Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells
Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells
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表皮生长因子诱导最大胶原酶-1（MMP-1）和 T24 膀胱癌细胞恶性特征需要 STAT3 激活
DOI：
10.1038/sj.onc.1209149
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发表时间：
2006-02-23
期刊：
影响因子：
8
通讯作者：
Yoshida, K
中科院分区：
文献类型：
--
作者：
Itoh, M;Murata, T;Yoshida, K
信号转导和转录激活因子（stat）是介导细胞因子和生长因子诱导的转录的潜在转录因子。STAT3的组成激活已在人类癌症和转化细胞系中得到证实。我们报道了STAT3，而不是STAT1和STAT5，在表皮生长因子（EGF）的作用下发生磷酸化，并通过与c-JUN相互作用最大程度地诱导胶原酶-1 （MMP1）的转录。STAT3蛋白的磷酸化是双相的，第一个峰发生在30min内，第二个峰发生在4 ~ 8h之间。检测到STAT3与c-JUN的关联，其构成STAT3的磷酸化程度越来越高。STAT和AP-1元件是EGF有效诱导MMP-1启动子所必需的。靠近STAT位点的AP-1元件的突变不仅使c-JUN与MMP-1启动子的结合消失，而且使STAT3与MMP-1启动子的结合消失，导致对EGF的响应性丧失。通过以显性阴性形式阻断STAT3活性，我们发现EGF诱导MMP-1和MMP-10（基质溶素-2）需要STAT3。此外，显性阴性STAT3的表达足以抑制裸鼠组成型和egf诱导的细胞迁移侵袭和肿瘤形成。这些结果表明，STAT3的磷酸化及其可能与c-JUN的相互作用是MMP-1对EGF的强响应性所必需的，而STAT3的激活对于T24膀胱癌细胞表现出恶性特征至关重要。
Signal transducers and activators of transcription (STATs) are latent transcription factors that mediate cytokine- and growth factor-induced transcription. Constitutive activation of STAT3 has been shown in human cancers and transformed cell lines. We report that STAT3, but not STAT1 and STAT5, becomes phosphorylated in response to epidermal growth factor (EGF) and achieves maximal induction of collagenase-1 (MMP1) transcription by interacting with c-JUN. Phosphorylation of STAT3 protein is biphasic: the first peak within 30 min and the second peak between 4 and 8 h. Association of STAT3 with c-JUN is detected and its constituting STAT3 is increasingly phosphorylated. The STAT and AP-1 elements are necessary for effective induction of MMP-1 promoter by EGF. Mutation of AP-1 element closely located at the STAT site abolishes the binding not only of c-JUN but also of STAT3 to MMP-1 promoter, resulting in the loss of the responsiveness to EGF. By blocking STAT3 activity with the dominant-negative form, we show the requirement of STAT3 for EGF induction of MMP-1 and MMP-10 (stromelysin-2). Furthermore, expression of the dominant-negative STAT3 is sufficient to inhibit the constitutive and EGF-inducible cell migration and invasion and the tumor formation in nude mice. These results demonstrate that STAT3 phosphorylation and its possible interaction with c-JUN are required for the strong responsiveness of MMP-1 to EGF, and STAT3 activation is crucial for exhibition of malignant characteristics in T24 bladder cancer cells.