EGFR variant-mediated invasion by enhanced CXCR4 expression through transcriptional and post-translational mechanisms.
EGFR variant-mediated invasion by enhanced CXCR4 expression through transcriptional and post-translational mechanisms.
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DOI：
10.1002/ijc.24964
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发表时间：
2010-04-15
影响因子：
6.4
通讯作者：
Tang, Careen
中科院分区：
文献类型：
--
作者：
Rahimi, Massod;George, Jessica;Tang, Careen
有效的、组成型激活的EGFR变体EGFRvIII的表达与乳腺癌转移有关，但EGFRvIII和CXCR4串扰可能促进乳腺癌侵袭的机制从未被探索过。在这里，我们报告了CXCR4在表达EGFRvIII的乳腺癌细胞中的表达增加，而不管细胞的ER/PgR状态如何。用酪氨酸激酶抑制剂AG1478治疗表达egfrviii的乳腺癌细胞，可将CXCR4的表达逆转回亲代细胞中的表达水平。此外，表达EGFRvIII可增强CXCL12/CXCR4介导的侵袭，而这种侵袭可被CXCR4抑制剂抑制。令人惊讶的是，CXCR4 mRNA及其转录调节因子HIF-1α仅在ER+/PgR+雌激素依赖性egfrviii表达的乳腺癌细胞中上调，而在ER-/PgR-或雌激素非依赖性细胞系中不上调，这表明HIF-1α和激素受体介导的作用可能在CXCR4的转录调节中起作用。我们还证明p38 MAPK是EGFRvIII/ cxcr4介导的侵袭的主要下游信号分子之一，因为在常氧和缺氧条件下，CXCL12刺激都会诱导p38 MAPK活性。更有趣的是，p38 MAPK活性的抑制显著降低了CXCR4的表达，抑制了表达EGFRvIII的乳腺癌细胞的侵袭潜力，这表明p38 MAPK在EGFRvIII/CXCR4诱导的侵袭中发挥了重要作用。此外，CXCR4在翻译后通过降低AIP4和β-阻滞蛋白1/2（参与CXCR4内化、细胞运输和降解的分子）的表达而受到调控。这些结果为EGFRvIII介导的侵袭提供了一个合理的机制，并在EGFRvIII和CXCR4信号通路之间建立了功能联系。
The expression of the potent, constitutively activated EGFR variant, EGFRvIII, has been linked to breast cancer metastasis, but the mechanisms of EGFRvIII and CXCR4 crosstalk, which may facilitate breast cancer invasion, have never been explored. Here we report that CXCR4 expression is increased in breast cancer cells expressing EGFRvIII regardless of the ER/PgR status of the cells. Treatment of EGFRvIII-expressing breast cancer cells with the tyrosine kinase inhibitor, AG1478, reverses CXCR4 expression back to levels expressed in parental cells. In addition, expressing EGFRvIII enhances CXCL12/CXCR4-mediated invasion, which can be inhibited by CXCR4 inhibitors. Surprisingly, CXCR4 mRNA and its transcriptional regulator, HIF-1α, are up-regulated only in ER+/PgR+ estrogen-dependent EGFRvIII-expressing breast cancer cells, but not in ER-/PgR- or estrogen-independent cell lines, suggesting that HIF-1α and hormone receptor-mediated actions may have a role in the transcriptional regulation of CXCR4. We also demonstrate that p38 MAPK is one of the major down-stream signaling molecules responsible for EGFRvIII/CXCR4-mediated invasion as p38 MAPK activity was induced by CXCL12 stimulation under both normoxic and hypoxic conditions. More interestingly, inhibition of p38 MAPK activity significantly reduced CXCR4 expression and inhibited the invasive potential of EGFRvIII-expressing breast cancer cells, suggesting an essential role for p38 MAPK in EGFRvIII/CXCR4 induced invasion. Furthermore, CXCR4 is regulated post-translationally through decreased expression of AIP4 and β-arrestin 1/2, molecules involved in CXCR4 internalization, cellular trafficking, and degradation. These results provide a plausible mechanism for EGFRvIII-mediated invasion and establish a functional link between EGFRvIII and CXCR4 signaling pathways.
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