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.