Autocrine motility factor modulates EGF-mediated invasion signaling.
Autocrine motility factor modulates EGF-mediated invasion signaling.
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DOI：
10.1158/0008-5472.can-13-2937
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发表时间：
2014-04-15
期刊：
影响因子：
11.2
通讯作者：
Raz A
中科院分区：
文献类型：
--
作者：
Kho DH;Zhang T;Balan V;Wang Y;Ha SW;Xie Y;Raz A
自分泌运动因子（AMF）增强乳腺癌细胞的侵袭，但其分泌和效应信号在肿瘤微环境中的控制机制尚不完全清楚。在这项研究中，我们研究了这些问题与嵌合AMF，分泌高水平通过一个典型的ER/高尔基体途径。利用这个工具，我们发现AMF通过激活AKT/ERK，改变肌动蛋白组织和刺激β-catenin/TCF和AP-1转录来增强肿瘤细胞的运动性。EGF通过其酪蛋白激酶2介导的磷酸化促进AMF的分泌。RNAi介导的AMF表达减弱通过抑制ERK信号传导抑制EGF诱导的侵袭。相反，外源性AMF通过激活HER 2信号转导克服EGFR抑制剂吉非替尼对侵袭运动的抑制作用。总之，我们的研究结果显示AMF如何调节EGF诱导的侵袭，同时影响肿瘤微环境中对细胞毒性药物的获得性耐药性。
Autocrine motility factor (AMF) enhances invasion by breast cancer cells, but how its secretion and effector signaling are controlled in the tumor microenvironment is not fully understood. In this study, we investigated these issues with a chimeric AMF that is secreted at high levels through a canonical ER/Golgi pathway. Using this tool, we found that AMF enhances tumor cell motility by activating AKT/ERK, altering actin organization and stimulating β-catenin/TCF and AP-1 transcription. EGF enhanced secretion of AMF through its casein kinase 2-mediated phosphorylation. RNAi-mediated attenuation of AMF expression inhibited EGF-induced invasion by suppressing ERK signaling. Conversely, exogenous AMF overcame the inhibitory effect of EGFR inhibitor gefitinib on invasive motility by activating HER2 signaling. Taken together, our findings show how AMF modulates EGF-induced invasion while affecting acquired resistance to cytotoxic drugs in the tumor microenvironment.