title: Methylation-mediated repression of GADD45A and GADD45G expression in gastric cardia adenocarcinoma.
abstract: The growth arrest DNA damage-inducible gene (GADD45) family, which is composed of GADD45A, GADD45B, and GADD45G, may play similar but not identical roles in tumorigenesis. Genetic changes associated with or responsible for their dysregulation are in general uncommon. This study was to detect the role of GADD45 gene family in gastric cardia adenocarcinoma (GCA) and the relationship of GADD45A and GADD45G methylation to a series of pathological parameters in a large GCA sample, in order to elucidate more information on the role of GADD45 gene family with regard to the pathogenesis of GCA. Decreased mRNA and protein expression of GADD45A and GADD45G but not GADD45B were found in 138 GCA tumor tissues. The methylation frequency of 5' 4 CpG region located in distal promoter of GADD45A and proximal promoter of GADD45G in GCA tumor tissues was significantly higher than that in corresponding normal tissues. The expression levels of GADD45A and GADD45G were inversely correlated with methylation levels. GADD45B expression was not correlated with GCA patients survival, while GADD45A and GADD45G methylation status and protein expression were independently associated with GCA patients' survival. These results suggest that GADD45A and GADD45G gene may act as functional tumor suppressor but being frequently inactivated epigenetically in patients with GCA. Silencing of GADD45A and GADD45G, negative regulator of cell growth, is most likely responsible for conferring a selective growth advantage during GCA evolution and outgrowth.
authors.affiliation: Department of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Dong
authors.forename: Yanli
authors.initials: Y
authors.lastname: Guo
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Kuang
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002299:Cardia / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000032:analysis / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D005753:Gastric Mucosa / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D000097642:GADD45 Proteins
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004247:DNA; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C485654:GADD45G protein, human
keywords: GADD45; expression; gastric cardia adenocarcinoma; methylation