Journal
CANCER LETTERS
Volume 314, Issue 2, Pages 147-154Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2011.09.024
Keywords
MMP-9; Smad7; Smad3; EGF signaling
Categories
Funding
- Ministry for Health & Welfare Affairs, Republic of Korea [A092255]
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Although it has been suggested that smad7 blocks downstream signaling of TGF-beta, the role of smad7 in the EGF signaling pathway has not been fully elucidated. We determined the effect of smad7 on EGF-induced MMP-9 expression in SKBR3 breast cancer cells. The expression of smad7 and MMP-9 was increased by EGF or TGF-beta 1, respectively, and further increased by EGF and TGF-beta 1 co-treatment. EGF induced the phosphorylation of EGFR, smad3, ERK, and JNK, and MMP-9 expression was decreased by the EGFR inhibitor, AG1478. In addition, EGF-induced MMP-9 expression was inhibited by UO126 (a MEK1/2 inhibitor) or SIS3 (a smad3 inhibitor), but not by SP600125 (a JNK inhibitor). Interestingly. EGF-induced smad3 phosphorylation was completely blocked by smad7 over-expression, but not the phosphorylation of ERK and JNK. EGF- or TGF-beta 1-induced MMP-9 expression was completely decreased by adenoviral-smad7 (Ad-smad7) over-expression. We also investigated the role of smad3 on EGF-induced MMP-9 expression and showed that EGF-induced MMP-9 expression was decreased by smad3 siRNA transfection, whereas EGF-induced MMP-9 expression was further increased by smad3 over-expression, as expected. This study showed that EGF-induced smad3 phosphorylation mediates the induction of MMP-9, whereas smad7 inhibits TGF-beta 1 as well as the EGF signaling pathway in SKBR3 cells. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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