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NDN is an imprinted tumor suppressor gene that is downregulated in ovarian cancers through genetic and epigenetic mechanisms

2015; Impact Journals LLC; Volume: 7; Issue: 3 Linguagem: Inglês

10.18632/oncotarget.6576

1949-2553

Hailing Yang, Partha Das, Yinhua Yu, Weiqun Mao, Yan Wang, Keith Baggerly, Ying Wang, Rebecca T. Marquez, Anuja Bedi, Jinsong Liu, David M. Fishman, Zhen Lü, Robert C. Bast,

Prenatal Screening and Diagnostics

// Hailing Yang *, 1 , Partha Das *, 1 , Yinhua Yu 4 , Weiqun Mao 1 , Yan Wang 1 , Keith Baggerly 2 , Ying Wang 2 , Rebecca T. Marquez 1 , Anuja Bedi 5 , Jinsong Liu 3 , David Fishman 6 , Zhen Lu 1 , Robert C. Bast Jr 1 1 Departments of Experimental Therapeutics, U.T.M.D. Anderson Cancer Center, Houston, TX 77030, USA 2 Departments of Bioinformatics, U.T.M.D. Anderson Cancer Center, Houston, TX 77030, USA 3 Departments of Pathology, U.T.M.D. Anderson Cancer Center, Houston, TX 77030, USA 4 Department of Gynecology, Obstetrics and the Gynecology Hospital, Fudhan University, Shanghai, PR China 5 Texas College of Osteopathic Medicine, Fort Worth, TX 76107, USA 6 Gynecology and Reproductive Science, Mount Sinai Hospital, New York, NY 10029, USA * These authors have contributed equally to this work Correspondence to: Robert C. Bast, e-mail: rbast@mdanderson.org Zhen Lu, e-mail: zlu@mdanderson.org Keywords: NDN, FAK, tumor suppressor gene, imprinting, growth inhibition, cell motility Received: July 09, 2015 Accepted: November 21, 2015 Published: December 12, 2015 ABSTRACT NDN is a maternally imprinted gene consistently expressed in normal ovarian epithelium, is dramatically downregulated in the majority of ovarian cancers. Little or no NDN expression could be detected in 73% of 351 epithelial ovarian cancers. NDN was also downregulated in 10 ovarian cancer cell lines with total loss in 6 of 10. Re-expression of NDN decreased Bcl-2 levels and induced apoptosis, which significantly inhibited ovarian cancer cell growth in cell culture and in xenografts. In addition, re-expression of NDN inhibited cell migration by decreasing actin stress fiber and focal adhesion complex formation through deactivation of Src, FAK and RhoA. Loss of NDN expression in ovarian cancers could be attributed to LOH in 28% of 18 informative cases and to hypermethylation of CpG sites 1 and 2 of NDN promoter in 23% and 30% of 43 ovarian cancers, respectively. Promoter hypermethylation was also found in 5 of 10 ovarian cancer cell lines. Treatment with the demethylating agent 5-aza-2′-deoxycytidine restored NDN expression in 4 of 7 cell lines with enhanced promoter methylation levels. These observations support the conclusion that NDN is an imprinted tumor suppressor gene which affects cancer cell motility, invasion and growth and that its loss of function in ovarian cancer can be caused by both genetic and epigenetic mechanisms.