MET4 expression predicts poor prognosis of gastric cancers with Helicobacter pylori infection. Issue 3 (3rd April 2017)

• Record Type: Journal Article
• Authors: Sakamoto, Naoko; Tsujimoto, Hironori; Takahata, Risa; Cao, Brian; Zhao, Ping; Ito, Nozomi; Shimazaki, Hideyuki; Ichikura, Takashi; Hase, Kazuo; Vande Woude, George F.; Shinomiya, Nariyoshi
• Is Part Of: Cancer science. Volume 108:Issue 3(2017)
• Page Start: 322
• Page End: 330
• Publication Date: 2017-04-03
• Subjects: Gastric cancer -- Helicobacter pylori -- MET -- MET4 antibody -- prognosis; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.13146
• Languages: English
• ISSNs: 1347-9032

Abstract

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. Abstract : Poor prognosis of MET4‐positive gastric cancers is observed in H. pylori ‐positive but not in H. pylori ‐negative patients, and positive staining of both HGF/SF and MET4 showed a tendency of worst prognosis. Exposure of H. pylori stimulated MET downstream signaling, conferring proliferative and anti‐apoptotic activity on cancer cells, which suggests the importance of the elimination of H. pylori from gastric epithelial surface.