title: NDN is an imprinted tumor suppressor gene that is downregulated in ovarian cancers through genetic and epigenetic mechanisms.
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.
authors.affiliation: Departments of Experimental Therapeutics, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hailing
authors.initials: H
authors.lastname: Yang
authors.affiliation: Departments of Experimental Therapeutics, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Das
authors.affiliation: Department of Gynecology, Obstetrics and the Gynecology Hospital, Fudhan University, Shanghai, PR China.
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Departments of Experimental Therapeutics, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Mao
authors.affiliation: Departments of Experimental Therapeutics, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Bioinformatics, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Baggerly
authors.affiliation: Departments of Bioinformatics, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Experimental Therapeutics, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Marquez
authors.affiliation: Texas College of Osteopathic Medicine, Fort Worth, TX, USA.
authors.forename: Anuja
authors.initials: A
authors.lastname: Bedi
authors.affiliation: Departments of Pathology, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Gynecology and Reproductive Science, Mount Sinai Hospital, New York, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fishman
authors.affiliation: Departments of Experimental Therapeutics, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Departments of Experimental Therapeutics, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D000077209:Decitabine; D004848:Epithelium / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics*; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D022502:Stress Fibers / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C000612102:NDN protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; C069766:necdin; C066737:RHOA protein, human; D000077209:Decitabine; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D020742:rhoA GTP-Binding Protein; D001374:Azacitidine
keywords: FAK; NDN; cell motility; growth inhibition; imprinting; tumor suppressor gene