Subcellular localization of FANCD2 is associated with survival in ovarian carcinoma
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Sonali Joshi1,2, Shawn Campbell1,2, Jeong Y. Lim3, Shannon McWeeney4, Adam Krieg1, Yukie Bean1,2, Nadja Pejovic5, Paulette Mhawech-Fauceglia6 and Tanja Pejovic1,2
1 Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon, 97239, USA
2 Division of Gynecologic Oncology, Oregon Health & Science University and Knight Cancer Institute, Portland, Oregon, 97239, USA
3 Biostatistics Shared Resource, Knight Cancer Institute Oregon Health & Science University, Portland, Oregon, 97239, USA
4 Division of Bioinformatics and Computational Biology, Knight Cancer Institute, Portland, Oregon, 97239, USA
5 School of Medicine, Saint Louis University, St. Louis, Missouri, 63104, USA
6 Sonic Healthcare USA, Austin, Texas, 78727, USA
Keywords: FANCD2; ovarian carcinoma; subcellular localization
Received: November 03, 2019 Accepted: December 21, 2019 Published: February 25, 2020
Objective: Ovarian cancer is a leading cause of death from gynecological cancers. Late diagnosis and resistance to therapy results in mortality and effective screening is required for early diagnosis and better treatments. Expression of the Fanconi Anemia complementation group D2 protein (FANCD2) is reduced in ovarian surface epithelial cells (OSE) in patients with ovarian cancer. FANCD2 has been studied for its role in DNA repair; however multiple studies have suggested that FANCD2 has a role outside the nucleus. We sought to determine whether subcellular localization of FANCD2 correlates with patient outcome in ovarian cancer.
Methods: We examined the subcellular localization of FANCD2 in primary OSE cells from consenting patients with ovarian cancer or a normal ovary. Ovarian tissue microarray was stained with anti-FANCD2 antibody by immunohistochemistry and the correlation of FANCD2 localization with patient outcomes was assessed. FANCD2 binding partners were identified by immunoprecipitation of cytoplasmic FANCD2.
Results: Nuclear and cytoplasmic localization of FANCD2 was observed in OSEs from both normal and ovarian cancer patients. Patients with cytoplasmic localization of FANCD2 (cFANCD2) experienced significantly longer median survival time (50 months), versus patients without cytoplasmic localization of FANCD2 (38 months; p < 0.05). Cytoplasmic FANCD2 was found to bind proteins involved in the innate immune system, cellular response to heat stress, amyloid fiber formation and estrogen mediated signaling.
Conclusions: Our results suggest that the presence of cytoplasmic FANCD2 modulates FANCD2 activity resulting in better survival outcome in ovarian cancer patients.
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