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Trefoil factor 2 promotes cell proliferation in pancreatic β-cells through CXCR-4-mediated ERK1/2 phosphorylation

Kazuki Orime1, Jun Shirakawa, Yu Togashi

  • 1Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan.

Endocrinology
|November 28, 2012
PubMed

Insights

Trefoil factor 2 (TFF2) promotes pancreatic beta-cell proliferation by activating ERK1/2 signaling via CX-chemokine receptor-4. This finding suggests TFF2 as a potential therapeutic target for increasing beta-cell mass in type 2 diabetes.

Area of Science:

  • Endocrinology
  • Cell Biology
  • Molecular Medicine

Background:

  • Decreased pancreatic beta-cell mass is a key feature of type 2 diabetes.
  • Gastrointestinal incretin peptides are known to promote beta-cell proliferation.
  • Trefoil factor 2 (TFF2), a stomach-derived peptide, has roles in cell migration and proliferation, but its function in pancreatic beta-cells was unclear.

Purpose of the Study:

  • To investigate the mechanism by which TFF2 enhances pancreatic beta-cell proliferation.
  • To explore the potential of TFF2 as a therapeutic target for increasing beta-cell mass.

Main Methods:

  • TFF2 was overexpressed using adenovirus vectors or administered as a recombinant peptide in INS-1 cells, MIN6 cells, and mouse islets.
  • Cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation.
  • Gene expression of cyclins was analyzed using quantitative PCR.
  • ERK1/2 phosphorylation was measured by Western blot.
  • Specific inhibitors (U0126 for MAPK kinase, CX-chemokine receptor-4 antagonist) were used to elucidate signaling pathways.

Main Results:

  • TFF2 overexpression significantly increased BrdU incorporation in beta-cells, indicating enhanced proliferation, without affecting insulin secretion.
  • TFF2 upregulated the expression of key cell cycle regulators, including cyclins A2, D1, D2, D3, and E1.
  • TFF2 peptide treatment led to increased ERK1/2 phosphorylation and BrdU incorporation in MIN6 cells.
  • Inhibition of MAPK kinase or CX-chemokine receptor-4 abolished TFF2-induced beta-cell proliferation and ERK1/2 activation.

Conclusions:

  • TFF2 promotes pancreatic beta-cell proliferation through the CX-chemokine receptor-4-mediated activation of the ERK1/2 signaling pathway.
  • TFF2 represents a novel therapeutic target for strategies aimed at increasing beta-cell mass in type 2 diabetes.
  • Further research into TFF2's role could lead to new treatments for diabetes.

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