ORIGINAL ARTICLE A role for the substance P ⁄ NK-1 receptor complex in cell proliferation and apoptosis in oral lichen planus MA Gonza´lez Moles 1 , F Esteban 2 , I Ruiz-A ´ vila 3 , JA Gil Montoya 4 , S Brener 1 , A Bascones-Martı´nez 5 , M Mun˜oz 6 1 Granada School of Dentistry, Oral Medicine, Granada University, Granada, Spain; 2 Department of Otorhinolaryngology, Virgen del Rocio University Hospital, Sevilla, Spain; 3 Jaen Central Hospital, Pathology Department, Jaen, Spain; 4 Granada School of Dentistry, Special Care in Dentistry, Granada University, Granada, Spain; 5 Complutense School of Dentistry, Oral Medicine, Complutense University, Madrid, Spain; 6 Department of Paediatric Medicine, Virgen del Rocio University Hospital, Sevilla, Spain OBJECTIVES: To determine whether substance P (SP) and NK-1 receptor (NK-1R) are expressed in oral lichen planus (OLP) and are related to cell proliferation and apoptosis in this disease. MATERIAL AND METHODS: Tissue samples from 50 OLP patients and 26 healthy controls were studied. Immunohistochemistry was performed with anti-SP, anti-NK-1R, anti-ki-67 and anti-caspase-3 monoclonal antibodies and the clinical and pathological data of the OLP patients were evaluated. RESULTS: With the exception of NK-1R expression in epithelial cell membrane and cytoplasm, all markers were more frequently present in OLP patients than in controls (P < 0.05). Higher cytoplasmatic expression of NK-1R was associated with higher epithelial expression of caspase-3 (P < 0.05). Higher epithelial expression of NK- 1R and SP was associated with higher suprabasal and basal epithelial expression of ki-67 (P < 0.05 and P < 0.005, respectively). CONCLUSIONS: Actions of the SP ⁄ NK-1R complex may contribute to the immune disorder underlying OLP and trigger stimuli to induce cell proliferation. These results indicate that this complex might play a role in the malignant transformation of OLP. Oral Diseases (2008) doi: 10.1111/j.1601-0825.2008.01504.x Keywords: oral lichen planus; substance P; NK-1 receptor; malignant transformation Introduction Malignant transformation of oral lichen planus (OLP) may be related to or dependent on molecular stimuli originating in the inflammatory infiltrate (Gonza´ lez- Moles et al, 2006; Gonzalez-Moles et al, 2008a). Chronic inflammation has been associated with various types of cancer (Coussens and Werb, 2002; Clevers, 2004; Philip et al, 2004) and it has been widely reported that inflammatory infiltrate may be a strong risk factor for cancer development in ulcerous colitis, atrophic gastritis and Barret’s oesophagus, among other diseases (Balkwill and Mantovani, 2001; O’Byrne and Dalgleish, 2001). It was recently proposed that OLP could be included in this group (Gonza´lez-Moles et al, 2006). Some molecules and radicals generated by inflammatory cells can act as mutagenic agents for epithelial cells or affect important cell cycle regulation mechanisms, e.g., apoptosis, cell cycle arrest or cell proliferation. Thus, reactive oxygen species and reactive nitrogen species appear to play key roles in the association between chronic inflammation and cancer (Chaiyarit et al, 2005) and inflammatory cells in OLP patients may contribute an excess of nitric oxide (NO) via expression of inducible NO synthetase (iNOS) (Chaiyarit et al, 2005). The NO generated by iNOS reacts with O 2 to produce ONOO – (Wink and Mitchell, 1998), which induces the formation of both 8-oxo-7.8-dihydro-2’-deoxyguanosine (8-ox- odG) and 8-nitroguanine (Yermilov et al, 1995) in the nucleus of epithelial cells. Formation of 8-oxodG is a known cause of G–T transversion, which can promote carcinogenesis (Shibutani et al, 1991; Normark et al, 2003). However, despite the mutagenic effects to which basal cells are exposed in OLP, remarkably few apop- totic phenomena are observed in this cell compartment, as demonstrated by several researchers (Dekker et al, 1997; Bloor et al, 1999; Neppelberg et al, 2001; Tobo´n- Arroyaye et al, 2004), including our own group (Bas- cones-Ilundain et al, 2005, 2006, 2007; Gonza´lez-Moles et al, 2006), by applying TUNEL technique and anal- ysing the immunohistochemical expression of caspase-3. Moreover, most studies on cell proliferation in OLP have reported a markedly elevated proliferation rate of basal epithelial cells (Schifter et al, 1998; Tanda et al, Correspondence: MA Gonza´ lez-Moles, Facultad de Odontologı´a, Paseo de Cartuja s ⁄ n, 18071, Granada, Spain. Tel: +34 958243804, Fax: +34 958240908, E-mail: magonzal@ugr.es Received 27 June 2008; revised 25 October 2008; accepted 30 October 2008 Oral Diseases (2008). doi:10.1111/j.1601-0825.2008.01504.x Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Munksgaard All rights reserved http://www.blackwellmunksgaard.com