title: Loss of autophagy-related protein Beclin 1 may define poor prognosis in ovarian clear cell carcinomas.
abstract: The aim of the present study was to clarify the role of autophagy in cisplatin (CDDP) sensitivity in OCCCs and the role of Beclin 1 in OCCC progression. Autophagy was measured using: i) western blot analysis of LC3 and p62 and ii) microscopic observation of GFP-LC3 puncta. Autophagy was suppressed using chloroquine and Beclin 1 siRNA. Surgical specimens were examined for Beclin 1 protein expression by immunohistochemistry. The correlations between the loss of Beclin 1 expression and clinicopathological characteristics, prognosis and chemosensitivity were investigated. Inhibition of autophagy by chloroquine or Beclin 1 siRNA did not enhance the sensitivity of the ES2 and TOV-21G OCCC cell lines to CDDP. Loss of Beclin 1 expression was observed in 38.3% (23/60) of the analyzed tumors. There was no significant correlation between loss of Beclin 1 expression and FIGO stage, CA125 levels, patient age, status of endometriosis, Ki-67 labeling index, chemotherapy regimen or status of residual tumor. However, negative expression of Beclin 1 was associated with a shorter progression-free survival in comparison to positive Beclin 1 expression in OCCC who received cytoreductive surgery, followed by a standard platinum-based chemotherapy regimen (P=0.027, log-rank test). Beclin 1-negative tumors were no more resistant to primary adjuvant chemotherapy than were Beclin 1-positive tumors (50.0 vs. 66.7%, P=0.937). Beclin 1 knockdown using siRNA increased cell growth but not cell migration and invasion in ES2 and TOV-21G OCCC cell lines. Autophagy defects caused by loss of Beclin 1 are not related to chemoresistance and metastasis, but may be associated with malignant phenotype and poor prognosis of OCCC.
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katagiri
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Sultana
authors.initials: S
authors.lastname: Razia
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Sato
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Iida
authors.affiliation: Department of Organ Pathology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Ishikawa
authors.affiliation: Department of Pathology, Seirei Hamamatsu General Hospital, Hamamatsu 430-8558, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Otsuki
authors.affiliation: Department of Obstetrics and Gynecology, Seirei Hamamatsu General Hospital, Hamamatsu 430-8558, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Nakayama
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kyo
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D015153:Blotting, Western; D002945:Cisplatin / Q000627:therapeutic use; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D034741:RNA, Small Interfering; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D002945:Cisplatin