Transforming growth factor-α activates pancreatic stellate cells and may be involved in matrix metalloproteinase-1 upregulation

Hiroki Tahara, Ken Sato, Yuichi Yamazaki, Tatsuya Ohyama, Norio Horiguchi, Hiroaki Hashizume, Satoru Kakizaki, Hitoshi Takagi, Iwata Ozaki, Hideo Arai, Junko Hirato, Ralf Jesenofsky, Atsushi Masamune, Masatomo Mori

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The role that transforming growth factor-α (TGF-α) has in chronic pancreatitis and pancreatic cancer has not been fully elucidated. We evaluated the effects of TGF-α on the human pancreatic stellate cell (PSC) line RLT-PSC and primary human PSCs, and the expression levels of TGF-α and metalloproteinase-1 (MMP-1) in human chronic pancreatitis and pancreatic cancer tissues. TGF-α stimulated the proliferation and migration of PSCs. Although the mRNA expression levels of tissue inhibitor of metalloproteinase-1 and α1(I) collagen were unchanged, the mRNA expression levels of MMP-1 increased concomitant with increases in MMP-1 protein levels and collagenase activity. TGF-α-stimulated migration of RLT-PSC cells was partially blocked by tissue inhibitor of metalloproteinase-1 protein and MMP-1 small interfering RNA. MMP-1 was also observed to stimulate the migration of PSCs. TGF-α-induced MMP-1 expression was completely blocked by gefitinib in PSCs. The Ras-ERK and PI3/Akt pathways appear to be involved in the activation of MMP-1 in PSCs. Immunohistochemical analyses showed that MMP-1 expression was significantly increased in the pancreatic interstitial tissues in case of chronic pancreatitis or pancreatic cancer compared with those in case of normal pancreas. In conclusion, TGF-α increased proliferation and migration of PSCs. TGF-α-induced migration of cells may be partly due to upregulation of MMP-1. TGF-α and MMP-1 upregulation may contribute to the pathogenesis of chronic pancreatitis and pancreatic cancer.

Original languageEnglish
Pages (from-to)720-732
Number of pages13
JournalLaboratory Investigation
Volume93
Issue number6
DOIs
Publication statusPublished - 2013 Jun 1

Keywords

  • PI3/Akt
  • RLT-PSC
  • Ras-ERK
  • pancreatic cancer
  • pancreatic fibrosis
  • primary PSC

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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    Tahara, H., Sato, K., Yamazaki, Y., Ohyama, T., Horiguchi, N., Hashizume, H., Kakizaki, S., Takagi, H., Ozaki, I., Arai, H., Hirato, J., Jesenofsky, R., Masamune, A., & Mori, M. (2013). Transforming growth factor-α activates pancreatic stellate cells and may be involved in matrix metalloproteinase-1 upregulation. Laboratory Investigation, 93(6), 720-732. https://doi.org/10.1038/labinvest.2013.59