목적: This study aimed to assess aberrant Dickkopf-3 (DKK3) expression in primary ovarian carcinoma and to determine the role of DKK3 in ovarian carcinogenesis.
방법: DKK3 protein expression was examined by immunohistochemistry using tissue blocks from 82 patients with invasive adenocarcinoma, and 15 normal, 19 benign, and 10 borderline tumors as controls. Clinicopathological parameters of 42 serous adenocarcinomas were reviewed. Survival data were estimated using Kaplan-Meier estimates, and multivariate analysis was performed using the Cox regression method. Anti-proliferative and anti- invasive effects were estimated from colony formation and invasion assays using the SKOV3 ovarian cancer cell line. The expression of β-catenin and matrix metalloproteinases (MMPs) was determined by RT-PCR.
결과: DKK3 was significantly down-regulated in invasive carcinoma compared to normal, benign, and borderline tumors (p<0.001). DKK3 loss occurred in 56.1% invasive carcinoma cases and was significantly associated with chemo-resistance in serous adenocarcinoma (p=0.029). Multivariate analysis showed that women with chemo-sensitivity had a significantly lower risk of recurrence than those with chemo-resistance (p<0.01). Colony formation activity of DKK3-transfected cells was significantly lower than that of control vector-transfected cells (p=0.002). DKK3-overexpressing cells had less invasive capacity and significantly lower MMP-2, MMP-9, and β-catenin than control cells (p<0.01).
결론: Loss of DKK3 expression occurs more often in invasive epithelial ovarian cancer than in normal, benign, and borderline tumors. DKK3 has an anti-proliferative effect and inhibits the invasive capacity of ovarian cancer cells by attenuating MMP-2, MMP-9 and β-catenin indicating that DKK3 is tumor suppressor of ovarian cancer.