Helicobacter pylori-Induced HB-EGF Upregulates Gastrin Expression via the EGF Receptor, C-Raf, Mek1, and Erk2 in the MAPK Pathway

Abstract

Helicobacter pylori is associated with hypergastrinemia, which has been linked to the development of gastric diseases. Although the molecular mechanism is not fully understood, H. pylori is known to modulate the Erk pathway for induction of gastrin expression. Herein we found that an epidermal growth factor (EGF) receptor kinase inhibitor significantly blocked H. pylori-induced gastrin promoter activity, suggesting involvement of EGF receptor ligands. Indeed, H. pylori induced mRNA expression of EGF family members such as amphiregulin, EGF, heparin-binding EGF-like growth factor (HB-EGF), and transforming growth factor-α. Of these, specific siRNA targeting of HB-EGF significantly blocked H. pylori-induced gastrin expression. Moreover, H. pylori induced HB-EGF ectodomain shedding, which we found to be a critical process for H. pylori-induced gastrin expression. Thus, we demonstrate a novel role for human mature HB-EGF in stimulating gastrin promoter activity during H. pylori infection. Further investigation using specific siRNAs targeting each isoform of Raf, Mek, and Erk elucidated that the mechanism underlying H. pylori-induced gastrin expression can be delineated as the sequential activation of HB-EGF, the EGF receptor, C-Raf, Mek1, and the Erk2 molecules in the MAPK pathway. Surprisingly, whereas Erk2 acts as a potent activator of gastrin expression, siRNA knockdown of Erk1 induced gastrin promoter activity, suggesting that Erk1 typically acts as a repressor of gastrin expression. Elucidation of the mechanism of gastrin modulation by HB-EGF-mediated EGF receptor transactivation should facilitate the development of therapeutic strategies against H. pylori-related hypergastrinemia and consequently gastric disease development, including gastric cancers.

Human vascular endothelial cells express epithelial growth factor in response to infection by Bartonella bacilliformis

“…In another study, levels of EGF, EGFR and a homolog of EGFR (c-erb-B2) were shown to be elevated in gastric mucosa of patients suffering from chronic gastritis with a Helicobacter pylori infection, and were comparable to samples from gastric cancer patients [28]. Subsequent work showed that H. pylori possessing an intact T4SS induced gastrin promoter activity through HB-EGF and EGFR [29]. In turn, gastrin could affect a variety of epithelial cell activities, including proliferation [30].…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…MMP-7 and HB-EGF expression is upregulated by H. pylori infection and is associated with EMT [274,275]. Likewise, MMP-7 overexpression is because of increased levels of gastrin, activator protein 1 (AP-1), and NF-kB induced by H. pylori infection [276][277][278][279]. Levels of MMP-7 might correlate with the degree of rehabilitation after treatment and poor prognosis in gastric cancer survival [270,280].…”

Helicobacter: Inflammation, immunology, and vaccines

“…Hence, transgenic mice overexpressing gastrin under the transcriptional control of the insulin promoter (INS‐GAS mice) rapidly develop gastric malignancies after H. pylori infection . Gunawardhana et al found that the induction of the gene encoding gastrin by H. pylori is abolished in the presence of AG1478, an inhibitor of epidermal growth factor receptor (EGFR) in AGS cells . Using siRNAs to specifically knockdown various signaling molecules, these authors demonstrated that H. pylori first induces the release of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), which in turn signals via Raf‐1 proto‐oncogene, serine/threonine kinase (RAF1), mitogen‐activated protein kinase kinase 1 (MAP2K1, previously known as MEK1), and mitogen‐activated protein kinase 1 (MAPK1, also called ERK2) to stimulate the transcription of the gene encoding gastrin .…”

“…Gunawardhana et al found that the induction of the gene encoding gastrin by H. pylori is abolished in the presence of AG1478, an inhibitor of epidermal growth factor receptor (EGFR) in AGS cells . Using siRNAs to specifically knockdown various signaling molecules, these authors demonstrated that H. pylori first induces the release of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), which in turn signals via Raf‐1 proto‐oncogene, serine/threonine kinase (RAF1), mitogen‐activated protein kinase kinase 1 (MAP2K1, previously known as MEK1), and mitogen‐activated protein kinase 1 (MAPK1, also called ERK2) to stimulate the transcription of the gene encoding gastrin . In the same way, it has been already reported that there is increased EGFR phosphorylation in the H. pylori ‐induced human gastric inflammation and cancer development .…”

“…17 Using siRNAs to specifically knockdown various signaling molecules, these authors demonstrated that H. pylori first induces the release of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which in turn signals via Raf-1 proto-oncogene, serine/ threonine kinase (RAF1), mitogen-activated protein kinase kinase 1 (MAP2K1, previously known as MEK1), and mitogen-activated protein kinase 1 (MAPK1, also called ERK2) to stimulate the transcription of the gene encoding gastrin. 17 In the same way, it has been already reported that there is increased EGFR phosphorylation in the H. pylori-induced human gastric inflammation and cancer development. 18 This year, the Wilson group also showed that treatment of H. pylori-infected INS-GAS mice or Mongolian gerbils with the EGFR inhibitor gefitinib resulted in (a) reduced activation of MAPK1/3 and activator protein 1 in GECs, (b) inhibition of chemokine synthesis by the gastric mucosa, (c) a decrease in myeloperoxidase-positive inflammatory cells, and (d) a marked reduction of gastric dysplasia and carcinoma.…”