Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Mail Drop D2-05, Room D248A, Rall Building, 111T. W. Alexander Drive, Research Triangle Park, NC 27709, USA.
Br J Cancer. 2012 Jun 26;107(1):129-36. doi: 10.1038/bjc.2012.214. Epub 2012 May 29.
Tumour cell metastasis involves cell adhesion and invasion, processes that depend on signal transduction, which can be influenced by the tumour microenvironment. N-6 polyunsaturated fatty acids, found both in the diet and in response to inflammatory responses, are important components of this microenvironment.
We used short hairpin RNA (shRNA) knockdown of TGF-β-activated kinase-1 (TAK1) in human tumour cells to examine its involvement in fatty acid-stimulated cell adhesion and invasion in vitro. An in vivo model of metastasis was developed in which cells, stably expressing firefly luciferase and either a control shRNA or a TAK1-specific shRNA, were injected into the mammary fat pads of mice fed diets, rich in n-6 polyunsaturated fatty acids. Tumour growth and spontaneous metastasis were monitored with in vivo and in situ imaging of bioluminescence.
Arachidonic acid activated TAK1 and downstream kinases in MDA-MB-435 breast cancer cells and led to increased adhesion and invasion. Knockdown of TAK1 blocked this activation and inhibited both cell adhesion and invasion in vitro. Tumour growth at the site of injection was not affected by TAK1 knockdown, but both the incidence and extent of metastasis to the lung were significantly reduced in mice injected with TAK1 knockdown cells compared with mice carrying control tumour cells.
These data demonstrate the importance of TAK1 signalling in tumour metastasis in vivo and suggest an opportunity for antimetastatic therapies.
肿瘤细胞转移涉及细胞黏附和侵袭，这些过程依赖于信号转导，而信号转导又会受到肿瘤微环境的影响。N-6 多不饱和脂肪酸存在于饮食中，也可作为炎症反应的产物，是该微环境的重要组成部分。
我们采用短发夹 RNA(shRNA) 敲低人肿瘤细胞中的转化生长因子-β激活激酶 1(TAK1)，以研究其在体外脂肪酸刺激的细胞黏附和侵袭中的作用。我们构建了一个转移的体内模型，将稳定表达萤火虫荧光素酶和对照 shRNA 或 TAK1 特异性 shRNA 的细胞注射到喂食富含 n-6 多不饱和脂肪酸饮食的小鼠乳腺脂肪垫中。通过体内和原位生物发光成像监测肿瘤生长和自发性转移。
花生四烯酸激活了 MDA-MB-435 乳腺癌细胞中的 TAK1 和下游激酶，导致细胞黏附和侵袭增加。敲低 TAK1 阻断了这种激活，并抑制了细胞在体外的黏附和侵袭。注射部位的肿瘤生长不受 TAK1 敲低的影响，但与携带对照肿瘤细胞的小鼠相比，注射 TAK1 敲低细胞的小鼠肺部转移的发生率和程度均显著降低。
这些数据表明 TAK1 信号在体内肿瘤转移中的重要性，并为抗转移治疗提供了机会。
