Smad7 acts as a negative regulator of the epidermal growth factor (EGF) signaling pathway in breast cancer cells

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• 作者：Sangmin  ; Kim^a ; Jeonghun  ; Han^a ; Se Kyung  ; Lee^a ; Minyoung  ; Koo^a ; Dong Hui  ; Cho^a ; Soo Youn  ; Bae^b ; Min-Young  ; Choi^a ; Jee Soo  ; Kim^a ; Jung-Han  ; Kim^a ; Jun-Ho  ; Choe^a ; Jung-Hyun  ; Yang^b ; Seok Jin  ; Nam^a ;   ; ^{sjnam@skku.edu} ; Jeong Eon  ; Lee^a ;   ; ^{paojlus@hanmail.net}
• 关键词：MMP-9 ; Smad7 ; Smad3 ; EGF signaling
• 刊名：Cancer Letters
• 出版年：2012
• 出版时间：28 January 2012
• 年：2012
• 卷：314
• 期：2
• 页码：147-154
• 全文大小：725 K

文摘

Although it has been suggested that smad7 blocks downstream signaling of TGF-¦Â, 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-¦Â1, respectively, and further increased by EGF and TGF-¦Â1 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-¦Â1-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-¦Â1 as well as the EGF signaling pathway in SKBR3 cells.