HIF-1α contributes to tube malformation of human lymphatic endothelial cells by upregulating VEGFR-3.

Hypoxia‑inducible factor‑1α (HIF‑1α) is upregulated in various tumors and associated with lymphangiogenesis and angiogenesis during tumor development and metastasis. However, the role of HIF‑1α in cystic lymphatic malformations (cLM) remains unclear. In the present study, expression of HIF‑1α and vascular endothelial growth factor receptor 3 (VEGFR‑3) was evaluated in 20 pairs of cLM specimens from patients who accepted curative surgery at Children's Hospital of Nanjing Medical University (Nanjing, China). Additionally, a stable HIF‑1α‑overexpressing human lymphatic endothelial cell (HLEC) line was established. Overexpression and silencing of HIF‑1α were used to investigate the biological role in colony formation, migration and lymphatic tube formation. HIF‑1α and VEGFR‑3 were upregulated in cLM specimens compared with adjacent normal tissues. In addition, HIF‑1α effectively induced HLEC colony formation and migration. Furthermore, lymphatic malformation of HLECs was promoted in vitro by overexpression of HIF‑1α. HIF‑1α overexpression upregulated VEGFR‑3 during lymphangiogenesis. Additionally, expression of lymphatic endothelial markers prospero homeobox protein 1 and lymphatic vessel endothelial hyaluronan receptor 1 increased significantly during lymphatic tube malformation. The presented data demonstrated that HIF‑1α overexpression in HLECs promoted colony formation, migration and tube malformation via upregulation of VEGFR‑3. These findings may assist in the development of HIF‑1α‑targeted cLM therapeutics in the future.