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The pathogenesis of cholesteatoma behind an intact tympanic membrane remains controversial. Squamous metaplasia of the middle ear mucosa is thought to be a possible mechanism in such cases. However, to date, no definitive experimental results have proved this association. This study was undertaken to investigate whether normal human middle ear epithelial (NHMEE) cells undergo keratinizing squamous differentiation in a retinoic acid (RA)-deficient culture.We examined the morphological differences between RA-deficient and -sufficient cultures, and determined the expressions of the mucin gene and cornifin-α mRNAs as indicators of mucous and squamous differentiation, respectively.Histomorphologically, the NHMEE cells differentiated into a keratinizing squamous epithelium in RA-deficient cultures. In addition, the expressions of mucin gene 5AC (MUC5AC) and MUC8 mRNAs were suppressed, and the expression of cornifin-α mRNA increased progressively as a function of differentiation in RA-deficient cultures.This study shows that RA depletion induces keratinizing squamous differentiation in NHMEE cell cultures. This finding supports the hypothesis that middle ear cholesteatoma originates from metaplastic middle ear mucosa.