DKK3 expression and function in head and neck squamous cell carcinoma and other cancers

Cancer arises from cumulative genetic or epigenetic aberrations, or the destabilization of central signaling pathways that regulate cell proliferation, differentiation, cell cycle, gene transcription, migration, angiogenesis and apoptosis. Investigating the cancer-specific genetic background is important to get deeper apprehension of cancer biology. In this review, we aimed to identify head and neck squamous cell carcinoma (HNSCC)-specific genes and identified DKK3 gene as a candidate.DKK3 belongs to the DKK family (DKK1, DKK2, DKK3 and DKK4), which codes for an evolutionally conserved secreted glycoprotein that is characterized by two distinct cysteine rich domains and functions as an antagonist of the oncogenic Wnt signaling pathway. It has been reported that DKK3 expression is decreased in many kinds of cancers, and it is thus thought to be a tumor suppressor gene. However, our investigations have demonstrated unique expression and function of DKK3 in HNSCC. DKK3 protein expression is predominantly positive in HNSCC, and DKK3-positive patients show significantly shorter disease-free survival rates, whereas DKK3-negative cases do not show metastasis. Molecular biological analyses demonstrated that DKK3 over expression significantly increased HNSCC cell proliferation, migration, and invasion via increased phosphorylation of AKT. Moreover, DKK3 knockdown in HNSCC cells significantly decreased these malignant potentials through decreased AKT phosphorylation.Our previously published data, alongside those from other reports, indicate that DKK3 may have an additional oncogenic function other than tumor suppression.