Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1864, Issue 1, Pages 76-88Publisher
ELSEVIER
DOI: 10.1016/j.bbamcr.2016.10.012
Keywords
Breast cancer; Cell migration; Focal adhesion dynamics; Integrin; SALL4
Categories
Funding
- Taiho Pharmaceutical Co., Ltd.
- Ichiro Kanehara Foundation [15KI275]
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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.
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