Regulation of ROCK1 via Notch1 during breast cancer cell migration into dense matrices

BMC Cell Biology

Lilian Soon²  Erik W Thompson¹  J Guy Lyons³  Hsin-Ya Chien⁴  Jifei Zhao⁴  Sandra Fok⁴  Vanisri Raviraj⁴ 

[1] University of Melbourne Department of Surgery, St Vincent’s Hospital, Melbourne, Australia;ACMM, Madsen Building F09, Room 243, The University of Sydney, Sydney, NSW 2006, Australia;Dermatology, Central Clinical School, The University of Sydney, Sydney, NSW 2006, Australia;Australian Centre for Microscopy and Microanalysis (ACMM), AMMRF, The University of Sydney, Sydney, NSW 2006, Australia

关键词: Histone deacetylase inhibitors;    ROCK expression;    Cancer cell migration;    High-density matrix;    Breast cancer;   

Others  :  856983
DOI  :  10.1186/1471-2121-13-12

 received in 2011-07-19, accepted in 2012-02-15,  发布年份 2012

【 摘 要 】

Background

The behaviour of tumour cells depends on factors such as genetics and the tumour microenvironment. The latter plays a crucial role in normal mammary gland development and also in breast cancer initiation and progression. Breast cancer tissues tend to be highly desmoplastic and dense matrix as a pre-existing condition poses one of the highest risk factors for cancer development. However, matrix influence on tumour cell gene expression and behaviour such as cell migration is not fully elucidated.

Results

We generated high-density (HD) matrices that mimicked tumour collagen content of 20 mg/cm³ that were ~14-fold stiffer than low-density (LD) matrix of 1 mg/cm³. Live-cell imaging showed breast cancer cells utilizing cytoplasmic streaming and cell body contractility for migration within HD matrix. Cell migration was blocked in the presence of both the ROCK inhibitor, Y-27632, and the MMP inhibitor, GM6001, but not by the drugs individually. This suggests roles for ROCK1 and MMP in cell migration are complicated by compensatory mechanisms. ROCK1 expression and protein activity, were significantly upregulated in HD matrix but these were blocked by treatment with a histone deacetylase (HDAC) inhibitor, MS-275. In HD matrix, the inhibition of ROCK1 by MS-275 was indirect and relied upon protein synthesis and Notch1. Inhibition of Notch1 using pooled siRNA or DAPT abrogated the inhibition of ROCK1 by MS-275.

Conclusion

Increased matrix density elevates ROCK1 activity, which aids in cell migration via cell contractility. The upregulation of ROCK1 is epigenetically regulated in an indirect manner involving the repression of Notch1. This is demonstrated from inhibition of HDACs by MS-275, which caused an upregulation of Notch1 levels leading to blockade of ROCK1 expression.

【 授权许可】

   
2012 Raviraj et al.; licensee BioMed Central Ltd.

【 图 表 】

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