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AHRR contributes to inflammatory lymphangiogenesis by activating the EPAS1/VEGFD signaling axis in head and neck cancer.

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.