Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells

• Published in: Cancer science 2014-05, Vol.105 (5), p.545-552
• Main Authors: Niimi, Kaoru, Murakumo, Yoshiki, Watanabe, Naoki, Kato, Takuya, Mii, Shinji, Enomoto, Atsushi, Asai, Masato, Asai, Naoya, Yamamoto, Eiko, Kajiyama, Hiroaki, Shibata, Kiyosumi, Kikkawa, Fumitaka, Takahashi, Masahide
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - genetics; Carcinoma, Ovarian Epithelial; Cell Cycle - genetics; Cell Proliferation; chemosensitivity; cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; DNA damage; DNA Repair - genetics; Drug Resistance, Neoplasm - genetics; Female; Humans; Mad2 Proteins - genetics; Male; Mice; Mice, Nude; Middle Aged; Neoplasms, Glandular and Epithelial - drug therapy; Original; ovarian clear cell carcinoma; Ovarian Neoplasms - drug therapy; RNA Interference; RNA, Small Interfering; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Young Adult
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12390

Human REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene transcription, and carcinogenesis. In this study, we evaluated the expression of REV7 in epithelial ovarian cancer (EOC) and analyzed the association between its expression and chemosensitivity in ovarian clear cell carcinoma (CCC) cells. Expression of REV7 in human EOC tissues was assessed by immunohistochemical staining. Expression was detected in the majority of EOCs (92.0%) with especially high levels of expression frequently observed in CCCs (73.5%) compared with that of non‐CCCs (53.4%). Enhanced immunoreactivity to REV7 was associated with poor prognosis represented by reduced progression‐free survival in advanced stage (stage II–IV) EOC as assessed using Kaplan–Meier curves and log–rank tests. The effects of REV7 knockdown on cell proliferation and chemosensitivity in CCC cells were also analyzed in vitro and in vivo. Knockdown of REV7 in CCC cells decreased cell proliferation without affecting cell cycle distribution. Additionally, the number of apoptotic cells and DNA damaged cells were increased after cisplatin treatment. In a nude mouse tumor xenograft model, inoculated REV7‐knockdown tumors showed significantly reduced tumor volumes after cisplatin treatment compared with those of the control group. These findings indicate that depletion of REV7 enhances sensitivity to cisplatin treatment in CCC, suggesting that REV7 is a candidate molecular target in CCC management. Immunohistochemical analysis of 137 epithelial ovarian cancer specimens revealed that high levels of REV7 expression were detected in clear cell carcinomas (CCC), and were associated with poor prognosis of advanced epithelial ovarian cancer. REV7 depletion in CCC cells enhanced sensitivity to cisplatin in vitro and in vivo, suggesting that REV7 could be a molecular target for CCC therapy.