期刊
ONCOTARGET
卷 7, 期 9, 页码 9788-9800出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7125
关键词
gastric cancer development; H. pylori CagA; DNMT1; hypermethylation; AKT-NF-kB pathway
资金
- National Natural Science foundation of China [91529302, 81572798, 81272749]
- Key Projects in the National Science & Technology Pillar Program of China [2014BAI09B03]
- Shanghai Health Bureau [2012306]
Methylation of CpG islands in tumor suppressor gene prompter is one of the most characteristic abnormalities in Helicobacter pylori (HP)-associated gastric carcinoma (GC). Here, we investigated the pathogenic and molecular mechanisms underlying hypermethylation of tumor suppressor genes in HP induced GC development. We found that tumor suppressor genes hypermethylation, represented by MGMT, positively correlated with CagA in clinical specimens, gastric tissues from HP infected C57 mice and GC cell lines transfected by CagA or treated by HP infection. CagA enhanced PDK1 and AKT interaction and increased AKT phosphorylation. The P-AKT subsequent activated NF kappa B, which then bound to DNMT1 promoter and increased its expression. Finally, the upregulated DNMT1 promoted tumor suppressor genes hypermethylation with MGMT as a representative. In conclusion, CagA increased tumor suppressor genes hypermethylation via stimulating DNMT1 expression through the AKT-NF kappa B pathway.
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