title: MET4 expression predicts poor prognosis of gastric cancers with Helicobacter pylori infection.
abstract: The role of HGF/SF-MET signaling is important in cancer progression, but its relation with Helicobacter pylori-positive gastric cancers remains to be elucidated. In total, 201 patients with primary gastric carcinoma who underwent curative or debulking resection without preoperative chemotherapy were studied. MET4 and anti-HGF/SF mAbs were used for immunohistochemical analysis. Survival of gastric cancer patients was estimated by Kaplan-Meier method and compared with log-rank. Cox proportional hazards models were fit to determine the independent association of MET-staining status with outcome. The effect of live H. pylori bacteria on cell signaling and biological behaviors was evaluated using gastric cancer cell lines. MET4-positive gastric cancers showed poorer prognosis than MET4-negative cases (overall survival, P = 0.02; relapse-free survival, P = 0.06). Positive staining for MET4 was also a statistically significant factor to predict poor prognosis in H. pylori-positive cases (overall survival, P < 0.01; relapse-free survival, P = 0.01) but not in H. pylori-negative cases. Gastric cancers positively stained with both HGF/SF and MET4 showed a tendency of the worst prognosis. Stimulation of MET-positive gastric cancer cells with live H. pylori bacteria directly upregulated MET phosphorylation and activated MET downstream signals such as p44/42MAPK and Akt, conferring cell proliferation and anti-apoptotic activity. In conclusion, positive staining for MET4 was useful for predicting poor prognosis of gastric cancers with H. pylori infection. Helicobacter pylori stimulated MET-positive gastric cancers and activated downstream signaling, thereby promoting cancer proliferation and anti-apoptotic activity. These results support the importance of H. pylori elimination from gastric epithelial surface in clinical therapy.
authors.affiliation: Department of Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: Department of Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Tsujimoto
authors.affiliation: Department of Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Takahata
authors.affiliation: Laboratory of Antibody Technology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Cao
authors.affiliation: Laboratory of Antibody Technology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Ito
authors.affiliation: Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shimazaki
authors.affiliation: Court Physician in Chief, The Imperial Household Agency, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ichikura
authors.affiliation: Department of Surgery, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hase
authors.affiliation: Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Vande Woude
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology*; D016481:Helicobacter Infections / Q000382:microbiology / Q000473:pathology*; D016480:Helicobacter pylori; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000382:microbiology / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: 
  Helicobacter pylori
  ; 
  MET
  ; Gastric cancer; MET4 antibody; prognosis