Lymph node metastasis (LNM) is associated with poor survival in patients with
Head and Neck cancer (HNC).
Aryl hydrocarbon receptor repressor (AHRR) is thought to be responsible for increased lymphangiogenesis and LNM. AHRR and
endothelial PAS domain-containing protein 1 (EPAS1) are basic helix-loop-helix/per-arnt-sim family
transcription factors, however, its central role in lymphangiogenesis remains to be explored. In this study, we explored that EPAS1 dimerizes with HIF-1β during lymphangiogenes and
tumor growth, inducing expression of many genes, including
vascular endothelial growth factor-d (VEGFD). AHRR wild-type (Ahrr +/+) transgenic
carcinoma of the mice develop
tumors with greater frequency than AHRR-null (Ahrr -/-) mice, even though prevalence of squamous epithelial
hyperplasia is not inhibited.
Hypoxia induced VEGFD
protein in a genotype-dependent fashion in Ahrr +/+, Ahrr +/- and Ahrr -/- HNC. However,
hypoxia induced upstream
proteins in the
phosphatidylinositol 3-kinase-signaling cascade to a similar extent in HNC of each Ahrr genotype, evidenced by Akt phosphorylation. These findings suggest that AHRR induces HIF-1β expression, increasing interaction with EPAS1 enhancing VEGFD production and lymphangiogenesis in HNC.