N-myc oncogene overexpression down-regulates IL-6;: evidence that IL-6 inhibits angiogenesis and suppresses neuroblastoma tumor growth
N-myc oncogene overexpression down-regulates IL-6;: evidence that IL-6 inhibits angiogenesis and suppresses neuroblastoma tumor growth
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DOI：
10.1038/sj.onc.1205440
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发表时间：
2002-05-16
期刊：
影响因子：
8
通讯作者：
Fotsis, T
中科院分区：
文献类型：
--
作者：
Hatzi, E;Murphy, C;Fotsis, T
血管生成是实体恶性肿瘤进展和转移不可或缺的先决条件。肿瘤血管生成似乎受到多种肿瘤中肿瘤抑制基因或癌基因操作的改变的控制。我们已经在神经母细胞瘤中解决了这个问题，这是一种以 N-Myc 癌基因近乎独有的扩增和过度表达为特征的恶性肿瘤。在此，我们报告 N-Myc 过表达导致白介素 6 (IL-6) 下调，并且 IL-6 是内皮细胞增殖和 VEGF 诱导的兔角膜血管生成的抑制剂。 STAT3 对于 IL-6 活性至关重要，因为表达磷酸化缺陷 STAT3 突变体的腺病毒感染会使内皮细胞对 IL-6 的抗增殖作用不敏感。最后，尽管 IL-6 不影响神经母细胞瘤细胞的生长，但小鼠中表达 IL-6 的异种移植肿瘤表现出新血管形成减少并抑制生长。我们的数据为 N-myc 癌基因扩增增强神经母细胞瘤恶性表型的机制提供了新的线索。
Angiogenesis is an indispensable prerequisite for the progression and metastasis of solid malignancies. Tumor angiogenesis appears to be governed by alterations of tumor suppressor or oncogenes operant in a broad range of tumors. We have addressed this issue in neuroblastoma, a malignancy characterized by the near-exclusive amplification and overexpression of the N-Myc oncogene. Here, we report that N-Myc overexpression results in down-regulation of interleukin-6 (IL-6) and that IL-6 is an inhibitor of endothelial cell proliferation and VEGF-induced rabbit corneal angiogenesis. STAT3 is instrumental for IL-6 activity as infection with adeno-viruses expressing a phosphorylation deficient STAT3 mutant renders endothelial cells insensitive to the antiproliferative action of IL-6. Finally, though IL-6 does not influence neuroblastoma cell growth, IL-6-expressing xenograft tumors in mice exhibit reduced neovascularization and suppressed growth. Our data shed new light on the mechanisms by which N-myc oncogene amplification enhances the malignant phenotype in neuroblastomas.