| First Author | Yang J | Year | 2012 |
| Journal | Cancer Res | Volume | 72 |
| Issue | 18 | Pages | 4682-95 |
| PubMed ID | 22836752 | Mgi Jnum | J:191329 |
| Mgi Id | MGI:5461452 | Doi | 10.1158/0008-5472.CAN-12-0440 |
| Citation | Yang J, et al. (2012) Ikk4a/Arf inactivation with activation of the NF-kappaB/IL-6 pathway is sufficient to drive the development and growth of angiosarcoma. Cancer Res 72(18):4682-95 |
| abstractText | 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-kappaB 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-kappaB 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 Ikkbeta solely in myeloid cells was insufficient to block angiosarcoma development; in contrast, systemic inhibition of Ikkbeta, 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. |
