N-myc oncogene overexpression down-regulates IL-6; evidence that IL-6 inhibits angiogenesis and suppresses neuroblastoma tumor growth.
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 adenoviruses 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.
Hatzi
Elissavet
E
Laboratory of Biological Chemistry, Medical School, University of Ioannina, Ioannina, Greece.
Murphy
Carol
C
Zoephel
Andreas
A
Rasmussen
Heidi
H
Morbidelli
Lucia
L
Ahorn
Horst
H
Kunisada
Keita
K
Tontsch
Ulrike
U
Klenk
Michael
M
Yamauchi-Takihara
Keiko
K
Ziche
Marina
M
Rofstad
Einar K
EK
Schweigerer
Lothar
L
Fotsis
Theodore
T
D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016543:Central Nervous System Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000628:therapy; D009447:Neuroblastoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011817:Rabbits; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016274:Oncogene Protein p55(v-myc); D012334:RNA, Neoplasm; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators