Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR-beta1 integrin complex in colon cancer cells.
Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR-beta1 integrin complex in colon cancer cells.
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DOI：
10.1038/sj.bjc.6601098
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发表时间：
2003-07-21
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
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肿瘤的侵袭受细胞表面蛋白酶和粘附分子的调节。特异性细胞表面分子如尿激酶纤溶酶原激活物受体（uPAR）和整合素之间的相互作用对于肿瘤的侵袭和转移至关重要。在这项研究中，我们研究了uPAR和β1整合素是否形成功能复合物来介导肿瘤侵袭所需的信号传导。我们评估了uPAR/β1整合素复合物的表达，Erk信号通路，粘附，uPA和基质金属蛋白酶（MMP）的表达，迁移/侵袭和基质降解在uPAR表达被修饰的结肠癌细胞系中。在人结肠癌HCT 116细胞（A/S）中，将uPAR的细胞表面表达反义抑制50%，Erk-MAP激酶活性被抑制两倍。HCT 116细胞的尿激酶纤溶酶原激活物受体反义处理与1.3倍的粘附抑制、大约4倍的HMW-uPA分泌抑制和pro-MMP-9分泌抑制相关。在功能水平上，uPAR反义导致迁移/侵袭下降四倍，并减少纤溶酶介导的基质降解。在空载体转染的细胞（模拟）中，uPA强烈升高基础Erk激活。相反，在A/S细胞中，未观察到uPA诱导Erk活化。模拟转染细胞中与β1整合素相关的尿激酶纤溶酶原激活物受体。用特异性肽（P25）阻断uPAR-β1整合素复合物在模拟转染细胞中的表达，可抑制uPA介导的Erk-MAP激酶通路，并通过抑制pro-MMP-9/MMP-2的表达抑制细胞的迁移/侵袭和纤溶酶依赖性基质降解。这种uPAR-整联蛋白信号传导的新范例可能为治疗癌症的替代治疗策略提供机会。
Cancer invasion is regulated by cell surface proteinases and adhesion molecules. Interaction between specific cell surface molecules such as urokinase plasminogen activator receptor (uPAR) and integrins is crucial for tumour invasion and metastasis. In this study, we examined whether uPAR and β1 integrin form a functional complex to mediate signalling required for tumour invasion. We assessed the expression of uPAR/β1 integrin complex, Erk signalling pathway, adhesion, uPA and matrix metalloproteinase (MMP) expression, migration/invasion and matrix degradation in a colon cancer cell line in which uPAR expression was modified. Antisense inhibition of the cell surface expression of uPAR by 50% in human colon carcinoma HCT116 cells (A/S) suppressed Erk-MAP kinase activity by two-fold. Urokinase plasminogen activator receptor antisense treatment of HCT116 cells was associated with a 1.3-fold inhibition of adhesion, approximately four-fold suppression of HMW-uPA secretion and inhibition of pro-MMP-9 secretion. At a functional level, uPAR antisense resulted in a four-fold decline in migration/invasion and abatement of plasmin-mediated matrix degradation. In empty vector-transfected cells (mock), uPA strongly elevated basal Erk activation. In contrast, in A/S cells, uPA induction of Erk activation was not observed. Urokinase plasminogen activator receptor associated with β1 integrin in mock-transfected cells. Disruption of uPAR–β1 integrin complex in mock-transfected cells with a specific peptide (P25) inhibited uPA-mediated Erk-MAP kinase pathway and inhibited migration/invasion and plasmin-dependent matrix degradation through suppression of pro-MMP-9/MMP-2 expression. This novel paradigm of uPAR–integrin signalling may afford opportunities for alternative therapeutic strategies for the treatment of cancer.
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影响因子：
4.4
作者：
Ferrero, E;Vettoretto, K;Zocchi, MR
通讯作者：
Zocchi, MR
影响因子：
9.2
作者：
Dumler, I;Stepanova, V;Gulba, DC
通讯作者：
Gulba, DC
影响因子：
4.8
作者：
Nguyen, DHD;Hussaini, IM;Gonias, SL
通讯作者：
Gonias, SL
DOI：
10.1073/pnas.90.11.5021
发表时间：
1993-06-01
影响因子：
11.1
作者：
CROWLEY, CW;COHEN, RL;LEVINSON, AD
通讯作者：
LEVINSON, AD
影响因子：
4.8
作者：
Hapke, S;Kessler, H;Reuning, U
通讯作者：
Reuning, U