PAI-1 mediates the TGF-beta1+EGF-induced "scatter" response in transformed human keratinocytes.
PAI-1 mediates the TGF-beta1+EGF-induced "scatter" response in transformed human keratinocytes.
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DOI：
10.1038/jid.2010.106
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发表时间：
2010-09
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生长因子信号通路之间的协同相互作用是肿瘤进展的重要因素。建立了一个结合转化生长因子-β1 （TGF-β1）和表皮生长因子（EGF）的模型系统，以研究ras转化的人（HaCaT II-4）角质形成细胞诱导上皮-间质转化（EMT）的机制。TGF-β1+EGF的双重刺激导致角质形成细胞“可塑性”和明显的集落分散。通过mRNA谱分析鉴定，最高表达的转录物编码纤溶酶原激活物抑制剂-1 （PAI-1; SERPINE1）。PAI-1负性调节纤溶蛋白依赖的基质降解，保持基质支架允许角化细胞运动。有丝分裂原激活的细胞外激酶(MEK)/细胞外信号调节激酶（ERK）和p38信号是最大PAI-1上调和TGF-β1+ egf刺激的细胞运动所必需的，因为MEK/p38活性的药物破坏会消除这两种反应。此外，单独敲低PAI-1可有效抑制TGF-β1+ egf依赖性细胞的散射，表明该SERPIN在诱导运动的双生长因子模型中具有功能作用。此外，EGFR信号阻断或EGFR敲低会减弱TGF-β1诱导的PAI-1表达，这意味着EGFR反激活TGF-β1刺激的PAI-1表达，并减少TGF-β1+ egf处理的培养物中的菌落扩散。识别这种协同信号网络及其对特定侵袭促进靶基因（如PAI-1）的影响，可能会导致通路特异性治疗的发展，影响人类肿瘤进展的晚期事件。
Cooperative interactions between growth factor signaling pathways are important elements in carcinoma progression. A model system combining transforming growth factor-β1 (TGF-β1) and EGF was developed to investigate mechanisms underlying induced epithelial-to-mesenchymal transition (EMT) in ras-transformed human (HaCaT II-4) keratinocytes. Dual stimulation with TGF-β1+EGF resulted in keratinocyte “plasticity” and pronounced colony dispersal. The most highly expressed transcript, identified by mRNA profiling, encoded plasminogen activator inhibitor-1 (PAI-1; SERPINE1). PAI-1 negatively regulates plasmin-dependent matrix degradation, preserving a stromal scaffold permissive for keratinocyte motility. Mitogen-activated extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) and p38 signaling were required for maximal PAI-1 upregulation and TGF-β1+EGF-stimulated cell locomotion, as pharmacologic disruption of MEK/p38 activity ablated both responses. Moreover, PAI-1 knockdown alone effectively inhibited TGF-β1+EGF-dependent cell scattering, indicating a functional role for this SERPIN in the dual-growth factor model of induced motility. Moreover, EGFR signaling blockade or EGFR knockdown attenuated TGF-β1-induced PAI-1 expression, implicating EGFR transactivation in TGF-β1-stimulated PAI-1 expression, and reduced colony dispersal in TGF-β1+EGF-treated cultures. Identification of such cooperative signaling networks and their effect on specific invasion-promoting target genes, such as PAI-1, may lead to the development of pathway-specific therapeutics that affect late-stage events in human tumor progression.
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影响因子：
8.7
作者：
Arts, J;Grimbergen, J;Kooistra, T
通讯作者：
Kooistra, T
影响因子：
3.8
作者：
Kim, ES;Kim, MS;Moon, A
通讯作者：
Moon, A
影响因子：
4.8
作者：
Kim, JT;Joo, CK
通讯作者：
Joo, CK
DOI：
10.1111/j.1349-7006.2001.tb01090.x
发表时间：
2001-03-01
期刊：
JAPANESE JOURNAL OF CANCER RESEARCH
影响因子：
--
作者：
Akiyoshi, S;Ishii, M;Miyazono, K
通讯作者：
Miyazono, K
DOI：
10.1111/j.1610-0387.2005.05037.x
发表时间：
2005-07-01
期刊：
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG
影响因子：
--
作者：
Boukamp, Petra
通讯作者：
Boukamp, Petra