Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Cancer Res. 2012 Sep 15;72(18):4682-95. doi: 10.1158/0008-5472.CAN-12-0440. Epub 2012 Jul 26.
Although human angiosarcoma has been associated frequently with mutational inactivation of the tumor suppressor gene Ink4a/Arf, the underlying mechanisms have not been delineated. Here we report that malignant angiosarcoma is associated with high levels of RelA/NF-κB and IL-6 in contrast to normal vessels or benign hemagiomas. Studies of Ink4a/Arf deficient mice not only recapitulate genetic traits observed in human angiosarcoma, but also unveil a possible therapeutic link comprised of the NF-kB/IL-6/Stat3 signaling axis. In Ink4a/Arf(-/-) cells, NF-κB controlled Stat3 signaling by transcriptionally controlling the expression of IL-6, gp130, and Jak2. Further, IL-6 mediated Stat3 signaling through the sIL-6R. Inhibition of Ikkβ solely in myeloid cells was insufficient to block angiosarcoma development; in contrast, systemic inhibition of Ikkβ, IL-6, or Stat3 markedly inhibited angiosarcoma growth. Our findings offer clinical implications for targeting the NF-kB/IL-6/STAT3 pathway as a rational strategy to treat angiosarcoma.
虽然人类血管肉瘤常与肿瘤抑制基因 Ink4a/Arf 的突变失活有关，但潜在的机制尚未阐明。在这里，我们报告恶性血管肉瘤与高水平的 RelA/NF-κB 和 IL-6 相关，与正常血管或良性血管瘤形成对比。Ink4a/Arf 缺陷小鼠的研究不仅重现了在人类血管肉瘤中观察到的遗传特征，而且还揭示了一个可能的治疗联系，由 NF-κB/IL-6/Stat3 信号轴组成。在 Ink4a/Arf(-/-)细胞中，NF-κB 通过转录控制 IL-6、gp130 和 Jak2 的表达来控制 Stat3 信号。此外，IL-6 通过 sIL-6R 介导 Stat3 信号。仅在髓样细胞中抑制 Ikkβ不足以阻止血管肉瘤的发展；相比之下，系统抑制 Ikkβ、IL-6 或 Stat3 显著抑制血管肉瘤的生长。我们的发现为靶向 NF-κB/IL-6/STAT3 途径提供了临床意义，作为治疗血管肉瘤的合理策略。
