title: BAG3 upregulates Mcl-1 through downregulation of miR-29b to induce anticancer drug resistance in ovarian cancer.
abstract: OBJECTIVE
  Ovarian cancer is the leading cause of death from gynecologic cancer, reflecting its often late diagnosis and its chemoresistance. We identified a set of microRNAs whose expression is altered upon BAG3 knockdown. Our primary objective was to examine the relationships between BAG3, miR-29b and Mcl-1, an antiapoptotic Bcl-2 family protein, in ovarian cancer cells.
  
  
  METHODS
  Ovarian cancer cells were cultured and their responsiveness to paclitaxel was tested. Microarray analysis was performed to identify microRNAs differentially expressed in ES2 BAG3 knockdown ovarian cancer cells and their control cells. Primary ovarian cancer tissues were obtained from 56 patients operated on for ovarian cancer. The patients' clinical and pathological data were obtained from their medical records.
  
  
  RESULTS
  BAG3 knockdown increased the chemosensitivity to paclitaxel of ES2 ovarian clear cell carcinoma cells to a greater degree than AMOC2 serous adenocarcinoma cells. qRT-PCR analysis showed that miR-29b expression was significantly upregulated in primary cancer tissue expressing low levels of BAG3, as compared to tissue expressing high levels. Moreover, levels of miR-29b correlated significantly with progression-free survival. Upregulation of miR-29b also reduced levels of Mcl-1 and sensitized ES2 cells to low-dose paclitaxel.
  
  
  CONCLUSIONS
  BAG3 knockdown appears to downregulate expression of Mcl-1 through upregulation of miR-29b, thereby increasing the chemosensitivity of ovarian clear cell carcinoma cells. This suggests that BAG3 is a key determinant of the responsiveness of ovarian cancer cells, especially clear cell carcinoma, to paclitaxel and that BAG3 may be a useful therapeutic target for the treatment of ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Sugio
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan. Electronic address: miwasaki@sapmed.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwasaki
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Shutaro
authors.initials: S
authors.lastname: Habata
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Mariya
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osogami
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Tamate
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy* / Q000235:genetics; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017239:Paclitaxel / Q000627:therapeutic use*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C579095:MCL1 protein, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017239:Paclitaxel
keywords: BAG3; Chemoresistance; Mcl-1; Ovarian cancer; miR-29b