Helicobacter Pylori Infection-induced Histone Modification In Stepwise Gastric Carcinogenesis And Its Clinical Implications

Background and ObjectiveHistone modification is one of the important parts of epigenetics,and plays an important role in adjusting the various functions of human's biology.Our previous works have demonstrated Helicobacter pylori?Hp?infection can alter histone H3serine 10 phosphorylation?p-H3S10?and H3 lysine 23 acetylation?H3K23ac?statuses in gastric epithelial cells.Other's study had shown that the expression of H3Lysine 9 trimethylation?H3k9me3?was associated with the prognosis of gastric cancer patients.However,the mechanism of Hp-induced histone modification in gastric carcinogenesis is unclear.To clarify the role of Hp infection induced histone modification in the development of disease,and to explore its clinical implication,we investigate the expression of p-H3S10,H3K23ac and H3k9me3 in various stages of gastric carcinogenesis.At the same time,ki67 was used to evaluate the cells proliferation.This study can contribute to further understand the pathogenesis of Hp infection,and provide new ideas and approaches for prevention and reduction of chronic gastritis,peptic ulcer and gastric cancer caused by Hp infection in clinical application.MethodsStomach biopsy samples from antrum and non-cardiac lesion region were collected from 134 patients under gastroscopy,and stained with p-H3S10,H3K23ac,H3k9me3,Ki67 and Hp by immunohistochemistry staining?IHS,expressed as labeling index,LI?.They were categorized into non-atrophic gastritis?NAG?,chronic atrophic gastritis?CAG?,intestinal metaplasia?IM?,low grade intraepithelial neoplasia?LGIN?,high grade intraepithelial neoplasia?HGIN?and intestinal type gastric cancer?GC?groups according with pathological results.Moreover,each group was further categorized into Hp positive group and Hp negative group,Hp infection was determined by either ¹³C-Urea breath test or IHS.We also investigated the change of p-H3S10 positive cells'location in gastric gland.ResultsIn Hp negative patients,LI of p-H3S10 were gradually increased in NAG,CAG,IM groups,peaked at LGIN and declined in HGIN and GC groups.In Hp-infected patients,LI of p-H3S10 followed the similar pattern as above,with increased expression over the corresponding Hp negative controls except in NAG patient whose LI was decreased when compared with Hp negative control?5.24±1.98 vs3.52±1.39,P<0.05?.LI of Ki67 in Hp negative groups were higher in GC than CAG and LGIN groups ?P<0.05?,and higher in IM group compared with CAG group?P<0.05?.In Hp positive groups,Ki67 LI were increased stepwise from NAG to GC except slightly decrease in CAG group;and its higher in GC than any other groups?P<0.01?.In addition,we noted that p-H3S10 staining is accompanied with its location changes from gastric gland bottom expanded to whole gland as disease stage progress.However,there were no significant variations about labeling indexes of H3K23ac and H3k9me3 in different stages of gastric carcinogenesis?P>0.05?,and the correlation among the expression of p-H3S10,H3K23ac,H3K9me and ki67 had no significant difference?P>0.05?.Conclusions1.These results indicate that stepwise gastric carcinogenesis is associated with altered p-H3S10,Hp infection enhances p-H3S10 expression in these processes.2.With the development of gastric cancer,p-H3S10 location change from gland bottom staining expand to whole gland expression.This suggest that p-H3S10 may play an important role in cell malignant transformation.