DKK3, Downregulated in Invasive Epithelial Ovarian Cancer, Is Associated with Chemoresistance and Enhanced Paclitaxel Susceptibility via Inhibition of the β-Catenin-P-Glycoprotein Signaling Pathway

Abstract

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.

Lumbrokinase, a Fibrinolytic Enzyme, Prevents Intra‐Abdominal Adhesion by Inhibiting the Migrative and Adhesive Activities of Fibroblast via Attenuation of the AP‐1/ICAM‐1 Signaling Pathway

“…Western Blot Analysis. The western blot analyses were performed as previously described [21]. The following antibodies were used for the western blot analysis: anti-c-Jun (sc-166540), anti-phospho-c-Jun (sc-822), anti-intracellular adhesion molecule-1 (anti-ICAM-1) (sc-8439), and anti-βactin (all from Santa Cruz Biotechnology, Santa Cruz, CA, USA).…”

The Multifaceted Role of Human Dickkopf-3 (DKK-3) in Development, Immune Modulation and Cancer

“…The frequency of DKK-3 promoter hypermethylation varies from 26% (pleural mesothelia) to 61% (breast carcinoma). [7,50] Suppression of cell proliferation The overexpression of DKK-3 in hepatoma and cervical cancer cells diminishes cell proliferation in vitro [51,52] Response to chemotherapy [ 15,53] Serum DKK-3 is a prognosis biomarker DKK-3 levels are negatively correlated with the number of CD133+ circulating tumor cells in ovarian cancer [54] Regulation of the tumor immune microenvironment DKK-3 expression correlates with infiltrating CD8+ lymphocytes and macrophages in HPV-positive HNSCC and stimulates NF-κB signaling in macrophages [55]…”

“…DKK-3 decreases the levels of active non-phosphorylated β-catenin, as well as P-glycoprotein, an important chemoresistance-regulating protein. DKK-3 acts as an inhibitor of chemoresistance, since reducing DKK-3 levels decreases resistance to chemotherapy with paclitaxel [ 53 ]. In lung cancer cells, DKK-3 downregulates the expression of survivin at the protein level, and DKK-3 overexpression decreases c-myc and MMP7, which are Wnt signaling effector genes that control the fate of cancer development, progression and metastasis [ 15 ].…”