Aberrant Expression and Localization of Decorin in Human Oral Dysplasia and Squamous Cell Carcinoma

The small leucine-rich proteoglycan decorin has been associated with negative regulation of cell growth. It has a prominent role in transforming growth factor (TGF)-β and epidermal growth factor receptor activation pathways that contributes to its role in cellular proliferation, angiogenesis, and immunomodulation. Our studies are directed toward analysis of decorin gene expression, identified through DNA microarray studies, in oral premalignant and malignant tissues as well as representative cell lines of an oral cancer progression model. We have used long oligonucleotide microarray analysis, immunohistochemistry, confocal microscopy, reverse transcription-PCR, sequencing, and Western immunoblot techniques to characterize decorin expression in oral premalignant archival tissues and an oral cancer progression cellular model. We have further analyzed the deduced amino acid sequence derived from full-length cDNA that do not show any deletion or mutations of the decorin expressed in oral premalignant and malignant cell lines. In our studies, we show aberrant expression of decorin in dysplastic oral epithelial cells. Both promoters P1 and P2 drive the aberrant expression resulting in exon 1a as well as exon 1b carrying transcripts. Intracellular accumulation and nuclear localization of aberrantly expressed decorin were observed in dysplastic oral tissues and in the respective cell lines. Decorin expressed in oral cancer may have lost its ability to inhibit TGF-β signaling and activate epidermal growth factor receptor signaling pathways because of such aberrant nuclear localization, resulting in a major dysfunction of otherwise a natural extracellular antagonist of TGF-β and a putative tumor suppressor protein. The aberrant nuclear localization of a leucine-rich repeat protein might result in additional protein-protein interactions and resulting changes in gene expression. Further studies to characterize such interacting proteins and localization-dependent effects of aberrant decorin expressed in oral cancer progression are warranted.