Loss of E-cadherin leads to upregulation of NFκB activity in malignant melanoma
Loss of E-cadherin leads to upregulation of NFκB activity in malignant melanoma
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DOI：
10.1038/sj.onc.1207831
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发表时间：
2004-11-04
期刊：
影响因子：
8
通讯作者：
Bosserhoff, AK
中科院分区：
文献类型：
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作者：
Kuphal, S;Poser, I;Bosserhoff, AK
黑素细胞的恶性转化常常与E - 钙黏蛋白表达缺失同时发生。在此，我们表明E - 钙黏蛋白缺失会导致黑素瘤细胞系中核因子κB（NFκB）活性的诱导。黑素瘤细胞呈现出组成性激活的NFκB，而在原代黑素细胞中未发现此活性。在黑素瘤细胞中重新表达E - 钙黏蛋白后，发现NFκB活性显著下调。一致地，通过功能性阻断抗E - 钙黏蛋白抗体抑制E - 钙黏蛋白活性后，原代人黑素细胞中NFκB活性被诱导。有趣的是，E - 钙黏蛋白的重新表达阻断了p38丝裂原活化蛋白激酶（MAPK）活性，并且p38 MAPK抑制剂SB203580和SB202190几乎完全阻止了黑素瘤细胞中NFκB的激活。此外，细胞质β - 连环蛋白在恶性黑素瘤中诱导p38和NFκB激活。据我们所知，这是首次表明黑素细胞和黑素瘤细胞中E - 钙黏蛋白与NFκB活性之间存在相关性的报道。总之，我们得出结论：E - 钙黏蛋白缺失和细胞质β - 连环蛋白诱导p38介导的NFκB激活，这可能揭示了恶性黑素瘤肿瘤发生的一个重要机制。
Malignant transformation of melanocytes frequently coincides with loss of E-cadherin expression. Here, we show that loss of E-cadherin leads to induction of nuclear factor kappa B (NFkappaB) activity in melanoma cell lines. Melanoma cells show constitutively active NFkappaB, whereas no activity is found in primary melanocytes. After reexpression of E-cadherin in melanoma cells, strong downregulation of NFkappaB activity was found. Consistently, NFkappaB activity was induced in primary human melanocytes after inhibition of E-cadherin activity by functionally blocking anti-E-cadherin antibodies. Interestingly, reexpression of E-cadherin-blocked p38 MAPK activity and the p38 MAPK inhibitors SB203580 and SB202190 almost completely prevented NFkappaB activation in melanoma cells. Furthermore, cytoplasmatic beta-catenin induced p38 and NFkappaB activation in malignant melanoma. To our knowledge, this is the first report suggesting a correlation between E-cadherin and NFkappaB activity in melanocytes and melanoma cells. In summary, we conclude that loss of E-cadherin and cytoplasmatic beta-catenin induces p38-mediated NFkappaB activation, potentially revealing an important mechanism of tumorigenesis in malignant melanomas.