Mahdi Hosseinzadeh
1,2 
, Zahra Madjd
3,4,5, Mohsen Rashid
1, Elham Kalantari
3, Behrooz Shokouhi
6, Manizheh Sayyah-Melli
7,8, Mohammad Reza Sadeghi
1,9* 1 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
3 Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
4 Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
5 Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
6 Department of Pathology, Tabriz University of Medical Sciences, Tabriz, Iran
7 Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
8 Fellowship of Gynecologic Oncology. Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
9 Research Center for Pharmaceutical Nanotechnology, Biomedicine institute, Tabriz University of Medical Sciences, Tabriz, Iran
Abstract
Introduction: The clinical role of the transcription factor NRF3 in ovarian cancer (OC) remains unclear, particularly regarding the relationship between its mRNA and protein levels. This study investigates NRF3 expression as a potential prognostic indicator in OC.
Methods: This multicenter study analyzed 171 archival FFPE ovarian cancer specimens (2015–2023) alongside 29 prospectively collected, snap-frozen cases (2021–2024). Samples included diverse histologic subtypes predominantly high-grade serous carcinoma with comprehensive FIGO staging and Silverberg grading. We quantified NRF3 expression via tissue microarrays and qPCR, correlating the results with clinicopathological data. Diagnostic and prognostic performance were assessed using ROC curves, Kaplan-Meier survival analysis, and Cox regression.
Results: NRF3 was significantly upregulated in OC, as evidenced by both increased mRNA levels (P = 0.021) and elevated IHC H-scores in tumor cores (P < 0.001). These high expression levels correlated with aggressive clinical markers, such as advanced FIGO stage, metastasis and recurrence (P < 0.001), and were predictive of poor overall and progression-free survival (P = 0.001). The prognostic value was further supported by ROC analysis, which yielded an AUC of 0.779 for relapse prediction.
Conclusion: NRF3 is consistently upregulated at both the mRNA and protein levels in ovarian cancer, with its accumulation strongly linked to advanced disease and poor survival, pointing to its role in stress-driven tumor invasiveness. As NRF3 expression lost independent significance in our multivariate analysis, we identify it primarily as a molecular marker of aggressive disease burden rather than an independent prognostic factor. Future work should focus on validating its potential utility within broader diagnostic panels.