Expression pattern of DKK3, dickkopf WNT signaling pathway inhibitor 3, in the malignant progression of oral submucous fibrosis

Oral squamous cell carcinoma (OSCC) is a common malignant neoplasm of the head and neck. Oral submucous fibrosis (OSF) is one of its pre-cancerous lesions; however, the key molecular events in the tumorigenesis of OSF remain elusive. Dickkopf WNT signaling pathway inhibitor 3 (DKK3) is one of the Wnt antagonists, and its downregulation and methylation have been reported in multiple malignancies, while no report of its expression in the carcinogenesis of OSF exists. In the present study, we investigated DKK3 expression at the protein and mRNA levels by immunochemical staining and semi‑quantitative RT-PCR in normal oral, OSF and OSCC tissues. We found that DKK3 was readily expressed in normal oral mucous tissues, but was gradually increased in early, moderately advanced and advanced OSF tissues, and strongly expressed in OSCC tissues. DKK3 was localized in the cytoplasm during OSF progression. A rare mutation of DKK3 was observed in OSCC, along with increased copy numbers. Furthermore, through analysis of its co-expressed genes, DDK3 may deregulate Wnt signaling, p53 signaling, apoptosis, Ca2+ signaling and mitochondrial signaling pathways in OSCC pathogenesis. Thus, our results demonstrated that DKK3 is upregulated in the carcinogenesis of OSF, due to gain of copy number, which could be a potential tumor marker for the early detection of OSCC.