As observed in the case of cytokines expression regulation, this result may suggest that the cortisol effect on the cell cycle proteins may be dependent on the hormone levels. Further studies are necessary to evaluate CX-4945 clinical trial which underlying mechanisms are activated in OSCC cells after variations of the systemic and tissue levels of cortisol in response to chronic and acute stress conditions. In addition to confirming that OSCC cell lines express β1- and β2-AR, we have also demonstrated that these receptors are expressed in specimens of OSCC, oral leukoplakia, and normal oral mucosa. The β-adrenergic receptors are

members of the large family of G protein-coupled receptors (GPCR), and their activation involves protein-tyrosine-kinase-activated pathways, as well as cyclic-adenosine-monophosphate (cAMC)-linked pathways. It has been shown that several types of cancer express β-AR, which may affect proliferation and migration as well as induce metastasis (Askari et al., 2005, Cakir et al., 2002 and Shin et al., 2007). β1-AR expression in OSCC Hormones antagonist and oral leukoplakia specimens has not yet been reported. Quantitatively, the mean β1-AR expression level in OSCC was approximately 3- and 2-fold those encountered in the normal mucosa and leukoplakia, respectively. These findings suggest that the changes in epithelial and mesenchymal cells

during oral carcinogenesis can be accompanied by modifications in β1-AR expression. Moreover, β1-adrenergic receptor agonists, such as NE, could determine more pronounced effects in neoplastic tissues compared to normal tissues. β2-AR expression in OSCC biopsies

has been previously analyzed by Shang et al. (2009). Immunohistochemistry analysis showed that 67.7% of OSCC cases were positive for β2-AR protein expression, while only 20% of adjacent normal mucosa specimens were positive for β2-AR staining Fluorometholone Acetate (Shang et al., 2009). However, β1-AR expression was not evaluated. In our cases, only one specimen of normal mucosa was negative for β2-AR, and there was no expressive difference in its expression when tumor and normal mucosa specimens were compared. This distinct result in terms of β2-AR expression obtained by us and Shang et al. may be due to the use of different methods. In real-time PCR assay other cells of the tumor microenvironment that also express β-ARs in addition to epithelial cells are also included in the analysis. Previous studies have shown that patients with oral cancer can have high psychological distress levels (Kugaya et al., 2000 and Chen et al., 2009). The effects of stress-related hormones on oral cancer cells are still poorly understood. Although this study has limitations because it is composed mainly of in-vitro assays, the results reveal that stress-related mediators, mainly NE at concentration compatible with physiological stress levels in humans, can upregulate IL-6 expression and induce OSCC cell proliferation.