title: Inhibition of autophagy protein LC3A as a therapeutic target in ovarian clear cell carcinomas.
abstract: OBJECTIVE
  Ovarian clear cell carcinoma (CCC) is one of histological subtypes showing poor prognosis due to chemoresistance. The association of autophagy-related proteins and clinical implementation in CCC has not been determined.
  
  
  METHODS
  The present study investigated whether expression of autophagy-related protein, light chain 3A (LC3A), was related with prognoses in the patients with CCC using immuno-histochemical stainings, and whether inhibition of autophagy modified the sensitivity to cisplatin in CCC cells in vitro.
  
  
  RESULTS
  High expression of autophagy-related protein, LC3A, was detected in 78 cases (78%) in all CCC cases. The patients with high LC3A expression showed significantly lower response rate to primary chemotherapy (17% vs. 100%, p<0.010), and had worse progression-free survival (PFS) and overall survival (OS) compared with those with LC3A low expression. Furthermore, multivariate analyses revealed that high expression of LC3A was identified as independent worse prognostic factors for PFS and OS. Inhibition of autophagy protein LC3A using hydroxychloroquine (HCQ) increased sensitivity to cisplatin in CCC cells in vitro.
  
  
  CONCLUSIONS
  High expression of LC3A proteins was associated with lower response to platinum therapy, leading to worse prognoses in CCC. Although further studies are needed to confirm the results, inhibition of autophagy by HCQ was associated with platinum sensitivity. Autophagy protein LC3A could be a promising target for treatment for CCC.
authors.affiliation: Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Japan.
authors.forename: Morikazu
authors.identifier: http://orcid.org/0000-0003-4763-0926
authors.initials: M
authors.lastname: Miyamoto
authors.affiliation: Department of Clinical Oncology, National Defense Medical College Hospital, Tokorozawa, Japan. mastkn@ndmc.ac.jp.
authors.forename: Masashi
authors.identifier: http://orcid.org/0000-0001-6916-9398
authors.initials: M
authors.lastname: Takano
authors.affiliation: Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Japan.
authors.forename: Tadashi
authors.identifier: http://orcid.org/0000-0002-5092-9729
authors.initials: T
authors.lastname: Aoyama
authors.affiliation: Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Japan.
authors.forename: Hiroaki
authors.identifier: http://orcid.org/0000-0003-0841-7743
authors.initials: H
authors.lastname: Soyama
authors.affiliation: Department of Clinical Oncology, National Defense Medical College Hospital, Tokorozawa, Japan.
authors.forename: Tomoyuki
authors.identifier: http://orcid.org/0000-0002-3612-8490
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Department of Basic Pathology, National Defense Medical College Hospital, Tokorozawa, Japan.
authors.forename: Hitoshi
authors.identifier: http://orcid.org/0000-0003-3457-4224
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Department of Obstetrics and Gynecology, National Defense Medical College Hospital, Tokorozawa, Japan.
authors.forename: Kenichi
authors.identifier: http://orcid.org/0000-0002-1039-6235
authors.initials: K
authors.lastname: Furuya
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D000071183:Autophagy-Related Proteins; D004791:Enzyme Inhibitors; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D006886:Hydroxychloroquine; D002945:Cisplatin
keywords: Adenocarcinoma, Clear Cell; Autophagy; Ovarian Neoplasms; Prognosis