title: Helicobacter pylori CagA induces ornithine decarboxylase upregulation via Src/MEK/ERK/c-Myc pathway: implication for progression of gastric diseases.
abstract: Helicobacter pylori (H. pylori) dysregulates the expression of various genes resulting in gastric precursor lesions and cancer. Meanwhile, ornithine decarboxylase (ODC) is a key enzyme that catalyzes the formation of polyamines which are critical for cell growth. So far, the possible regulation of ODC by H. pylori and its virulence factors, and the associated mechanism in gastric epithelial cells remains undefined. In the present study, we found that cellular ODC protein was upregulated by wild-type H. pylori infection and ectopic expression of a cytotoxin-associated gene A (CagA). As a negative control, there was no such effect by cagA-mutant H. pylori infection. Results of signal protein inhibitor treatment demonstrated that the Src, MEK (mitogen-activated protein kinase kinase) and ERK (extracellular signal-regulated kinase) pathway was involved. Moreover, when c-Myc was inhibited, the stimulatory effect of CagA on ODC expression was abolished. Clinically, a positive correlation between c-Myc and ODC expression was observed in patient-derived abnormal gastric tissues. These results implied that the Src/MEK/ERK/c-Myc pathway was required for CagA-mediated ODC induction. Finally, inhibition of ODC expression led to decreased foci formation of gastric epithelial cells before and after H. pylori infection, and ODC protein was over-expressed in precancerous gastric lesions and primary gastric cancer. Collectively, our findings provide new insights into the mechanism behind H. pylori-infection-associated gastric diseases.
authors.affiliation: Department of Microbiology, Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University, Jinan 250012, PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Fang
authors.forename: Han
authors.initials: H
authors.lastname: Yu
authors.forename: Xiuming
authors.initials: X
authors.lastname: Liang
authors.forename: Xinpeng
authors.initials: X
authors.lastname: Li
authors.forename: Xianxi
authors.initials: X
authors.lastname: Liu
authors.forename: Chunyan
authors.initials: C
authors.lastname: Chen
authors.forename: Jihui
authors.initials: J
authors.lastname: Jia
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D001426:Bacterial Proteins / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005753:Gastric Mucosa / Q000378:metabolism; D016480:Helicobacter pylori / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D009955:Ornithine Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb / Q000502:physiology*; D015398:Signal Transduction; D013270:Stomach / Q000473:pathology; D013272:Stomach Diseases / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D020598:Proto-Oncogene Proteins c-myb; C080866:cagA protein, Helicobacter pylori; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D009955:Ornithine Decarboxylase