Cholesteatoma is the growth of keratinizing squamous epithelium in the middle ear. It is associated with severe complications and has a poorly understood etiopathogenesis. Here, we present the results from extensive bioinformatics analyses of the first large-scale proteomic investigation of
cholesteatoma. The purpose of this study was to take an unbiased approach to identifying alterations in
protein expression and in biological processes, in order to explain the characteristic phenotype of this skin-derived
tumor. Five different human tissue types (
cholesteatoma, neck of
cholesteatoma, tympanic membrane, external auditory canal skin, and middle ear mucosa) were analyzed. More than 2,400 unique
proteins were identified using nanoLC-MS/MS based proteomics (data deposited to the ProteomeXchange), and 295
proteins were found to be differentially regulated in
cholesteatoma. Validation analyses were performed by SRM mass spectrometry.
Proteins found to be up- or down-regulated in
cholesteatoma were analyzed using Ingenuity Pathway Analysis and clustered into functional groups, for which activation state and associations to disease processes were predicted.
Cholesteatoma contained high levels of pro-inflammatory
S100 proteins, such as S100A7A and S100A7. Several
proteases, such as ELANE, were up-regulated, whereas
extracellular matrix proteins, such as COL18A1 and NID2, were under-represented. This may lead to alterations in integrity and differentiation of the tissue (as suggested by the up-regulation of KRT4 in the
cholesteatoma). The presented data on the differential
protein composition in
cholesteatoma corroborate previous studies, highlight novel
protein functionalities involved in the pathogenesis, and identify new areas for targeted research that hold therapeutic potential for the disease.