Sustained extracellular signal-regulated kinase1/2 mitogen-activated protein kinase signalling is related to increased p21 expression in cholesteatoma epithelium

Conclusion. These results show for the first time that the RAS/RAF/ERK 1/2 AAAPK signalling pathway is active and involved in p21-mediated cell cycle arrest in human cholesteatoma epithelium. Objective. In a previous report we have demonstrated that the epithelium in human cholesteatoma is characterized by high p53-dependent p21 expression. The RAS/RAF/ extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) signalling pathway can induce p21 expression and subsequent cell cycle arrest via p53-dependent or -independent mechanisms. We designed the present study to investigate whether the RAS/RAF/ERK1/2 MAPK signalling pathway is involved in p53-dependent and p21-mediated cell cycle arrest in human cholesteatoma. Material and methods. A total of 18 cholesteatoma samples and 18 paired control retro-auricular skin samples were immunohistochemically stained for p53, p21, phosphorylated ERK1/2 (pERK1/2) and total ERK1/2. Positive cells were counted by means of digital image analysis. Double-label fluorescence immunohistochemistry was performed to demonstrate co-expression of p21 and pERK1/2. Results. Protein expression of p53, p21 and pERK1/2 differed significantly between cholesteatoma epithelium and retro-auricular skin (p <0.01). In cholesteatoma, co-expression of p21 and pERK1/2 was prominent, whereas in retro-auricular skin there was hardly any coexpression. Positive correlations were found between p53 and p21 (p =0.003) and between p21 and pERK1/2 (p =0.013).