Regulation of multidrug resistance 1 expression by CDX2 in ovarian mucinous adenocarcinoma

Abstract

Epithelial ovarian cancer is an aggressive gynecological malignancy with a high mortality rate. Resistance against chemotherapeutic agents often develops in ovarian cancer patients, contributing to high recurrence rates. The multidrug resistance 1 (MDR1/ABCB1) gene encodes P‐glycoprotein, which affects the pharmacokinetic properties of anticancer agents. We previously reported that the Caudal‐related homeobox transcription factor CDX2 transcriptionally regulates MDR1 expression in colorectal cancer. CDX2 is a factor that influences cancer cell differentiation, malignancy, and cancer progression. We hypothesized that profiling of CDX2 and MDR1 expression could be an effective strategy for predicting anticancer drug resistance. We studied the expression of these factors in clinical samples from ovarian cancer patients. We found that endogenous MDR1 expression was positively associated with CDX2 expression in ovarian mucinous adenocarcinoma. Using ovarian mucinous adenocarcinoma cell lines, we also observed decreased MDR1 expression following inhibition of CDX2 by RNA interference. In addition, CDX2 overexpression in MN‐1 cells, which display low endogenous CDX2, resulted in upregulation of MDR1 expression. CDX2 induced MDR1‐dependent resistance to vincristine and paclitaxel, which was reversed by treatment with the MDR1‐specific inhibitor verapamil. Our findings show that CDX2 promotes upregulation of MDR1 expression, leading to drug resistance in ovarian mucinous adenocarcinoma. Therefore, our study demonstrates the potential of novel chemotherapy regimens based on CDX2 status and MDR1 expression in ovarian mucinous adenocarcinoma.

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

“…The multidrug resistance genes MDR1 (also called ABCB1 ) and CFTR (also called ABCC7 ), coding for two ATP‐dependent drug efflux pumps, are transcriptional downstream targets of CDX2 (Kerschner and Harris, 2012; Koh et al ., 2016; Takakura et al ., 2010; Yan et al ., 2015). We found that both MDR1/ABCB1 and CFTR/ABCC7 were significantly downregulated in CDX2‐negative patient tumors and cell lines, independent of MSI status (Fig.…”

MicroRNA-9-5p-CDX2 Axis: A Useful Prognostic Biomarker for Patients with Stage II/III Colorectal Cancer

“…Recent studies showed that CDX2 targets the multidrug resistance gene MDR1 (ABCB1) and CFTR (ABCC7), coding for two ATP-dependent drug efflet pumps [36][37][38]. These genes are significantly down-regulated in CDX2-negative cell lines and CDX2-negative patient tumors and have also been reported to promote the response to chemotherapy [24,38].…”

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

“…CDX2 may regulate cancer cell proliferation by suppressing transcriptional activity of the β-catenin-TCF complex and β-catenin nuclear localization (69). CDX2 also upregulates MDR1 by binding to its element in the promoter of the MDR1 gene, which may lead to drug resistance in mucinous ovarian cancer (70,71). Huaier (Trametes robiniophila Murr), a traditional Chinese medicine, and PPI, a component in the traditional Chinese medicinal herb Paris polyphylla Smith, have been reported to inhibit the nuclear translocation of β-catenin and to transcriptionally downregulate certain WNT/β-catenin target genes (LRP6, WNT5A and cyclin D1) (72).…”