No abstract

Pim-1 is an oncogenic serine/threonine kinase with poorly defined function in epithelial cancers. In this study, we determined 1) associations of Pim-1 expression with clinicopathological parameters including responsiveness to irradiation in squamocellular cancers of head and neck and 2) how Pim-1 expression is controlled subsequent to irradiation. Moderate to high expression of Pim-1 correlated to poor response to radiation therapy (P = .003). It is also associated to the expression of epidermal growth factor receptor (EGFR, P < .0001), which has been shown to be activated by irradiation. In radioresistant tumors, irradiation promoted nuclear translocation of Pim-1 (P < .005). When directly testing EGFR dependence of Pim-1 expression, up-regulation and nuclear translocation of Pim-1 could be induced through stimulation of EGFR with its ligands EGF or transforming growth factor alpha. Both ligand- and irradiation-induced changes in Pim-1 expression and localization could be inhibited by the monoclonal anti-EGFR antibody cetuximab and by the tyrosine kinase inhibitor gefitinib also targeting EGFR. These results suggest that irradiation-induced activation of EGFR upregulates Pim-1, and Pim-1 may be used as a novel predictive marker of radiation response in patients with squamocellular cancers of head and neck.

Vascular adhesion protein 1 (VAP-1) is an endothelial adhesion molecule with an enzymatic activity. It deaminates biogenic amines, resulting in the formation of aldehydes and hydrogen peroxide. During the enzymatic reaction a transient Schiff base is formed between endothelial VAP-1 and its leukocytic ligand, and this interaction is important for lymphocyte adhesion. VAP-1 monomer has six potential N-linked, and three putative O-linked glycosylation sites and an SSSS sequence potentially forming an attachment site for an adjacent O-linked site. In this work we modeled the carbohydrate decorations on a structural model of VAP-1, and studied which of those potential glycosylation sites are utilized, and whether those decorations accessible to a lymphocyte ligand are important in lymphocyte adhesion and enzymatic activity of VAP-1. We show that, unlike the O-linked attachment sites, all six N-linked glycosylation sites are in use. Furthermore, mutation of the N-linked attachment sites strategically located on the top of the molecule reduces lymphocyte adhesion in non-static conditions, and enhances the catalytic activity of membrane-bound human VAP-1 in static conditions, suggesting that glycosylation regulates the functional properties of VAP-1.

Summary In many malignant diseases the expression levels of CD44 and its splice variant v6 (CD44v6) have been associated with the prognosis. The purpose of this study was to investigate the clinical significance of CD44 in adult soft tissue sarcomas (STS). 133 STS patients with a limb or superficial trunk tumour treated at the Helsinki University Central Hospital in 1987-1993 with a median follow-up time of 68 months were included in this study. The expression of CD44 and CD44v6 was determined immunohistochemically on paraffin-embedded tumour samples. 95% of the tumours expressed CD44 and CD44v6 was detected in 57%. Strong CD44 expression was associated with low grade (P = 0.04) and small tumour size (P = 0.02). In diploid tumours the CD44 expression was correlated with low S-phase fraction (P = 0.001). High expression of both, CD44 in general as well as that of CD44v6, predicted a higher risk for local recurrence (CD44: P = 0.01 and CD44v6: P = 0.05). Low CD44v6 content of the primary tumour correlated with poor survival (P = 0.02). Determining the expression of CD44 or CD44v6 in a primary STS could be a valuable tool for selecting the group of patients who might benefit from intensified local tumour treatment.