title: Transforming growth factor-α activates pancreatic stellate cells and may be involved in matrix metalloproteinase-1 upregulation.
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.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tahara
authors.forename: Ken
authors.initials: K
authors.lastname: Sato
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ohyama
authors.forename: Norio
authors.initials: N
authors.lastname: Horiguchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hashizume
authors.forename: Satoru
authors.initials: S
authors.lastname: Kakizaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takagi
authors.forename: Iwata
authors.initials: I
authors.lastname: Ozaki
authors.forename: Hideo
authors.initials: H
authors.lastname: Arai
authors.forename: Junko
authors.initials: J
authors.lastname: Hirato
authors.forename: Ralf
authors.initials: R
authors.lastname: Jesenofsky
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D058954:Pancreatic Stellate Cells / Q000378:metabolism*; D050500:Pancreatitis, Chronic / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D016211:Transforming Growth Factor alpha; D053773:Transforming Growth Factor beta1; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D018631:ras Proteins