Hypoxia promotes breast cancer cell invasion through HIF-1α-mediated up-regulation of the invadopodial actin bundling protein CSRP2.
Hypoxia promotes breast cancer cell invasion through HIF-1α-mediated up-regulation of the invadopodial actin bundling protein CSRP2.
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DOI：
10.1038/s41598-018-28637-x
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发表时间：
2018-07-05
影响因子：
4.6
通讯作者：
Thomas C
中科院分区：
文献类型：
--
作者：
Hoffmann C;Mao X;Brown-Clay J;Moreau F;Al Absi A;Wurzer H;Sousa B;Schmitt F;Berchem G;Janji B;Thomas C
缺氧是实体瘤的共同特征，其促进侵袭和转移性扩散。侵袭伪足是富含肌动蛋白的膜突起，其指导细胞外基质蛋白水解并促进肿瘤细胞侵袭。在这里，我们表明，CSRP 2，一种侵袭性肌动蛋白捆绑蛋白，在各种乳腺癌细胞系，以及在临床前和临床乳腺肿瘤标本中的缺氧上调。我们的功能特点的两个缺氧反应元件CSRP 2基因的近端启动子，这是由缺氧诱导因子-1（HIF-1）的目标和启动子的反式激活所需的响应缺氧。值得注意的是，CSRP 2敲低显著抑制了缺氧刺激的MDA-MB-231细胞中侵袭足的形成、ECM降解和侵袭，而CSRP 2强制表达足以增强缺氧条件下HIF-1α缺失的细胞的侵袭能力。在MCF-7细胞中，CSRP 2上调是缺氧诱导的侵袭前体形成所必需的，而侵袭前体不能促进ECM降解。总的来说，我们的数据支持CSRP 2是一种新的和直接的HIF-1的细胞骨架靶点，通过促进侵袭伪足的形成来促进缺氧诱导的乳腺癌细胞侵袭。
Hypoxia is a common feature of solid tumours that promotes invasion and metastatic dissemination. Invadopodia are actin-rich membrane protrusions that direct extracellular matrix proteolysis and facilitate tumour cell invasion. Here, we show that CSRP2, an invadopodial actin bundling protein, is upregulated by hypoxia in various breast cancer cell lines, as well as in pre-clinical and clinical breast tumour specimens. We functionally characterized two hypoxia responsive elements within the proximal promoter of CSRP2 gene which are targeted by hypoxia-inducible factor-1 (HIF-1) and required for promoter transactivation in response to hypoxia. Remarkably, CSRP2 knockdown significantly inhibits hypoxia-stimulated invadopodium formation, ECM degradation and invasion in MDA-MB-231 cells, while CSRP2 forced expression was sufficient to enhance the invasive capacity of HIF-1α-depleted cells under hypoxia. In MCF-7 cells, CSRP2 upregulation was required for hypoxia-induced formation of invadopodium precursors that were unable to promote ECM degradation. Collectively, our data support that CSRP2 is a novel and direct cytoskeletal target of HIF-1 which facilitates hypoxia-induced breast cancer cell invasion by promoting invadopodia formation.
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影响因子：
21.3
作者：
Lin A;Li C;Xing Z;Hu Q;Liang K;Han L;Wang C;Hawke DH;Wang S;Zhang Y;Wei Y;Ma G;Park PK;Zhou J;Zhou Y;Hu Z;Zhou Y;Marks JR;Liang H;Hung MC;Lin C;Yang L
通讯作者：
Yang L
影响因子：
64.5
作者：
Hotary, KB;Allen, ED;Weiss, SJ
通讯作者：
Weiss, SJ
影响因子：
5.1
作者：
Liu, Zhao-ji;Semenza, Gregg L.;Zhang, Hua-feng
通讯作者：
Zhang, Hua-feng
影响因子：
5.7
作者：
Li Z;Takino T;Endo Y;Sato H
通讯作者：
Sato H
缺氧诱导的Intopodia形成涉及P90核糖体S6激酶（P90RSK）激活NHE-1。
影响因子：
3.7
作者：
Lucien F;Brochu-Gaudreau K;Arsenault D;Harper K;Dubois CM
通讯作者：
Dubois CM