Coexpression of matrix metalloproteinase-7 (MMP-7) and epidermal growth factor (EGF) receptor in colorectal cancer: an EGF receptor tyrosine kinase inhibitor is effective against MMP-7-expressing cancer cells.
OBJECTIVE
Matrix metalloproteinase-7 (MMP-7) plays an important role in carcinoma invasion and metastasis of cancer. Recent studies focus on diverse roles of MMP-7, other than as a protease, during cancer progression. MMP-7 activates the epidermal growth factor (EGF) receptor by releasing an EGF ligand, tumor growth factor (TGF)-alpha.


METHODS
We examined expression of MMP-7 and EGF receptor in an immunohistochemical study of 40 colorectal cancer (CRC) cases. To determine the relationship between the EGF receptor and MMP-7, with a potential curative application, we compared the antitumor activity of the EGF receptor tyrosine kinase inhibitor (gefitinib) between MMP-7 transfectant, KYSE150 and HT29, and control cells.


RESULTS
We found a statistically significant correlation (P = 0.04) between MMP-7 and activated (phosphorylated) EGF receptor expression, both being positive in six (15%) cases. Gefitinib reduced the cell number ratio more for MMP-7 transfectant than mock cells, and the proportion of apoptotic cells was 1.5 times higher in MMP-7 transfectant than mock cells by annexin/propidium iodide staining. This was mediated by activation of a TGF-beta signal as confirmed by the abundant expression of TGF-beta protein, the cytoplasmic to nuclear translocation of Smad4 protein by the administration of gefitinib, and the quantitative assay of the plasminogen activator inhibitor-1 promoter/luciferase construction.


CONCLUSIONS
We propose that there are some cancers with up-regulated MMP-7 expression that leads to the activation of apoptotic activity of TGF-beta, which is susceptible to treatment with EGF receptor tyrosine kinase inhibitor.
Mimori
Koshi
K
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
Yamashita
Keishi
K
Ohta
Mitsuhiko
M
Yoshinaga
Keiji
K
Ishikawa
Kenji
K
Ishii
Hideshi
H
Utsunomiya
Tohru
T
Barnard
Graham F
GF
Inoue
Hiroshi
H
Mori
Masaki
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport; D011799:Quinazolines / Q000494:pharmacology; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011799:Quinazolines; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020783:Matrix Metalloproteinase 7; D000077156:Gefitinib