EGF-induced MMP-9 expression is mediated by the JAK3/ERK pathway, but not by the JAK3/STAT-3 pathway in a SKBR3 breast cancer cell line
EGF-induced MMP-9 expression is mediated by the JAK3/ERK pathway, but not by the JAK3/STAT-3 pathway in a SKBR3 breast cancer cell line
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DOI：
10.1016/j.cellsig.2009.01.034
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发表时间：
2009-06-01
影响因子：
4.8
通讯作者：
Yang, Jung-Hyun
中科院分区：
文献类型：
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作者：
Kim, Sangmin;Choi, Jae Hyuck;Yang, Jung-Hyun
表皮生长因子受体（FGFR）及其配体的数量在恶性肿瘤细胞中高表达。多达三分之一的乳腺癌患者的 EGF 信号通路也被激活。在本研究中，我们研究了JAK3抑制剂WHI-P131对EGF诱导的MMP-9表达的新功能以及EGF诱导的SKBR3细胞中MMP-9表达的调节机制。我们观察到 EGF 以剂量依赖性方式增加 MMP-9 mRNA 和蛋白表达。 EGF 还诱导 ECFR、ERK 和 STAT-3 的磷酸化，而这些作用可被 EGFR 抑制剂 AG1478 抑制。为了研究 STAT-3 通路对 EGF 诱导的 MMP-9 表达的影响，我们在 EGF 处理之前用 JAK1、JAK2 和 JAK3 抑制剂预处理 SKBR3 细胞。结果表明，JAK3 抑制剂 WHI-P131 以及 JAK3 siRNA 转染显着降低了 EGF 诱导的 MMP-9 表达，而 JAK1 和 JAK2 抑制剂则没有。此外，EGF 诱导的 STAT-3 磷酸化仅被 WHI-P131 抑制。然后我们用腺病毒 STAT-3 (Ad-STAT-3) 转染细胞，然后用 EGF 处理。有趣的是，Ad-STAT-3 过表达以剂量依赖性方式降低 EGF 诱导的 MMP-9 表达，而 STAT-3 siRNA 转染则显着增加 MMP-9 表达。我们的结果还表明，组成型活性 MEK (CA-MEK) 过表达显着增加了 MMP-9 表达的基础水平。 EGF 诱导的 ERK 磷酸化可被 WHI-P131 阻止，但不能被 JAM 和 JAK2 抑制剂阻止。另一方面，MEK1/2 抑制剂 UO126 降低了 EGF 诱导的 MMP-9 表达。因此，我们首次提出 JAK3 抑制剂 WHI-P131 抑制 EGF 诱导的 STAT3 磷酸化以及 ERK 磷酸化。 JAK3/ERK 通路可能在 EGF 诱导的 SKBR3 细胞中 MMP-9 表达中发挥重要作用。 (C) 2009 Elsevier Inc. 保留所有权利。
The number of epidermal growth factor receptors (FGFRs) and their ligands are highly expressed in malignant tumor cells. The EGF signaling pathway is also activated in up to one-third of patients with breast cancer. In this study, we investigated the novel function of the JAK3 inhibitor, WHI-P131, on EGF-induced MMP-9 expression and the regulatory mechanism of EGF-induced MMP-9 expression in SKBR3 cells. We observed that EGF increased MMP-9 mRNA and protein expression in a dose-dependent manner. EGF also induced the phosphorylation of ECFR, ERK, and STAT-3, and these effects were inhibited by the EGFR inhibitor, AG1478. To investigate the involvement of the STAT-3 pathway on EGF-induced MMP-9 expression, we pretreated SKBR3 cells with JAK1, JAK2, and JAK3 inhibitors prior to EGF treatment. The results showed that the JAK3 inhibitor, WHI-P131, as well as JAK3 siRNA transfection, but not the JAK1 and JAK2 inhibitors, significantly decreased EGF-induced MMP-9 expression. In addition, EGF-induced STAT-3 phosphorylation was only inhibited by WHI-P131. We then transfected cells with adenoviral STAT-3 (Ad-STAT-3), followed by treatment with EGF. Interestingly, EGF-induced MMP-9 expression was decreased by Ad-STAT-3 overexpression in a dose-dependent manner, while it was significantly increased by STAT-3 siRNA transfection. Our results also showed that basal levels of MMP-9 expression were significantly increased by constitutive active-MEK (CA-MEK) overexpression. EGF-induced ERK phosphorylation was prevented by WHI-P131, but not by JAM and JAK2 inhibitors. On the other hand, EGF-induced MMP-9 expression was decreased by the MEK1/2 inhibitor, UO126. Therefore, for the first time, we suggest that the JAK3 inhibitor, WHI-P131, inhibits EGF-induced STAT3 phosphorylation as well as ERK phosphorylation. The JAK3/ERK pathway may play an important role in EGF-induced MMP-9 expression in SKBR3 cells. (C) 2009 Elsevier Inc. All rights reserved.