Involvement of matrix metalloproteinase-7 in invasion-metastasis through induction of cell dissociation in pancreatic cancer.
Epidermal growth factor receptor (EGFR) mediated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway was isolated as invasion-metastasis related factor in pancreatic cancer in our previous studies. Matrix metalloproteinase-7 (MMP-7) and tight junction (TJ) proteins are indicated to be involved in cancer invasion-metastasis. To clarify the underlying mechanism of involvement of MMP-7 in cancer invasion, western blotting, invasion assay and immunohistochemistry were performed in dissociated (PC-1.0 and AsPC-1) and non-dissociated (PC-1 and Capan-2) pancreatic cancer cells, as well as pancreatic cancer tissues. Intracellular MMP-7 protein presented as pre-proenzyme and its expression was decreased by AG1478 (EGFR inhibitor) or U0126 (MEK inhibitor) treatment in pancreatic cancer cells. Activated MMP-7 protein was only detected in the medium of PC-1.0 and AsPC-1 cells, but not detected in the medium of PC-1 and Capan-2 cells. Moreover, MMP-7 treatment significant induced the dissociation of cell colonies in PC-1 and Capan-2 cells. Synchronously, TJ structure was apparently disrupted and translocation of TJ proteins to cytoplasm or extracellular medium was induced in PC-1 and Capan-2 cells. Furthermore, MMP-7 treatment markedly increased the in vitro invasion of PC-1 and Capan-2 cells. In addition, MMP-7 expression at the invasive front was obviously stronger than that at the center of pancreatic cancer tissues. Activation of MMP-7 protein is closely involved in disruption of TJ structure and consequent induction of cell dissociation as well as invasion in pancreatic cancer. EGFR mediated MEK/ERK signaling pathway is implied to be involved in regulation of MMP-7 expression in pancreatic cancer cells.
Tan
Xiaodong
X
Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan. tanxd@hotmail.com
Egami
Hiroshi
H
Ishikawa
Shinji
S
Sugita
Hideki
H
Kamohara
Hidenobu
H
Nakagawa
Masahide
M
Nozawa
Fumiaki
F
Abe
Michio
M
Ogawa
Michio
M
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D006224:Cricetinae; D066246:ErbB Receptors / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis* / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D066246:ErbB Receptors; D020783:Matrix Metalloproteinase 7