Open AccessMetformin attenuates synergic effect of diabetes mellitus and Helicobacter pylori infection on gastric cancer cells proliferation by suppressing PTEN expression
Author(s) -
Lu Huibin,
Han Xinwei,
Ren Jianzhuang,
Ren Kewei,
Li Zongming,
Zhang Quanhui
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15967
Subject(s) - pten , methylation , cancer research , dna methylation , helicobacter pylori , caga , apoptosis , biology , bisulfite sequencing , metformin , cancer , microbiology and biotechnology , pi3k/akt/mtor pathway , medicine , gene expression , diabetes mellitus , endocrinology , gene , biochemistry , virulence
It has been reported that CagA of Helicobacter pylori reduced PTEN expression by enhancing its promoter methylation. Furthermore, diabetes mellitus (DM) may also promote the methylation status of PTEN, a tumour suppressor gene in gastric cancer (GC). It is intriguing to explore whether DM may strengthen the tumorigenic effect of H pylori (HP) by promoting the methylation of PTEN promoter and whether the administration of metformin may reduce the risk of GC by suppressing the methylation of PTEN promoter. In this study, we enrolled 107 GC patients and grouped them as HP(−)DM(−) group, HP(+)DM(−) group and HP(+)DM(+) group. Bisulphite sequencing PCR evaluated methylation of PTEN promoter. Quantitative real‐time PCR, immunohistochemistry and Western blot, immunofluorescence, flow cytometry and MTT assay were performed accordingly. DNA methylation of PTEN promoter was synergistically enhanced in HP(+)DM(+) patients, and the expression of PTEN was suppressed in HP(+)DM(+) patients. Cell apoptosis was decreased in HP(+)DM(+) group. Metformin showed an apparent effect on restoring CagA‐induced elevation of PTEN promoter methylation, thus attenuating the PTEN expression. The reduced PTEN level led to increased proliferation and inhibited apoptosis of HGC‐27 cells. In this study, we collected GC tumour tissues from GC patients with or without DM/HP to compare their PTEN methylation and expression while testing the effect of metformin on the methylation of PTEN promoter. In summary, our study suggested that DM could strengthen the tumorigenic effect of HP by promoting the PTEN promoter methylation, while metformin reduces GC risk by suppressing PTEN promoter methylation.