Overexpression of Integrin-β1 in Leiomyoma Promotes Cell Spreading and Proliferation
Overexpression of Integrin-β1 in Leiomyoma Promotes Cell Spreading and Proliferation
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DOI：
10.1210/jc.2012-3647
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发表时间：
2013-05-01
影响因子：
5.8
通讯作者：
Tsai, Shaw-Jenq
中科院分区：
文献类型：
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作者：
Chen, Hsiu-Mei;Lin, Yi-Hsuan;Tsai, Shaw-Jenq
背景：子宫平滑肌瘤是育龄妇女最常见的肿瘤，可引起子宫异常出血，危及生命。与子宫肌瘤相比，平滑肌瘤含有过多的细胞外基质（ECM）。然而，ECM在平滑肌瘤发展中的病理作用在很大程度上仍然未知。整合素是细胞表面与ECM相互作用的主要粘附分子。ECM与整合素的相互作用调节细胞粘附并启动细胞生长、分化和迁移的信号。目的：探讨整合素- 1在肌瘤发病中的表达及其功能作用。设计：在配对的正常和平滑肌瘤组织（n = 15）中，采用Western blotting检测整合素- β 1蛋白水平。整合素- β 1的敲低和崩解素对ecm -整合素相互作用的抑制作用被用来评估整合素- β 1对细胞粘附、扩散和增殖的影响。结果：与正常细胞相比，平滑肌瘤细胞中整合素- 1水平显著上调。整合素- 1的下调不影响细胞对纤维连接蛋白和层粘连蛋白基质的粘附，但显著抑制细胞的扩散能力。与这一观点一致的是，在整合素- β 1敲低的细胞中，局灶粘附激酶的磷酸化和帕罗西林向局灶接触的募集减少，从而减弱了收缩力。细胞无法扩散导致细胞周期蛋白D1表达抑制，阻碍细胞周期进程。更重要的是，小蛋白崩解素破坏ecm -整合素的相互作用，抑制了cyclin D1的表达和细胞增殖。结论：这些数据表明整合素- 1是增强细胞- ecm接触力从而促进细胞增殖的关键配体。破坏ecm -整合素- β 1信号可能是抑制平滑肌瘤进展的一种选择。
Context: Uterine leiomyoma, the most common tumors found in the women of the reproductive age, may cause abnormal uterine bleeding and be life threatening. Compared with myometrium, leiomyoma contains excessive extracellular matrix (ECM). However, the pathological roles of ECM in the development of leiomyoma remain largely unknown. Integrins are the major adhesion molecules on cell surface to interact with ECM. The interactions of ECM with integrins regulate cell adhesion and initiate signals for cell growth, differentiation, and migration.Objective: The aim of this study was to investigate the expression and functional role of integrin-beta 1 in leiomyoma pathogenesis.Design: Levels of integrin-beta 1 protein were determined by Western blotting in paired normal and leiomyomal tissues (n = 15). Knockdown of integrin-beta 1 and inhibition of ECM-integrin interaction by disintegrin were used to evaluate the impact of integrin-beta 1 in cell adhesion, spreading, and proliferation.Results: Levels of integrin-beta 1 were significantly up-regulated in leiomyomal cells compared with their normal counterparts. Knockdown of integrin-beta 1 did not affect cell adhesion on fibronectin or laminin matrix but significantly inhibits cell spreading ability. Consistent with this notion, the phosphorylation of focal adhesion kinase and the recruitment of paxillin to the focal contact were decreased in integrin-beta 1 knockdown cells, which attenuates contraction force. The inability of cell spreading leads to inhibition of cyclin D1 expression and impedes cell cycle progression. More importantly, disruption of ECM-integrin interaction by the small protein, disintegrin inhibited cyclin D1 expression and cell proliferation.Conclusion: These data demonstrate that integrin-beta 1 is a critical ligand to enhance cell-ECM contact force and thus promotes cell proliferation. Disruption of ECM-integrin-beta 1 signaling may serve as an option to inhibit the progression of leiomyoma.