title: Metallothionein 2A inhibits NF-κB pathway activation and predicts clinical outcome segregated with TNM stage in gastric cancer patients following radical resection.
abstract: BACKGROUND
  Metallothionein 2A (MT2A) as a stress protein, plays a protective role in gastric mucosal barrier. Its role in the development of gastric cancer (GC) is unclear. The mechanism of MT2A will be investigated in gastric tumorigenesis.
  
  
  METHODS
  MT2A expression was detected in 973 gastric specimens. The biological function was determined through ectopic expressing MT2A in vitro and in vivo. The possible downstream effectors of MT2A were investigated in NF-κB signaling. The protein levels of MT2A, IκB-α and p-IκB-α (ser32/36) expression were analyzed in a subset of 258 patients by IHC staining. The prognostic effects of MT2A, status of IκB-α and TNM stage were evaluated using the Kaplan-Meier method and compared using the log-rank test.
  
  
  RESULTS
  Decreased MT2A expression was detected in cell lines and primary tumors of GC. In clinical data, loss of MT2A (MT2A + in Normal (n =171, 76.0%); Intestinal metaplasia (n = 118, 50.8%); GC (n = 684. 22.4%, P < 0.001)) was associated with poor prognosis (P < 0.001), advanced TNM stage (P = 0.05), and down-regulation of IκB-α expression (P < 0.001). Furthermore, MT2A was the independent prognostic signature segregated from the status of IκB-α and pathological features. In addition, MT2A inhibited cell growth through apoptosis and G2/M arrest, which negatively regulated NF-κB pathway through up-regulation of IκB-α and down-regulation of p-IκB-α and cyclin D1 expression.
  
  
  CONCLUSIONS
  MT2A might play a tumor suppressive activity through inhibiting NF-κB signaling and may be a prognostic biomarker and potential target for individual therapy of GC patients.
authors.affiliation: Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital & Institute, No,52 Fucheng Road, Beijing, Haidian District 100142, PR China.
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Pan
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Huang
authors.forename: Rui
authors.initials: R
authors.lastname: Xing
authors.forename: Xin
authors.initials: X
authors.lastname: Yin
authors.forename: Jiantao
authors.initials: J
authors.lastname: Cui
authors.forename: Wenmei
authors.initials: W
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Youyong
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011379:Prognosis; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000601:surgery*; D016896:Treatment Outcome; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C530104:CCND1 protein, human; D020672:I-kappa B Proteins; C491053:MT2A protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D019938:Cyclin D1; D000072000:NF-KappaB Inhibitor alpha; D008668:Metallothionein