Subcellular localization of MCM2 correlates with the prognosis of ovarian clear cell carcinoma

// Gulinisha Aihemaiti 1 , Morito Kurata 1 , Daichi Nogawa 1 , Akiko Yamamoto 1 , Tatsunori Mineo 1 , Iichiroh Onishi 1 , Yuko Kinowaki 1 , Xiao-Hai Jin 1 , Anna Tatsuzawa 2, 3 , Naoyuki Miyasaka 3 , Masanobu Kitagawa 1 and Kouhei Yamamoto 1 1 Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113–8510, Japan 2 Department of Analytical Information of Clinical Laboratory Medicine, Graduate School of Health Care Science, Bunkyo Gakuin University, Tokyo 113–8668, Japan 3 Department of Obstetrics and Gynecology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113–8510, Japan Correspondence to: Kouhei Yamamoto, email: yamamoto.pth2@tmd.ac.jp Keywords: ovarian cancer; pathology; clinicopathologic study; MCM2; cancer therapy target Received: February 16, 2018      Accepted: May 27, 2018      Published: June 15, 2018 ABSTRACT Highly malignant tumors overexpress the minichromosome maintenance 2 (MCM2) protein in the nucleus, which is associated with advanced tumor grade, advanced stage, and poor prognosis. In this study, we showed that MCM2 is highly expressed in clinical samples of ovarian clear cell carcinoma. Although MCM2 expression was mainly localized to the nuclei as in other cancers, a few cases exhibited cytoplasmic localization of MCM2. Surprisingly, tumor samples with cytoplasmic MCM2 demonstrated excellent prognosis, showing 100% survival during the observation period of more than 200 months. However, cases with nuclear expression of MCM2 exhibited approximately 78% 5-year-survival rate. In a previous study, we showed that Friend leukemia virus (FLV) envelope protein gp70 bound to MCM2, impaired its nuclear translocation, and enhanced DNA damage-induced apoptosis in FLV-infected hematopoietic cells with high levels of MCM2. As expected, clear cell carcinoma cells with cytoplasmic expression of MCM2 exhibited significantly higher apoptotic cell ratio than that of cells with nuclear MCM2 expression. In vitro experiments using ovarian cancer cells with cytoplasmic expression of MCM2 demonstrated that transfection of MCM2-ΔN enhanced DNA damage-induced apoptosis. Therefore, cytoplasmic localization of MCM2 significantly correlated with increased apoptosis in clear cell carcinoma cells, resulting in improved prognosis.