Sigma-2 Receptor Expression in Bovine Papillomavirus-Associated Urinary Bladder Tumours S. Roperto * , N. A. Colabufo † , C. Inglese † , C. Urraro * , R. Brun * , E. Mezza ‡ , S. Staibano ‡ , C. Raso * , P. Maiolino * , V. Russo * , E. Palma x and F. Roperto * * Department of Pathology and Animal Health, Faculty of Veterinary Medicine, Via Delpino 1, Naples University Federico II, 80137 Naples, † Dipartimento Farmacochimico, Facolta ` di Farmacia, Universita ` di Bari, 70125 Bari, ‡ Dipartimento di Scienze Biomorfologiche e Funzionali, Universita ` di Napoli Federico II, 80137 Napoli and x Dipartimento di Scienze Farmacobiologiche, Facolta ` di Farmacia, Universita ` di Catanzaro Magna Græcia, 88100 Catanzaro, Italy Summary The expression of sigma-2 receptors was investigated in nine urothelial tumours of the urinary bladder of cattle. Each tumour was associated with the presence of DNA of bovine papillomavirus type-2 (BPV-2) and expression of the E5 viral oncoprotein. Five tumours were classified as low-grade carcinoma on the basis of morphological criteria and calculation of mean nuclear area (MNA) and mean nuclear perimeter (MNP). Four tumours were classified as high-grade carcinoma. Sigma-2 receptors were overexpressed in both types of carcinoma. In control normal bovine bladder tissue the density of receptors (expressed as the B max ) was 0.37 pmol/mg of protein. Low-grade carcinomas had a mean B max of 1.37  0.32 pmol/mg of protein (range 1.03e1.86) and in high-grade carcinomas the mean B max was 10.9  2.8 pmol/mg of protein (range 8.2e14). The difference in B max between low- and high-grade carcinomas was statistically significant (P ¼ 0.0001). Ó 2009 Elsevier Ltd. All rights reserved. Keywords: cattle; papillomavirus type-2; sigma-2 ligand; sigma-2 receptor; urothelial tumour Introduction Sigma receptors are intracellular proteins first de- scribed as novel opioid receptors (Martin et al., 1976). They are classified into two subtypes termed sigma-1 and sigma-2 (Quirion et al., 1992), but more recently a third subtype has been proposed (Palmer et al., 2007). The sigma-1 receptor has been cloned (Hanner et al., 1996); however, the sequence of the sigma-2 receptors, that appear to be specifically localized to the cell membrane lipid raft, remains unknown (Gebreselassie and Bowen, 2004; Aydar et al., 2006). Sigma receptors are involved in regulating cell growth and proliferation (Crawford and Bowen, 2002; Crawford et al., 2002); however, their molecular function is not fully understood and conflicting data are reported (Aydar et al., 2004). Some sigma-2 recep- tor agonists lead to an increase of calcium ions, which may be responsible for the activation of several cal- cium-dependent proteins such as tissue transglutami- nase-2 (TG-2) (Prezzavento et al., 2007). TG-2 is implicated in numerous cellular processes including cellular differentiation, signal transduction, cell sur- vival and wound healing (Prezzavento et al., 2007). Some sigma-2 receptor agonists inhibit calcium re- lease from the endoplasmic reticulum of cancer cells (Cassano et al., 2006). Sigma-2 receptors are up-regulated when cells are in a state of rapid proliferation (Mach et al., 1997) and appear to play an important role in cancer biol- ogy, raising the possibility that sigma receptor ligands could be useful novel diagnostic or therapeutic agents (Aydar et al., 2004; Kashiwagi et al., 2007; Zeng et al., Correspondence to: S. Roperto (e-mail: sante.roperto@unina.it). 0021-9975/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jcpa.2009.06.001 J. Comp. Path. 2010, Vol. 142, 19e26 Available online at www.sciencedirect.com www.elsevier.com/locate/jcpa 680