DDA1 is induced by NR2F6 in ovarian cancer and predicts poor survival outcome.

OBJECTIVE

In this study, we investigated the dysregulated genes in ovarian cancer epithelial cells (CEPIs) compared to normal ovarian surface epithelia (OSE). The mechanism of co-upregulation between NR2F6 and DDA1 in CEPIs and their association with survival outcomes were further studied.

MATERIALS AND METHODS

The microarray that assessed gene expression profiles of ovarian CEPIs was searched in GEO datasets. The genes co-expressed with NR2F6 in the ovarian cohort in TCGA database were identified and analyzed using cBioportal and UCSC Xena. The association between NR2F6, DDA1 and overall survival (OS) and recurrence free survival (RFS) in ovarian cancer patients were assessed using Kaplan-Meier Plotter. The regulative effect of NR2F6 on DDA1 expression was verified by qRT-PCR, Western blotting and dual luciferase assay.

RESULTS

NR2F6 is significantly upregulated in CEPIs compared to OSE. High NR2F6 expression is associated with significantly worse OS (HR: 1.22, 95% CI: 1.07-1.4, p=0.0039, N=1656). NR2F6 and DDA1 are co-upregulated in ovarian cancer (Pearson's r=0.57). NR2F6 overexpression resulted in significantly upregulated DDA1 expression at both mRNA and protein levels in SKOV3 and A2780 cells. DDA1 promoter contains a NR2F6 binding site between -349 and -336 upstream the TSS site. High DDA1 expression is associated with significantly shorter RFS (HR: 1.38, 95% CI: 1.12-1.69, p=0.0023, N=614).

CONCLUSIONS

NR2F6 and DDA1 are co-upregulated in ovarian cancer. High NR2F6 expression is associated with significantly worse OS. NR2F6 can activate DDA1 transcription via binding to the DDA1 promoter. DDA1 upregulation is associated with significantly worse RFS among the ovarian cancer patients.