title: Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells.
abstract: 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.
authors.affiliation: Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Niimi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Murakumo
authors.forename: Naoki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Takuya
authors.initials: T
authors.lastname: Kato
authors.forename: Shinji
authors.initials: S
authors.lastname: Mii
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.forename: Masato
authors.initials: M
authors.lastname: Asai
authors.forename: Naoya
authors.initials: N
authors.lastname: Asai
authors.forename: Eiko
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kajiyama
authors.forename: Kiyosumi
authors.initials: K
authors.lastname: Shibata
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kikkawa
authors.forename: Masahide
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004260:DNA Repair / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D064246:Mad2 Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C120552:MAD2L2 protein, human; D064246:Mad2 Proteins; D034741:RNA, Small Interfering; D002945:Cisplatin
keywords: Apoptosis; DNA damage; chemosensitivity; cisplatin; ovarian clear cell carcinoma