Fascin is a key regulator of breast cancer invasion that acts via the modification of metastasis-associated molecules.
Fascin is a key regulator of breast cancer invasion that acts via the modification of metastasis-associated molecules.
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DOI：
10.1371/journal.pone.0027339
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Adra C
中科院分区：
文献类型：
--
作者：
Al-Alwan M;Olabi S;Ghebeh H;Barhoush E;Tulbah A;Al-Tweigeri T;Ajarim D;Adra C
肌动蛋白捆绑蛋白，束蛋白，是细胞骨架蛋白家族的成员，在特化的正常细胞中表达受限。然而，许多研究已经报道了这种蛋白在包括乳腺癌细胞在内的各种转化细胞中的诱导作用。虽然束蛋白在乳腺癌细胞迁移调控中的作用已被证实，但其潜在的分子机制仍不明确。我们使用了多种免疫学和功能分析来研究束状蛋白是否调节乳腺癌转移相关分子。在本报告中，我们发现乳腺癌患者中筋膜蛋白的表达与；转移和较短的无病生存期。最重要的是，在体外通过功能的丧失或获得对束蛋白表达的干扰证明了该蛋白在调节细胞形态、迁移和侵袭潜力方面的核心作用。我们的研究结果表明，束状蛋白对侵袭的调节是通过调节几个转移相关基因介导的。我们首次发现，束状蛋白下调乳腺癌转移抑制蛋白-1 （BRMS1）的表达和核易位。此外，筋膜蛋白上调NF-kappa B活性，这是转移所必需的。重要的是，肌束蛋白上调了其他已知对转移执行至关重要的蛋白质，如尿激酶型纤溶酶原激活物（uPA）和基质金属蛋白酶(MMP)-2和MMP-9。本研究表明，束蛋白在乳腺癌细胞中的表达建立了与转移性肿瘤一致的基因表达谱，并为通过束蛋白靶向治疗转移性乳腺癌提供了潜在的治疗干预。
The actin-bundling protein, fascin, is a member of the cytoskeletal protein family that has restricted expression in specialized normal cells. However, many studies have reported the induction of this protein in various transformed cells including breast cancer cells. While the role of fascin in the regulation of breast cancer cell migration has been previously shown, the underlying molecular mechanism remained poorly defined. We have used variety of immunological and functional assays to study whether fascin regulates breast cancer metastasis-associated molecules. In this report we found a direct relationship between fascin expression in breast cancer patients and; metastasis and shorter disease-free survival. Most importantly, in vitro interference with fascin expression by loss or gain of function demonstrates a central role for this protein in regulating the cell morphology, migration and invasion potential. Our results show that fascin regulation of invasion is mediated via modulating several metastasis-associated genes. We show for the first time that fascin down-regulates the expression and nuclear translocation of a key metastasis suppressor protein known as breast cancer metastasis suppressor-1 (BRMS1). In addition, fascin up-regulates NF-kappa B activity, which is essential for metastasis. Importantly, fascin up-regulates other proteins that are known to be critical for the execution of metastasis such as urokinase-type plasminogen activator (uPA) and the matrix metalloproteases (MMP)-2 and MMP-9. This study demonstrates that fascin expression in breast cancer cells establishes a gene expression profile consistent with metastatic tumors and offers a potential therapeutic intervention in metastatic breast cancer treatment through fascin targeting.
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