Abstract
Congenital cholesteatomas are epithelial lesions that present as an epithelial pearl behind an intact eardrum. Congenital and acquired cholesteatomas progress quite differently from each other and progress patterns can provide clues about the unique origin and pathogenesis of the abnormality. However, the exact pathogenic mechanisms by which cholesteatomas develop remain unknown. In this study, key proteins that directly affect cholesteatoma pathogenesis are investigated with proteomics and immunohistochemistry. Congenital cholesteatoma matrices and retroauricular skin were harvested during surgery in 4 patients diagnosed with a congenital cholesteatoma. Tissue was also harvested from the retraction pocket in an additional 2 patients during middle ear surgery. We performed 2-dimensional (2D) electrophoresis to detect and analyze spots that are expressed only in congenital cholesteatoma and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/MS) to separate proteins by molecular weight. Protein expression was confirmed by immunohistochemical staining. The image analysis of 2D electrophoresis showed that 4 congenital cholesteatoma samples had very similar protein expression patterns and that 127 spots were exclusively expressed in congenital cholesteatomas. Of these 127 spots, 10 major spots revealed the presence of titin, forkhead transcription activator homolog (FKH 5–3), plectin 1, keratin 10, and leucine zipper protein 5 by MALDI-TOF/MS analysis. Immunohistochemical staining showed that FKH 5–3 and titin were expressed in congenital cholesteatoma matrices, but not in acquired cholesteatomas. Our study shows that protein expression patterns are completely different in congenital cholesteatomas, acquired cholesteatomas, and skin. Moreover, non-epithelial proteins, including FKH 5–3 and titin, were unexpectedly expressed in congenital cholesteatoma tissue. Our data indicates that congenital cholesteatoma origins may differ from those of acquired cholesteatomas, which originate from retraction pocket epithelia.
Highlights
A congenital cholesteatoma is a keratinized squamous epithelial middle ear lesion that usually presents in young children who do not have a history of otitis media, middle ear surgery, or trauma
The pathogenesis of congenital cholesteatomas seems to be different from acquired cholesteatomas, which usually arise from the retraction pocket of the pars flaccida of tympanic membrane and have attic destruction [4, 5]
The 2-dimensional electophoresis (2-DE) analysis of the four congenital cholesteatoma samples showed very similar protein expression patterns (Fig 2) that were quite different from acquired cholesteatoma and retroauricular skin samples (Fig 3)
Summary
A congenital cholesteatoma is a keratinized squamous epithelial middle ear lesion that usually presents in young children who do not have a history of otitis media, middle ear surgery, or trauma. Congenital cholesteatomas commonly appear as pearl-like epidermoid cysts, mostly located in the antero-superior quadrant behind an intact tympanic membrane [1, 2]. Several pathogenic mechanisms of congenital cholesteatoma have been suggested, including epithelial rests from faulty embryogenesis, invagination or implantation of squamous epithelium, and metaplasia of middle ear epithelium [6]. Upregulation of P21, shorter telomere length, increased surviving expression, and absence of ICAM-1 expression and LFA-1 positive cells have all been suggested to play a role in congenital cholesteatoma pathogenesis. Their exact roles have not been fully identified [3,4,5, 13]. These studies investigated several target proteins, but no reports have identified differences in molecular expression between congenital and acquired cholesteatoma by mass screening of proteins in each tissue, largely because of the lack of an ideal animal model and a limited number of specimens, which restricted basic molecular and biochemical research on congenital cholesteatoma pathogenesis
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