PDF(Pubmed)
Abstract：
The actin cytoskeleton plays a critical role in cancer cell invasion and metastasis; however, the coordination of its multiple functions remains unclear. Actin dynamics in the cytoplasm control the formation of invadopodia, which are membrane protrusions that facilitate cancer cell invasion by focusing the secretion of extracellular matrix-degrading enzymes, including matrix metalloproteinases (MMPs). In this study, we investigated the nuclear role of cysteine-rich protein 2 (CRP2), a two LIM domain-containing F-actin-binding protein that we previously identified as a cytoskeletal component of invadopodia, in breast cancer cells. We found that F-actin depolymerization stimulates the translocation of CRP2 into the nucleus, resulting in an increase in the transcript levels of pro-invasive and pro-metastatic genes, including several members of the MMP gene family. We demonstrate that in the nucleus, CRP2 interacts with the transcription factor serum response factor (SRF), which is crucial for the expression of MMP-9 and MMP-13. Our data suggest that CRP2 and SRF cooperate to modulate of MMP expression levels. Furthermore, Kaplan-Meier analysis revealed a significant association between high-level expression of SRF and shorter overall survival and distant metastasis-free survival in breast cancer patients with a high CRP2 expression profile. Our findings suggest a model in which CRP2 mediates the coordination of cytoplasmic and nuclear processes driven by actin dynamics, ultimately resulting in the induction of invasive and metastatic behavior in breast cancer cells.
摘要：
肌动蛋白细胞骨架在癌细胞侵袭和转移中起着至关重要的作用；然而，其多种功能的协调仍不清楚。细胞质中的肌动蛋白动力学控制侵袭足的形成，它们是通过集中分泌细胞外基质降解酶来促进癌细胞侵袭的膜突起，包括基质金属蛋白酶(MMPs)。在这项研究中,我们研究了富含半胱氨酸的蛋白2（CRP2）的核作用，一种包含两个LIM结构域的F-肌动蛋白结合蛋白，我们先前将其鉴定为invadopodia的细胞骨架成分，在乳腺癌细胞中。我们发现，F-肌动蛋白解聚刺激CRP2的易位进入细胞核，导致前侵袭和前转移基因的转录水平增加，包括MMP基因家族的几个成员。我们证明了在细胞核中，CRP2与转录因子血清反应因子（SRF）相互作用，这对于MMP-9和MMP-13的表达至关重要。我们的数据表明CRP2和SRF协同调节MMP表达水平。此外，Kaplan-Meier分析显示，在具有高CRP2表达谱的乳腺癌患者中，SRF的高水平表达与较短的总生存期和无远处转移生存期之间存在显着关联。我们的发现提出了一个模型，其中CRP2介导了由肌动蛋白动力学驱动的细胞质和核过程的协调，最终导致乳腺癌细胞的侵袭和转移行为的诱导。
