title: Suppressor of cytokine signaling 4 detected as a novel gastric cancer suppressor gene using double combination array analysis.
abstract: BACKGROUND
  Molecular mechanisms behind the oncogenesis of gastric cancer (GC) have yet to be identified.
  
  
  METHODS
  A novel candidate tumor-suppressor gene, which is also associated with inhibition of epidermal growth factor (EGF), was sought by means of double combination array analysis for use as a prognostic marker of GC. This consisted of expression array and single nucleotide polymorphism array analysis, along with a literature search. Cancerous and noncancerous tissues from an 82-year-old man with GC were analyzed simultaneously.
  
  
  RESULTS
  The expression array and literature search identified that the suppressor of cytokine signaling 4 (SOCS4), a negative feedback regulator of EGF signaling, had significantly attenuated expression in tumor tissue. Although chromosomal deletion was not found at 14q22 where SOCS4 is located, numerous CpG sites were observed in the promoter region of the SOCS4 gene. Several GC cell lines showed reactivation of SOCS4 mRNA expression after treatment with 5-aza-2'-deoxycytidine. Using surgically resected specimens, we found that 40 of 50 (80%) tumor tissues exhibited promoter hypermethylation of the SOCS4 gene. Consequently, SOCS4 expression in tumor tissues was significantly weaker than in noncancerous counterparts (P < 0.0001). In the survival analysis, SOCS4 hypermethylation was associated with a poor prognosis of GC patients (P = 0.0320).
  
  
  CONCLUSIONS
  Double combination array analysis suggested that SOCS4 could be a novel candidate for further exploration as a tumor-suppressor gene in GC. Hypermethylation was the mechanism by which SOCS4 was silenced and was implicated in the development of GC. SOCS4 methylation might be an informative marker in predicting the prognosis.
authors: Department of Surgery II, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors: Daisuke
authors: D
authors: Kobayashi
authors: Shuji
authors: S
authors: Nomoto
authors: Yasuhiro
authors: Y
authors: Kodera
authors: Michitaka
authors: M
authors: Fujiwara
authors: Masahiko
authors: M
authors: Koike
authors: Goro
authors: G
authors: Nakayama
authors: Norifumi
authors: N
authors: Ohashi
authors: Akimasa
authors: A
authors: Nakao
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C473084:SOCS4 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D066246:ErbB Receptors