Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFκB pathway in gastric cancer development
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Bao-gui Zhang1,2,*, Lei Hu1,*, Ming-de Zang1,*, He-xiao Wang1, Wei Zhao3, Jian-fang Li1, Li-ping Su1, Zhifeng Shao4, Xiaodong Zhao4, Zheng-gang Zhu1, Min Yan1, Bingya Liu1
1Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
2Affiliated Hospital of Jining Medical University, Jining, People’s Republic of China
3Department of Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
4Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
*These authors have contributed equally to this work
Bingya Liu, e-mail: email@example.com
Keywords: gastric cancer development, H. pylori CagA, DNMT1, hypermethylation, AKT-NF-kB pathway
Received: August 24, 2015 Accepted: January 17, 2016 Published: February 02, 2016
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 NFκB, 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-NFκB pathway.
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