title: Hypermethylation of the TGF-β target, ABCA1 is associated with poor prognosis in ovarian cancer patients.
abstract: BACKGROUND
  The dysregulation of transforming growth factor-β (TGF-β) signaling plays a crucial role in ovarian carcinogenesis and in maintaining cancer stem cell properties. Classified as a member of the ATP-binding cassette (ABC) family, ABCA1 was previously identified by methylated DNA immunoprecipitation microarray (mDIP-Chip) to be methylated in ovarian cancer cell lines, A2780 and CP70. By microarray, it was also found to be upregulated in immortalized ovarian surface epithelial (IOSE) cells following TGF-β treatment. Thus, we hypothesized that ABCA1 may be involved in ovarian cancer and its initiation.
  
  
  RESULTS
  We first compared the expression level of ABCA1 in IOSE cells and a panel of ovarian cancer cell lines and found that ABCA1 was expressed in HeyC2, SKOV3, MCP3, and MCP2 ovarian cancer cell lines but downregulated in A2780 and CP70 ovarian cancer cell lines. The reduced expression of ABCA1 in A2780 and CP70 cells was associated with promoter hypermethylation, as demonstrated by bisulfite pyro-sequencing. We also found that knockdown of ABCA1 increased the cholesterol level and promoted cell growth in vitro and in vivo. Further analysis of ABCA1 methylation in 76 ovarian cancer patient samples demonstrated that patients with higher ABCA1 methylation are associated with high stage (P = 0.0131) and grade (P = 0.0137). Kaplan-Meier analysis also found that patients with higher levels of methylation of ABCA1 have shorter overall survival (P = 0.019). Furthermore, tissue microarray using 55 ovarian cancer patient samples revealed that patients with a lower level of ABCA1 expression are associated with shorter progress-free survival (P = 0.038).
  
  
  CONCLUSIONS
  ABCA1 may be a tumor suppressor and is hypermethylated in a subset of ovarian cancer patients. Hypermethylation of ABCA1 is associated with poor prognosis in these patients.
authors: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan ; Division of Gastroenterology, Chang Gung Memorial Hospital, Chia-Yi, Taiwan.
authors: Jian-Liang
authors: JL
authors: Chou
authors: Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, No 291, Zhongzheng Rd., Zhonghe District, New Taipei City, 23561 Taiwan.
authors: Rui-Lan
authors: RL
authors: Huang
authors: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan.
authors: Jacqueline
authors: J
authors: Shay
authors: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan.
authors: Lin-Yu
authors: LY
authors: Chen
authors: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan.
authors: Sheng-Jie
authors: SJ
authors: Lin
authors: Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH USA.
authors: Pearlly S
authors: PS
authors: Yan
authors: Department of Life Science, Tunghai University, Taichung, Taiwan.
authors: Wei-Ting
authors: WT
authors: Chao
authors: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan.
authors: Yi-Hui
authors: YH
authors: Lai
authors: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan.
authors: Yen-Ling
authors: YL
authors: Lai
authors: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors: Tai-Kuang
authors: TK
authors: Chao
authors: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan.
authors: Cheng-I
authors: CI
authors: Lee
authors: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan.
authors: Chien-Kuo
authors: CK
authors: Tai
authors: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan.
authors: Shu-Fen
authors: SF
authors: Wu
authors: Medical Sciences, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN USA.
authors: Kenneth P
authors: KP
authors: Nephew
authors: Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center, San Antonio, TX USA.
authors: Tim H-M
authors: TH
authors: Huang
authors: Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, No 291, Zhongzheng Rd., Zhonghe District, New Taipei City, 23561 Taiwan ; Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan ; Department of Clinical Pharmacology, Xiangya Hospital; Institute of Clinical Pharmacology, Central South University and Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors: Hung-Cheng
authors: HC
authors: Lai
authors: Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chia-Yi 621, Taiwan ; Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan.
authors: Michael W Y
authors: MW
authors: Chan
keywords: ABCA1; Epigenetics; Ovarian cancer
references: Nature. 1990 Feb 1;343(6257):425-30
references: 1967820
references: Biochemistry. 2000 Nov 21;39(46):14113-20
references: 11087359
references: Fed Proc. 1958 Jul;17(2):691-7
references: 13562198
references: Cell Cycle. 2009 Jan 1;8(1):23-6
references: 19098432
references: Cancer Res. 2013 Feb 1;73(3):1211-8
references: 23233737
references: Cancer Res. 2002 Sep 15;62(18):5358-64
references: 12235007
references: Anticancer Res. 2000 Mar-Apr;20(2A):729-33
references: 10810347
references: Nat Med. 2011 Oct 30;17(11):1498-503
references: 22037646
references: J Obstet Gynaecol Res. 2007 Feb;33(1):3-16
references: 17212660
references: Gynecol Oncol. 2010 Jan;116(1):109-16
references: 19854496
references: J Pathol. 2009 Oct;219(2):222-31
references: 19644956
references: J Pharmacol Exp Ther. 2011 Feb;336(2):496-505
references: 21059805
references: Nature. 2011 Jun 29;474(7353):609-15
references: 21720365
references: Reprod Biomed Online. 2002 Nov-Dec;5(3):254-8
references: 12470522
references: Gynecol Oncol. 2010 Jan;116(1):78-81
references: 19822357
references: J Int Med Res. 2010 Jul-Aug;38(4):1413-27
references: 20926014
references: Gynecol Oncol. 2008 Oct;111(1):102-5
references: 20698078
references: Mol Cell Biol. 2001 Nov;21(22):7558-68
references: 11604492
references: Cell Rep. 2012 Sep 27;2(3):580-90
references: 22981231
references: Cancer Chemother Pharmacol. 2009 May;63(6):997-1005
references: 18766339
references: BMC Cancer. 2010 Mar 18;10:103
references: 20298590
references: Cancer Lett. 2012 Nov 1;324(1):1-12
references: 22542807
references: Am J Obstet Gynecol. 2008 Sep;199(3):215-23
references: 18468571
references: J Natl Compr Canc Netw. 2008 Sep;6(8):803-10; quiz 811
references: 18926091
references: Br J Cancer. 1992 Nov;66(5):787-93
references: 1419621
references: Lab Invest. 2010 Mar;90(3):414-25
references: 20065949
references: BMC Syst Biol. 2009 Jul 17;3:73
references: 19615063
references: Clin Biochem. 2003 Feb;36(1):61-5
references: 12554062
references: J Atheroscler Thromb. 2010 May;17 (5):493-502
references: 20057170
references: Epigenetics. 2011 Jun;6(6):727-39
references: 21540640
references: Mutat Res. 2008 Dec 1;647(1-2):21-9
references: 18723033
references: Neoplasia. 2008 Sep;10(9):908-19
references: 18714391
references: Int J Oncol. 2014 Nov;45(5):2101-7
references: 25175925