肌动球蛋白介导的细胞张力增加组织硬度，并激活β-连环蛋白，从而诱导表皮过度增生和肿瘤生长。
Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth.
机构信息
Beatson Institute for Cancer Research, Glasgow, UK.
出版信息
Cancer Cell. 2011 Jun 14;19(6):776-91. doi: 10.1016/j.ccr.2011.05.008.
Abstract
Tumors and associated stroma manifest mechanical properties that promote cancer. Mechanosensation of tissue stiffness activates the Rho/ROCK pathway to increase actomyosin-mediated cellular tension to re-establish force equilibrium. To determine how actomyosin tension affects tissue homeostasis and tumor development, we expressed conditionally active ROCK2 in mouse skin. ROCK activation elevated tissue stiffness via increased collagen. β-catenin, a key element of mechanotranscription pathways, was stabilized by ROCK activation leading to nuclear accumulation, transcriptional activation, and consequent hyperproliferation and skin thickening. Inhibiting actomyosin contractility by blocking LIMK or myosin ATPase attenuated these responses, as did FAK inhibition. Tumor number, growth, and progression were increased by ROCK activation, while ROCK blockade was inhibitory, implicating actomyosin-mediated cellular tension and consequent collagen deposition as significant tumor promoters.
摘要
肿瘤及其相关基质表现出促进癌症的机械特性。组织硬度的机械感觉激活 Rho/ROCK 通路，增加肌动球蛋白介导的细胞张力，以重新建立力平衡。为了确定肌动球蛋白张力如何影响组织平衡和肿瘤发展，我们在小鼠皮肤中表达条件性激活的 ROCK2。ROCK 激活通过增加胶原蛋白来提高组织硬度。β-连环蛋白是机械转导途径的关键元件，ROCK 激活使其稳定，导致核内积累、转录激活以及随后的过度增殖和皮肤增厚。通过阻断 LIMK 或肌球蛋白 ATP 酶抑制肌动球蛋白收缩性可减弱这些反应，FAK 抑制也是如此。ROCK 激活增加了肿瘤数量、生长和进展，而 ROCK 阻断则具有抑制作用，这表明肌动球蛋白介导的细胞张力和随后的胶原蛋白沉积是重要的肿瘤促进剂。
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