Affiliations: Department of Basic Sciences, Dental School, University of Athens, Athens, Greece | Department of Biological Chemistry, Medical School, University of Athens, Athens, Greece | Department of Oral Medicine and Pathology, Dental School, University of Athens, Athens, Greece | Department of Histology–Embryology, Medical School, University of Athens, Athens, Greece
Note: [] Corresponding author: Hippokratis Kiaris, Department of Biological Chemistry, University of Athens Medical School, 75, M. Asias Str., 11527 Athens, Greece. Tel./Fax: +30 210 7462695; E-mail: hkiaris@med.uoa.gr.
Abstract: Background: Concerted alterations between stromal fibroblasts and neoplastic cells underline the carcinogenic process. Activation of alpha-smooth muscle actin (SMA) expression, a cytoskeleton protein normally expressed only in myoepithelial cells, is considered a landmark for the activation of stromal fibroblasts with little however being known regarding the mechanism governing the expression of SMA in the stroma. Methods: We have evaluated by immunohistochemistry the expression of SMA in the stroma of oral malignant and pre-malignant lesions, in association with the expression of p53 and p21 tumor suppressors that were shown previously to be deregulated and/or mutated in stromal fibroblasts of various cancers. The effects of p21 knockdown in SMA expression and cell migration and the mRNA levels of endogenous p21 in fibroblasts co-cultured with cancer cells were also assessed. Results: We found that both p21 and SMA expression was elevated in the stroma, but not the epithelium, of malignant as compared to pre-malignant lesions. We also noted that the expression of both was positively correlated, implying that SMA expression may be regulated by p21. Consistently with this notion we found that siRNA-mediated p21 suppression resulted in the reduction of SMA levels and also inhibited cell migration. Conclusion: Our results show that p21 deregulation is associated with the activation of stromal fibroblasts of oral cancers by a mechanism that involves the stimulation of SMA expression.
