Smad7 acts as a negative regulator of the epidermal growth factor (EGF) signaling pathway in breast cancer cells
Smad7 acts as a negative regulator of the epidermal growth factor (EGF) signaling pathway in breast cancer cells
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DOI：
10.1016/j.canlet.2011.09.024
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发表时间：
2012-01-28
期刊：
影响因子：
9.7
通讯作者：
Lee, Jeong Eon
中科院分区：
文献类型：
--
作者：
Kim, Sangmin;Han, Jeonghun;Lee, Jeong Eon
尽管已有研究表明Smad7可阻断转化生长因子-β的下游信号传导，但Smad7在EGF信号通路中的作用尚未完全阐明。我们检测了Smad7对EGF诱导的SKBR3乳腺癌细胞中基质金属蛋白酶-9表达的影响。表皮生长因子和转化生长因子-β1分别促进Smad7和基质金属蛋白酶-9的表达，两者共同作用后，Smad7和MMP-9表达进一步增加。EGF可诱导EGFR、SMAD3、ERK和JNK的磷酸化，而EGFR抑制剂AG1478可抑制MMP9的表达。此外，UO126(MEK1/2抑制剂)或SIS3(Smad3抑制剂)可抑制EGF诱导的基质金属蛋白酶-9的表达，但SP600125(JNK抑制剂)则不能。有趣的是。Smad7的过度表达可完全阻断EGF诱导的Smad3的磷酸化，但不能阻断ERK和JNK的磷酸化。腺病毒Smad7(Ad-Smad7)过表达可完全抑制EGF或TGF-β1诱导的基质金属蛋白酶-9的表达。我们还研究了Smad3在EGF诱导的MMP-9表达中的作用，结果表明，Smad3 siRNA转染后EGF诱导的MMP9的表达降低，而Smad3过表达则进一步增加EGF诱导的MMP9的表达。本研究表明，在SKBR3细胞中，Smad3的磷酸化介导了基质金属蛋白酶-9的诱导，而Smad7抑制了转化生长因子-β1和EGF信号通路。(C)2011爱思唯尔爱尔兰有限公司。保留所有权利。
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.