Matrix Rigidity Activates Wnt Signaling through Down-regulation of Dickkopf-1 Protein
Matrix Rigidity Activates Wnt Signaling through Down-regulation of Dickkopf-1 Protein
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DOI：
10.1074/jbc.m112.431411
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发表时间：
2013-01-04
影响因子：
4.8
通讯作者：
Stack, M. Sharon
中科院分区：
文献类型：
--
作者：
Barbolina, Maria V.;Liu, Yiuying;Stack, M. Sharon
细胞对细胞外基质物理性质的变化做出反应，改变行为和基因表达，突出了微环境在调节细胞功能中的重要作用。在目前的研究中，上皮性卵巢癌细胞在三维胶原蛋白I凝胶上的培养导致Wnt信号传导抑制剂dickkopf-1的显著下调，伴随着细胞核β-连环蛋白的增加和β-连环蛋白/Tcf/Lef转录活性的增强。三维胶原凝胶浸润的增加伴随着膜系胶原酶膜1型基质金属蛋白酶的转录上调，并且在人上皮性卵巢癌标本中观察到dickkopf-1和膜1型基质金属蛋白酶之间呈反比关系。在其他组织侵袭性细胞如血管内皮细胞中也获得了类似的结果，这表明基质粘附与Wnt信号传导的功能性偶联的新机制。
Cells respond to changes in the physical properties of the extracellular matrix with altered behavior and gene expression, highlighting the important role of the microenvironment in the regulation of cell function. In the current study, culture of epithelial ovarian cancer cells on three-dimensional collagen I gels led to a dramatic down-regulation of the Wnt signaling inhibitor dickkopf-1 with a concomitant increase in nuclear beta-catenin and enhanced beta-catenin/Tcf/Lef transcriptional activity. Increased three-dimensional collagen gel invasion was accompanied by transcriptional up-regulation of the membrane-tethered collagenase membrane type 1 matrix metalloproteinase, and an inverse relationship between dickkopf-1 and membrane type 1 matrix metalloproteinase was observed in human epithelial ovarian cancer specimens. Similar results were obtained in other tissue-invasive cells such as vascular endothelial cells, suggesting a novel mechanism for functional coupling of matrix adhesion with Wnt signaling.