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Oncol Lett. 3(2):273-280. 2012. 

Absence of Dickkopf (Dkk)-3 protein expression is correlated with longer disease-free survival and lower incidence of metastasis in head and neck squamous cell carcinoma.

Katase NLefeuvre MGunduz MGunduz EBeder LBGrenman RFujii MTamamura RTsujigiwa HNagatsuka H.


Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently occurring types of cancer worldwide. We focused on the fact that the aberrant function of Wnt/β-catenin signaling is a frequent event in malignancies. Dickkopf (Dkk)-3 is a major negative regulator of Wnt/β-catenin signaling, which is a known tumor suppressor and is down-regulated in various types of cancer. However, the expression profile of the Dkk-3 protein in HNSCC has not yet been reported. The present study was conducted to investigate Dkk-3 protein expression in 90 cases of HNSCC tissue samples and HNSCC-derived cell lines. In contrast to findings available on other types of cancer, the Western blot analysis revealed that HNSCC cell lines expressed the Dkk-3 protein. In immunohistochemistry, 76 cases (84.4%) out of 90 tissue samples were Dkk-3-positive, whereas only 14 cases (15.6%) were negative. Notably, survival analysis showed that the Dkk-3 (-) group exhibited significantly longer disease-free survival (p=0.038), metastasis-free survival (p=0.013) and longer overall survival (p=0.155). The results showed that the Dkk-3 protein was dominantly expressed and may be involved in carcinogenesis and metastasis in HNSCC. Moreover, the findings suggest that the function of Dkk-3 differs depending on the tissue of origin, and that it may exert an oncogenic function in HNSCC.


What to examine:Protein expression of DKK3 in HNSCC cell lines and tissue samples, and its clinical significance

Results:Unlike other types of cancers, DKK3 protein expression was observed in HNSCC cell lines and tissue samples.

               DKK3 protein expression significantly associated with poorer prognosis.


So far, I have identified DKK3 gene as a candidate specific cancer associated gene in HNSCC (Katase N et al. Oncol Res. 2008).

In the present research, I have investigated DKK3 protein expression and its clinical relevance in HNSCC tissue samples.


(1) DKK3 protein expression in HNSCC-derived cells and tissue samples


It had been reported that DKK3 expression was decresed or lost by promoter hypermethylation in many kinds of malignancy. However, western blotting and immunohistochemistry revealed that DKK3 protein was expressed by all of HNSCC cancer cells and most of the cases examined (76/90 cases,84.4%). DKK3 protein expression was observed in cancer cells, dysplastic epithelium adjacent to cancer tissue, cancer cells in metastatic lymph nodes and stromal endothelium (arrows). 


(2) Clinical relevance of DKK3 protein expression


Patients with DKK3 protein expression showed significantly shorter

disease-free survival and metastasis free survival.

​Surprisingly, DKK3 negative patients never occurred metastasis.

From these results, specific expression of DKK3 in HNSCC

was observed, and that implied oncogenic function of


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