Survival signaling and terminal differentiation in cholesteatoma epithelium.
CONCLUSIONS
There is a strong indication that epithelial keratinocytes in cholesteatoma are protected against apoptosis. The late terminal differentiation program in cholesteatoma epithelium is disturbed.


OBJECTIVE
Previously, minimal apoptosis has been demonstrated in cholesteatoma epithelium. The phosphoinositide 3-kinase/Akt/protein kinase B (PI3K/Akt/PKB) and the mitogen activated protein kinases (MAPK) signaling transduction pathways have been reported to protect epithelial cells against apoptosis. Both pathways have also been proven to regulate late terminal differentiation of keratinocytes. In cholesteatoma epithelium, MAPK activation has been shown to be associated with terminal differentiation. The purpose of this study was to investigate whether in human cholesteatoma epithelium protection against programmed cell death by means of PI3K/Akt survival signaling is present and associated with MAPK activation and terminal differentiation.


METHODS
Fifteen human cholesteatoma and patient-matched retro-auricular skin samples were immunohistochemically stained for pAkt/PKB, phosphorylated extracellular regulated kinase1/2 (pERK1/2), phosphorylated JNK/SAPK, phosphorylated p38, involucrin and filaggrin. Positive cells were counted by computer-assisted digital image analysis.


RESULTS
Protein expressions of pAkt/PKB, pERK1/2, pp38, and involucrin in cholesteatoma epithelium were significantly increased when compared with retro-auricular skin (p<0.01). Filaggrin expression was significantly decreased (p=0.03). The positive correlation was confirmed between both pERK1/2 and pp38, and involucrin (p < or = 0.05).
Huisman
Margriet A
MA
Department of Ear, Nose and Throat, Leiden University Medical Center, Leiden, The Netherlands. m.a.huisman@LUMC.nl
De Heer
Emile
E
Grote
Jan J
JJ
D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D018424:Cholesteatoma, Middle Ear / Q000473:pathology*; D000091344:Filaggrin Proteins; D006801:Humans; D007124:Immunoenzyme Techniques; D007381:Intermediate Filament Proteins / Q000032:analysis; D015603:Keratinocytes / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000032:analysis; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis; D048052:Mitogen-Activated Protein Kinase 3 / Q000032:analysis; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis*; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis*; D011498:Protein Precursors / Q000032:analysis; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis*; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis
D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D048670:MAP Kinase Kinase 4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D011498:Protein Precursors; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C000717249:FLG protein, human; C032253:involucrin