Hypoxia stimulates carcinoma invasion by stabilizing microtubules and promoting the Rab11 trafficking of the alpha6beta4 integrin.
Hypoxia stimulates carcinoma invasion by stabilizing microtubules and promoting the Rab11 trafficking of the alpha6beta4 integrin.
复制标题
DOI：
10.1158/0008-5472.can-04-4122
复制
发表时间：
2005-04
期刊：
影响因子：
11.2
通讯作者：
Sang-Oh Yoon;Sejeong Shin;A. Mercurio
中科院分区：
文献类型：
--
作者：
Sang-Oh Yoon;Sejeong Shin;A. Mercurio
缺氧在肿瘤细胞的存活、侵袭和转移中起着关键作用。在这里，我们表明，缺氧通过调节Rab11来增加肿瘤细胞的侵袭性，Rab11是囊泡运输的重要分子，特别是膜蛋白循环和蛋白质从跨高尔基网络到质膜的移位。显性阴性的Rab11可显著降低低氧诱导的乳腺癌细胞侵袭能力，而不影响细胞凋亡。低氧诱导的Rab11转运受微管稳定性的调节，研究结果表明，缺氧增加了Glu微管蛋白，秋水仙碱阻断了Rab11的转运和侵袭。低氧抑制GSK-3β活性似乎是微管稳定和侵袭的中心环节。事实上，显性阴性的GSK-3β的表达足以刺激正常氧条件下的侵袭。Rab11介导的有助于侵袭的交易的一个目标是整合素α6β4。低氧诱导α6β4表面表达显着增加，但对α3β1表面表达无明显影响。这种增加依赖于Rab11和稳定的微管。综上所述，我们认为囊泡运输是低氧刺激的一个新的靶点，对肿瘤的侵袭很重要。
Hypoxia plays a key role in tumor cell survival, invasion, and metastasis. Here we show that hypoxia increases tumor cell invasion by the modulation of Rab11, an important molecule for vesicular trafficking, especially membrane protein recycling and translocation of proteins from trans-Golgi network to plasma membrane. Dominant-negative Rab11 dramatically decreased hypoxia-induced invasion of MDA-MB-231 breast carcinoma cells without affecting cell apoptosis. Hypoxia-induced Rab11 trafficking is regulated by microtubule stability, as evidenced by the findings that hypoxia increases Glu tubulin and that colchicine blocks Rab11 trafficking and invasion. Inhibition of GSK-3beta activity by hypoxia seems to be central to microtubule stabilization and invasion. In fact, expression of a dominant-negative GSK-3beta was sufficient to stimulate invasion in normoxia. One target of Rab11-mediated trafficking that contributes to invasion is the integrin alpha6beta4. Hypoxia induced a significant increase in alpha6beta4 surface expression but it had no effect on the surface expression of alpha3beta1. This increase is dependent on Rab11 and stable microtubules. In summary, we identify vesicle trafficking as a novel target of hypoxic stimulation that is important for tumor invasion.