Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis.
Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis.
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Profilin1 （Pfn1）是一种普遍表达的肌动蛋白结合蛋白，在正常细胞的迁移和增殖中起着不可或缺的作用。Pfn1的表达在乳腺癌中下调，似乎与其基本的细胞功能相反，其意义尚不清楚。在这项研究中，Pfn1在人类乳腺癌标本中的表达谱将Pfn1的低表达水平与转移倾向联系起来。异种移植实验进一步证实了Pfn1表达缺失与原发性乳腺肿瘤中乳腺癌细胞（bcc）扩散增加之间的因果关系。当Pfn1表达受到抑制时，bcc表现出高侵袭性表型（以基质金属蛋白酶-9上调为标志，通过胶原基质的侵袭速度更快），并且通过内皮屏障的迁移能力增强（血管传播的必要步骤）。在pfn1缺乏的细胞中，高侵袭性涉及磷脂酰肌醇3-激酶- pi (3,4)P2信号轴，而增强的跨内皮迁移以血管内皮生长因子依赖的方式发生。然而，与这些促进传播的活性相比，Pfn1的缺失显著抑制了弥散性bcc的转移生长，这表明Pfn1在转移定殖过程中起关键作用。总之，本研究表明Pfn1在乳腺癌转移的早期和晚期阶段具有双重作用。
Profilin1 (Pfn1), a ubiquitously expressed actin-binding protein, has an indispensable role in migration and proliferation of normal cells. Seemingly contrary to its essential cellular functions, Pfn1’s expression is downregulated in breast cancer, the significance of which is unclear. In this study, expression profiling of Pfn1 in human breast cancer specimens correlates lower Pfn1 expression levels with propensity to metastasize. Xenograft experiments further establish a causal relationship between loss of Pfn1 expression and increased dissemination of breast cancer cells (BCCs) from the primary mammary tumor. BCCs exhibit a hyperinvasive phenotype (marked by matrix metalloproteinase-9 upregulation, faster invasion through collagen matrix) and acquire increased proficiency to transmigrate through endothelial barrier (an obligatory step for vascular dissemination) when Pfn1 expression is suppressed. In Pfn1-deficient cells, hyperinvasiveness involves a phosphatidylinositol 3-kinase-PI(3,4)P2 signaling axis while augmented transendothelial migration occurs in a vascular endothelial growth factor-dependent manner. Contrasting these dissemination promoting activities, loss of Pfn1, however, dramatically inhibits metastatic outgrowth of disseminated BCCs, suggesting that Pfn1 has a key role in the metastatic colonization process. In summary, this study shows that Pfn1 has a dichotomous role in early vs late steps of breast cancer metastasis.
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影响因子：
11.2
作者：
Barkan D;Kleinman H;Simmons JL;Asmussen H;Kamaraju AK;Hoenorhoff MJ;Liu ZY;Costes SV;Cho EH;Lockett S;Khanna C;Chambers AF;Green JE
通讯作者：
Green JE
影响因子：
5.2
作者：
Ho, Ming-Yi;Tang, Shye-Jye;Sun, Kuang-Hui
通讯作者：
Sun, Kuang-Hui
影响因子：
64.5
作者：
HAUGWITZ, M;NOEGEL, AA;SCHLEICHER, M
通讯作者：
SCHLEICHER, M
影响因子：
--
作者：
Roy, P;Jacobson, K
通讯作者：
Jacobson, K
影响因子：
3.8
作者：
Gorges TM;Tinhofer I;Drosch M;Röse L;Zollner TM;Krahn T;von Ahsen O
通讯作者：
von Ahsen O