Hypoxia-inducible factor-1-mediated regulation of semaphorin 4D affects tumor growth and vascularity.
Tumor progression and metastasis depend on the ability of cancer cells to initiate angiogenesis to ensure delivery of oxygen, nutrients, and growth factors to tumor cells and provide access to the systemic circulation. Hypoxia-inducible factor-1 (HIF-1) can activate expression of a broad range of genes that mediate many of the adaptive responses to decreased oxygen concentration, such as enhanced glucose uptake and formation of new blood vessels. Acting through Plexin-B1 on endothelial cells, Semaphorin 4D (Sema4D) has been shown to promote angiogenesis and enhance invasive growth and proliferation in some tumors. Here we show that the gene for Sema4D, the product of which is elevated in head and neck squamous cell carcinoma (HNSCC) cells, contains upstream hypoxia response elements (HRE) and is strongly induced in hypoxia in a HIF-1-dependent manner. Knocking down Sema4D expression with short hairpin (sh) RNA reduces in vitro endothelial cell migration and growth and vascularity of HNSCC xenografts expressing a degradation resistant HIF-1alpha subunit. We also demonstrate a correlation between HIF-1 activity and Sema4D expression in HNSCC specimens. These findings indicate that Sema4D is induced by hypoxia in a HIF-1-dependent manner and influences endothelial cell migration and tumor vascularity. Expression of Sema4D may be a strategy by which carcinomas promote angiogenesis and therefore could represent a therapeutic target for these malignancies.
Sun
Qiangming
Q
Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland 21201, USA.
Zhou
Hua
H
Binmadi
Nada O
NO
Basile
John R
JR
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
D015703:Antigens, CD; C093224:CD100 antigen; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D039961:Semaphorins; D008156:Luciferases