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

BMC Cell Biology

Research Article

Hsin-Ya Chien¹  Vanisri Raviraj¹  Jifei Zhao¹  Sandra Fok¹  Lilian Soon²  J Guy Lyons³  Erik W Thompson⁴ 

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

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

DOI  :  10.1186/1471-2121-13-12

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

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsWe 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.ConclusionIncreased 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】

Unknown   
© Raviraj et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.