Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Departments of Pediatrics, Oncology, Medicine, Radiation Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):E384-93. doi: 10.1073/pnas.1321510111. Epub 2013 Dec 9.
Overexpression of Rho kinase 1 (ROCK1) and the G protein RhoA is implicated in breast cancer progression, but oncogenic mutations are rare, and the molecular mechanisms that underlie increased ROCK1 and RhoA expression have not been determined. RhoA-bound ROCK1 phosphorylates myosin light chain (MLC), which is required for actin-myosin contractility. RhoA also activates focal adhesion kinase (FAK) signaling. Together, these pathways are critical determinants of the motile and invasive phenotype of cancer cells. We report that hypoxia-inducible factors coordinately activate RhoA and ROCK1 expression and signaling in breast cancer cells, leading to cell and matrix contraction, focal adhesion formation, and motility through phosphorylation of MLC and FAK. Thus, intratumoral hypoxia acts as an oncogenic stimulus by triggering hypoxia-inducible factor → RhoA → ROCK1 → MLC → FAK signaling in breast cancer cells.
Rho 激酶 1（ROCK1）和 G 蛋白 RhoA 的过表达与乳腺癌的进展有关，但致癌突变很少，并且导致 ROCK1 和 RhoA 表达增加的分子机制尚不清楚。RhoA 结合的 ROCK1 磷酸化肌球蛋白轻链（MLC），这是肌动球蛋白收缩所必需的。RhoA 还激活粘着斑激酶（FAK）信号通路。这些途径共同决定了癌细胞的运动和侵袭表型。我们报告说，缺氧诱导因子协同激活乳腺癌细胞中 RhoA 和 ROCK1 的表达和信号转导，导致细胞和基质收缩、粘着斑形成以及通过 MLC 和 FAK 的磷酸化而产生的运动性。因此，肿瘤内缺氧通过触发乳腺癌细胞中的缺氧诱导因子→RhoA→ROCK1→MLC→FAK 信号转导，充当致癌刺激物。
