MET4 expression predicts poor prognosis of gastric cancers with Helicobacter pylori infection |
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| Authors: | Naoko Sakamoto Hironori Tsujimoto Risa Takahata Brian Cao Ping Zhao Nozomi Ito Hideyuki Shimazaki Takashi Ichikura Kazuo Hase George F. Vande Woude Nariyoshi Shinomiya |
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| Affiliation: | 1. Department of Surgery, National Defense Medical College, Tokorozawa, Japan;2. Laboratory of Antibody Technology, Van Andel Research Institute, Grand Rapids, MI, USA;3. Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Japan;4. Court Physician in Chief, The Imperial Household Agency, Tokyo, Japan;5. Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI, USA;6. Department of Integrative Physiology and Bio‐Nano Medicine, National Defense Medical College, Tokorozawa, Japan |
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| 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. |
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| Keywords: | Gastric cancer
Helicobacter pylori
MET
MET4 antibody prognosis |
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