CRP2, a new invadopodia actin bundling factor critically promotes breast cancer cell invasion and metastasis.
CRP2, a new invadopodia actin bundling factor critically promotes breast cancer cell invasion and metastasis.
复制标题
DOI：
10.18632/oncotarget.7327
复制
发表时间：
2016-03-22
期刊：
影响因子：
--
通讯作者：
Thomas C
中科院分区：
文献类型：
--
作者：
Hoffmann C;Mao X;Dieterle M;Moreau F;Al Absi A;Steinmetz A;Oudin A;Berchem G;Janji B;Thomas C
肿瘤转移的关键过程是肿瘤细胞获得侵袭性表型。在亚细胞水平，侵袭是由称为侵袭伪足的富含肌动蛋白的突起促进的，其指导细胞外基质（ECM）降解。在这里，我们报告了一个新的乳腺癌细胞侵袭伪足，即富含半胱氨酸蛋白2（CRP 2）的细胞骨架成分的鉴定。我们发现CRP2在上皮性乳腺癌细胞中不表达或仅弱表达，而在间充质/浸润性乳腺癌细胞中表达上调。此外，CRP2编码基因CSRP2的高表达与基底样乳腺癌患者转移风险显着增加相关。CRP2敲低显著降低了侵袭性乳腺癌细胞的侵袭潜力，而它并不损害2D细胞迁移。与此一致，CRP2耗尽的乳腺癌细胞表现出促进ECM降解以及分泌和表达MMP-9（一种与癌症进展和转移反复相关的基质金属蛋白酶）的能力降低。反过来，CRP2在弱侵袭性细胞中的异位表达足以刺激细胞侵袭。GFP融合和内源性CRP 2定位于侵袭伪足的延伸肌动蛋白核心，这是一种主要由肌动蛋白束组成的结构。纯化的重组CRP 2自主交联肌动蛋白丝成粗束，表明CRP 2有助于形成/维持肌动蛋白核心。最后，CRP 2耗竭显著降低了两种乳腺癌异种移植小鼠模型中肺转移性病变的发生率。总的来说，我们的数据确定CRP 2作为一种新的细胞骨架成分的侵袭伪足，严重促进乳腺癌细胞的侵袭和转移。
A critical process underlying cancer metastasis is the acquisition by tumor cells of an invasive phenotype. At the subcellular level, invasion is facilitated by actin-rich protrusions termed invadopodia, which direct extracellular matrix (ECM) degradation. Here, we report the identification of a new cytoskeletal component of breast cancer cell invadopodia, namely cysteine-rich protein 2 (CRP2). We found that CRP2 was not or only weakly expressed in epithelial breast cancer cells whereas it was up-regulated in mesenchymal/invasive breast cancer cells. In addition, high expression of the CRP2 encoding gene CSRP2 was associated with significantly increased risk of metastasis in basal-like breast cancer patients. CRP2 knockdown significantly reduced the invasive potential of aggressive breast cancer cells, whereas it did not impair 2D cell migration. In keeping with this, CRP2-depleted breast cancer cells exhibited a reduced capacity to promote ECM degradation, and to secrete and express MMP-9, a matrix metalloproteinase repeatedly associated with cancer progression and metastasis. In turn, ectopic expression of CRP2 in weakly invasive cells was sufficient to stimulate cell invasion. Both GFP-fused and endogenous CRP2 localized to the extended actin core of invadopodia, a structure primarily made of actin bundles. Purified recombinant CRP2 autonomously crosslinked actin filaments into thick bundles, suggesting that CRP2 contributes to the formation/maintenance of the actin core. Finally, CRP2 depletion significantly reduced the incidence of lung metastatic lesions in two xenograft mouse models of breast cancer. Collectively, our data identify CRP2 as a new cytoskeletal component of invadopodia that critically promotes breast cancer cell invasion and metastasis.