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Background: Dickkopf-4 (DKK4), a member of DKK family, appears to be a divergent protein. It remained multi-biological functions in carcinogenesis. The effect of DKK4 on the ovarian cancer cells remains unclear. This study detected the clinical significance of DKK4 in epithelial ovarian cancer (EOC) patients and its role in invasion., Methods: QRT-PCR and western blot analysis were used to examine the levels of DKK4 mRNA and protein in 33 EOC tissues and 33 benign ovarian tumors. Immunohistochemical analysis was performed to assess DKK4 expression in 239 EOC samples. siRNA-mediated DKK4 silence was conducted. Transwell assay was used to detect the invasive ability. Phalloidin was used to stain the formations of actin filaments., Results: The expressions of DKK4 mRNA and protein were elevated in EOC tissues as compared with those in benign ovarian tumors (p = 0.001 and <0.0001 respectively). Immunohistochemical results showed the strong expression of DKK4 protein was positively associated with late FIGO stage (p = 0.005) and poor disease free survival in univariate and multivariate analysis (p < 0.0001 and p = 0.001, respectively). SiRNA-mediated DKK4 knockdown inhibited cell invasive ability (all p < 0.0001) and the formations of actin filaments. DKK4 could promote the phosphration of c-JUN and JNK (p < 0.0001 and p = 0.001, respectively)., Conclusions: Our results indicated that DKK4 might be contributed to predicting EOC progression and prognosis. DKK4 could promote the invasion of EOC through JNK activation.

Dickkopf-1 (DKK1) was known as a negative regulator of the Wnt signaling pathway, which played a crucial role in carcinogenesis. However, its function in human cancers remained elusive. In this study, we aimed to investigate the role of DKK1 in ovarian serous papillary adenocarcinoma (OSC) tumor progression and invasion. Quantitative real-time RT-PCR and Western blot analysis showed that the expression of DKK1 mRNA and protein in 32 OSC tissues were elevated as compared with those in 10 normal ovarian tissues (P = 0.005, P = 0.003, respectively). Immunohistochemical analysis in 178 clinical OSC samples showed that the expression of DKK1 was positively associated with FIGO stage (P = 0.016). Furthermore, the expression of DKK1 protein was positively associated with P-JNK1 protein expression in 178 OSC tissues. DKK1, P-JNK1 and the co-expression of DKK1 and P-JNK1 were all unfavorable prognosis factors for OSC patients (P < 0.0001). DKK1, alone or combined with P-JNK1, was an independent predictor for the 5 year survival (P = 0.015, P < 0.0001, respectively). DKK1 could promote OSC cells invasion and the growth of OSC nude mice xenograft. DKK1 in OSC cells could activate P-JNK1 expression and significantly promote formations of actin filaments and filopodia. Thus, DKK1, alone or combined with P-JNK1, was a novel prognostic predictor for OSC patients and contributed to the invasion of OSC.

Aim: The expression of Dkk-3, as a number of the Dkk family was different in different cancer. Because Dkk-3 encodes a secreted protein, we investigated whether the Dkk-3 protein is secreted into the sera of patients with gynecological cancer., Material & Methods: The levels of Dkk-3 protein were assessed by enzyme-linked immunosorbent assay in the sera of 104 patients with gynecological cancer: 36 with ovarian, 40 with cervical and 28 with endometrial cancers., Results: The serum levels of Dkk-3 protein in patients with ovarian cancer [25.54 (7.99) pg/mL] was lower than in normal individuals [42.08 (14.89) pg/mL] (P = 0.000). But serum levels of Dkk-3 protein in patients with cervical [166.39 (300.68) pg/mL] (P = 0.013) and endometrial cancers [73.64 (23.36) pg/mL] (P = 0.000) were higher than in normal individuals. The serum levels of Dkk-3 protein were associated with clinical stage in patients with cervical and endometrial cancers. In patients with ovarian cancer, the serum levels of Dkk-3 protein were associated with lymphatic metastasis. In patients with cervical cancer, the serum levels of Dkk-3 protein were associated with tumor diameters., Conclusion: Dkk-3 protein detection using enzyme-linked immunosorbent assay as molecular markers can contribute to detection and diagnosis of gynecological cancer, especially for ovarian cancer and endometrial cancer.

Dickkopf-1 (DKK-1) is a secreted protein involved in embryonic development. Dickkopf-1 is also implicated in osteoporosis, arthritis, and cancer and represents a potential therapeutic target for the treatment of these diseases. Because DKK-1 encodes a secreted protein, we investigated whether the DKK-1 protein is secreted into the sera of patients with gynecological cancer. The levels of DKK-1 protein were assessed by enzyme-linked immunosorbent assay in the sera of 104 patients with gynecological cancer including 36 with ovarian, 40 with cervical, and 28 with endometrial cancers. The serum levels of DKK-1 protein were higher in patients with cervical (314.13 [385.02] pg/mL, P = 0.000) and endometrial (46.95 [21.62] pg/mL, P = 0.000) cancers than in healthy individuals (29.45 [11.86] pg/mL). The serum levels of DKK-1 protein were associated with clinical stage in all patients with gynecological cancer. In patients with cervical cancer, the serum levels of DKK-1 protein were also associated with histological type and lymphatic metastasis. Dickkopf-1 protein detection using enzyme-linked immunosorbent assay as a molecular marker can contribute to the detection and the diagnosis of cervical and endometrial cancers, especially for cervical squamous cell cancer.