Abstract
Simple SummaryDickkopf-3 (DKK3) is considered a tumor suppressor as it possesses anti-tumoral properties and is frequently downregulated in various cancers. However, the role of DKK3 in ovarian cancer is not known. In this study, we showed that DKK3 loss occurred in 56.1% of patients with ovarian cancer and that it was significantly associated with poor survival and chemoresistance. Secreted DKK3 possessed anti-tumoral properties and enhanced paclitaxel susceptibility by inhibiting the β-catenin-P-glycoprotein signaling pathway in ovarian cancer. This study revealed promising therapeutic effects of secreted DKK3, which targets paclitaxel-resistant ovarian cancer.Dickkopf-3 (DKK3), a tumor suppressor, is frequently downregulated in various cancers. However, the role of DKK3 in ovarian cancer has not been evaluated. This study aimed to assess aberrant DKK3 expression and its role in epithelial ovarian carcinoma. DKK3 expression was assessed using immunohistochemistry with tissue blocks from 82 patients with invasive carcinoma, and 15 normal, 19 benign, and 10 borderline tumors as controls. Survival data were analyzed using Kaplan–Meier and Cox regression analysis. Paclitaxel-resistant cells were established using TOV-21G and OV-90 cell lines. Protein expression was assessed using Western blotting and immunofluorescence analysis. Cell viability was assessed using the MT assay and 3D-spheroid assay. Cell migration was determined using a migration assay. DKK3 was significantly downregulated in invasive carcinoma compared to that in normal, benign, and borderline tumors. DKK3 loss occurred in 56.1% invasive carcinomas and was significantly associated with disease-free survival and chemoresistance in serous adenocarcinoma. DKK3 was lost in paclitaxel-resistant cells, while β-catenin and P-glycoprotein were upregulated. Exogenous secreted DKK3, incorporated by cells, enhanced anti-tumoral effect and paclitaxel susceptibility in paclitaxel-resistant cells, and reduced the levels of active β-catenin and its downstream P-glycoprotein, suggesting that DKK3 can be used as a therapeutic for targeting paclitaxel-resistant cancer.
Highlights
Ovarian cancer remains the most lethal gynecological malignancy worldwide
As DKK3 loss is associated with chemoresistance and upregulation of the active form of β-catenin and P-glycoprotein, we investigated the relationship between them
A previous study did not find any correlation between DKK3 loss and clinicopathological parameters of ovarian cancer [20], the results of univariate survival analysis in this study showed that DKK3 loss was a prognostic factor, along with the Federation of Gynecology and Obstetrics (FIGO) stage, suboptimality of debulking surgery, and chemoresistance
Summary
Ovarian cancer remains the most lethal gynecological malignancy worldwide. Current therapeutic approaches for treating epithelial ovarian cancer are relatively effective for the early stage; more than 60% of patients with ovarian cancer are diagnosed at an advanced stage (stage III or IV) with metastasis to distant organs beyond the pelvis [1,2]. Most patients with advanced epithelial ovarian cancer develop recurrent disease, despite achieving clinical remission after completing the initial treatment. The serous subtype accounts for nearly 70% of cases of epithelial ovarian cancer and has a poorer prognosis than the other major subtypes, including mucinous, endometroid, and clear cell carcinoma. Chemoresistance is considered the main cause of treatment failure [1,3]. To facilitate treatment of this subtype identification of therapeutic candidates that can overcome chemoresistance is critical
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