Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFκB pathway in gastric cancer development

Bao-gui Zhang; Lei Hu; Ming-de Zang; He-xiao Wang; Wei Zhao; Jian-fang Li; Li-ping Su; Zhifeng Shao; Xiaodong Zhao; Zheng-gang Zhu; Min Yan; Bingya Liu

doi:10.18632/oncotarget.7125

Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFκB pathway in gastric cancer development

Oncotarget. 2016 Mar 1;7(9):9788-800. doi: 10.18632/oncotarget.7125.

Authors

Bao-gui Zhang^{1

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

Affiliations

¹ Shanghai 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.
² Affiliated Hospital of Jining Medical University, Jining, People's Republic of China.
³ Department of Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
⁴ Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China.

Abstract

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.

Keywords: AKT-NF-kB pathway; DNMT1; H. pylori CagA; gastric cancer development; hypermethylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Bacterial / genetics
Antigens, Bacterial / metabolism*
Bacterial Proteins / genetics
Bacterial Proteins / metabolism*
Cell Line, Tumor
CpG Islands / genetics
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases / biosynthesis*
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA Methylation / genetics*
DNA Modification Methylases / genetics
DNA Modification Methylases / metabolism
DNA Repair Enzymes / genetics
DNA Repair Enzymes / metabolism
Enzyme Activation
Genes, Tumor Suppressor
Helicobacter Infections / microbiology
Helicobacter pylori / metabolism*
Humans
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
NF-kappa B / metabolism*
Phosphorylation
Promoter Regions, Genetic / genetics
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism*
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
RNA Interference
RNA, Small Interfering / genetics
Stomach Neoplasms / genetics*
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism

Substances

Antigens, Bacterial
Bacterial Proteins
NF-kappa B
PDK1 protein, human
Pdk1 protein, mouse
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
RNA, Small Interfering
Tumor Suppressor Proteins
cagA protein, Helicobacter pylori
DNA Modification Methylases
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNMT1 protein, human
Dnmt1 protein, mouse
MGMT protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
DNA Repair Enzymes