Helicobacter pylori-induced HB-EGF upregulates gastrin expression via the EGF receptor, C-Raf, Mek1, and Erk2 in the MAPK pathway

Niluka Gunawardhana, Sungil Jang, Yun Hui Choi, Youngmin A. Hong, Yeong Eui Jeon, Aeryun Kim, Hanfu Su, Ji Hye Kim, Yun Jung Yoo, D. Scott Merrell, Jinmoon Kim, Jeong Heon Cha

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Article number541
JournalFrontiers in Cellular and Infection Microbiology
Volume7
Issue numberJAN
DOIs
Publication statusPublished - 2018 Jan 15

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Gastrins
Epidermal Growth Factor Receptor
Helicobacter pylori
Up-Regulation
Epidermal Growth Factor
Stomach Diseases
Small Interfering RNA
Heparin-binding EGF-like Growth Factor
Transforming Growth Factors
Helicobacter Infections
Transcriptional Activation
Stomach Neoplasms
Heparin
Intercellular Signaling Peptides and Proteins
Protein Isoforms
Ligands
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

Cite this

Gunawardhana, Niluka ; Jang, Sungil ; Choi, Yun Hui ; Hong, Youngmin A. ; Jeon, Yeong Eui ; Kim, Aeryun ; Su, Hanfu ; Kim, Ji Hye ; Yoo, Yun Jung ; Merrell, D. Scott ; Kim, Jinmoon ; Cha, Jeong Heon. / Helicobacter pylori-induced HB-EGF upregulates gastrin expression via the EGF receptor, C-Raf, Mek1, and Erk2 in the MAPK pathway. In: Frontiers in Cellular and Infection Microbiology. 2018 ; Vol. 7, No. JAN.
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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.",
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Helicobacter pylori-induced HB-EGF upregulates gastrin expression via the EGF receptor, C-Raf, Mek1, and Erk2 in the MAPK pathway. / Gunawardhana, Niluka; Jang, Sungil; Choi, Yun Hui; Hong, Youngmin A.; Jeon, Yeong Eui; Kim, Aeryun; Su, Hanfu; Kim, Ji Hye; Yoo, Yun Jung; Merrell, D. Scott; Kim, Jinmoon; Cha, Jeong Heon.

In: Frontiers in Cellular and Infection Microbiology, Vol. 7, No. JAN, 541, 15.01.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Helicobacter pylori-induced HB-EGF upregulates gastrin expression via the EGF receptor, C-Raf, Mek1, and Erk2 in the MAPK pathway

AU - Gunawardhana, Niluka

AU - Jang, Sungil

AU - Choi, Yun Hui

AU - Hong, Youngmin A.

AU - Jeon, Yeong Eui

AU - Kim, Aeryun

AU - Su, Hanfu

AU - Kim, Ji Hye

AU - Yoo, Yun Jung

AU - Merrell, D. Scott

AU - Kim, Jinmoon

AU - Cha, Jeong Heon

PY - 2018/1/15

Y1 - 2018/1/15

N2 - 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.

AB - 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.

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