, 2015 ABSTRACT 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.