HIF-1α contributes to tube malformation of human lymphatic endothelial cells by upregulating VEGFR-3.
HIF-1α contributes to tube malformation of human lymphatic endothelial cells by upregulating VEGFR-3.
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DOI：
10.3892/ijo.2018.4623
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发表时间：
2019-01
影响因子：
5.2
通讯作者：
Zou J
中科院分区：
文献类型：
--
作者：
Han T;Yan J;Chen H;Ji Y;Chen J;Cui J;Shen W;Zou J
缺氧诱导因子-1 α（HIF-1α）在多种肿瘤中表达上调，并与肿瘤发生和转移过程中的淋巴管生成和血管生成相关。然而，HIF-1α在囊性淋巴管畸形（cLM）中的作用仍不清楚。在本研究中，HIF-1α和血管内皮生长因子受体3（VEGFR-3）的表达在20对cLM标本中进行了评估，这些标本来自南京医科大学儿童医院（中国南京）接受根治性手术的患者。此外，建立了稳定过表达HIF-1α的人淋巴管内皮细胞（HLEC）系。通过HIF-1α的过表达和沉默研究其在集落形成、迁移和淋巴管形成中的生物学作用。cLM组织中HIF-1α和VEGFR-3的表达均高于癌旁正常组织。此外，HIF-1α能有效诱导HLEC集落形成和迁移。此外，HIF-1α过表达可促进体外培养的HLECs淋巴管畸形。HIF-1α过表达上调淋巴管生成过程中的VEGFR-3。此外，在淋巴管畸形过程中，淋巴管内皮标志物β-同源框蛋白1和淋巴管内皮透明质酸受体1的表达显著增加。结果表明，HIF-1α过表达可通过上调VEGFR-3表达促进HLECs集落形成、迁移和管腔畸形。这些发现可能有助于未来开发针对HIF-1α的cLM治疗方法。
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.
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