The Sal-like 4-integrin α6β1 network promotes cell migration for metastasis via activation of focal adhesion dynamics in basal-like breast cancer cells
The Sal-like 4-integrin α6β1 network promotes cell migration for metastasis via activation of focal adhesion dynamics in basal-like breast cancer cells
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DOI：
10.1016/j.bbamcr.2016.10.012
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发表时间：
2017-01-01
影响因子：
5.1
通讯作者：
Toi, Masakazu
中科院分区：
文献类型：
--
作者：
Itou, Junji;Tanaka, Sunao;Toi, Masakazu
在转移过程中，癌细胞迁移增强。然而，这一过程背后的机制仍然难以捉摸。在这里，我们通过对基底样乳腺癌细胞中的转录因子 Sal-like 4 (SALL4) 进行功能分析来解决这个问题。 SALL4 的功能丧失研究表明，该转录因子是纺锤形形态和增强癌细胞迁移所必需的。 SALL4 还上调整合素基因表达。在 SALL4 敲低细胞中观察到的受损细胞迁移通过整合素 α 6 和 β 1 的过度表达得以恢复。此外，我们阐明整合素 α 6 和 β 1 形成异二聚体。在分子水平上，SALL4-整合素α6β1网络的丧失会丧失粘着斑动力学，从而损害细胞迁移。已知 Rho 的过度激活会抑制粘着斑动力学。我们观察到 SALL4 敲低细胞表现出 Rho 过度激活。整合素 α 6 β 1 表达可抑制异常的 Rho 激活，而对 Rho 活性的药理学抑制可恢复 SALL4 敲低细胞中的细胞迁移。这些结果表明，SALL4-整合素α6β1网络通过调节Rho活性来促进细胞迁移。此外，我们的斑马鱼转移测定表明，该基因网络增强了体内细胞迁移。我们的研究结果确定了预防转移的潜在新治疗靶点，并提高了对癌细胞迁移的理解。 (C) 2016 Elsevier B.V. 保留所有权利。
During metastasis, cancer cell migration is enhanced. However, the mechanisms underlying this process remain elusive. Here, we addressed this issue by functionally analyzing the transcription factor Sal-like 4 (SALL4) in basal-like breast cancer cells. Loss-of-function studies of SALL4 showed that this transcription factor is required for the spindle-shaped morphology and the enhanced migration of cancer cells. SALL4 also up-regulated integrin gene expression. The impaired cell migration observed in SALL4 knockdown cells was restored by overexpression of integrin alpha 6 and beta 1 In addition, we clarified that integrin alpha 6 and beta 1 formed a heterodimer. At the molecular level, loss of the SALL4- integrin alpha 6 beta 1 network lost focal adhesion dynamics, which impairs cell migration. Over-activation of Rho is known to inhibit focal adhesion dynamics. We observed that SALL4 knockdown cells exhibited over-activation of Rho. Aberrant Rho activation was suppressed by integrin alpha 6 beta 1 expression, and pharmacological inhibition of Rho activity restored cell migration in SALL4 knockdown cells. These results indicated that the SALL4- integrin alpha 6 beta 1 network promotes cell migration via modulation of Rho activity. Moreover, our zebrafish metastasis assays demonstrated that this gene network enhances cell migration in vivo. Our findings identify a potential new therapeutic target for the prevention of metastasis, and provide an improved understanding of cancer cell migration. (C) 2016 Elsevier B.V. All rights reserved.