Lysophosphatidic Acid Induces Lymphangiogenesis and IL-8 Production in Vitro in Human Lymphatic Endothelial Cells
Lysophosphatidic Acid Induces Lymphangiogenesis and IL-8 Production in Vitro in Human Lymphatic Endothelial Cells
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DOI：
10.1016/j.ajpath.2012.03.003
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发表时间：
2012-05-01
影响因子：
6
通讯作者：
Gershenwald, Jeffrey E.
中科院分区：
文献类型：
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作者：
Mu, Hong;Calderone, Tiffany L.;Gershenwald, Jeffrey E.
生物活性磷脂溶血磷脂酸(LPA)及其受体LPA(1-3)在多种类型的人类肿瘤中异常表达。据报道，LPA可诱导肿瘤细胞的增殖、迁移和细胞因子的产生。然而，LPA是否对淋巴管内皮细胞(LECs)或淋巴管生成(一种与癌症患者转移增加和预后不良相关的新淋巴管形成过程)起作用尚不清楚。在这里，我们展示了LPA在体外诱导人真皮LEC的细胞增殖、存活、迁移和管状形成，并促进淋巴管的生成。此外，LPA通过激活晶状体上皮细胞中的核因子-kappa B途径来增强IL-8启动子的活性，从而诱导IL-8的表达。利用IL-8 siRNA和IL-8中和抗体，我们发现IL-8在体外LPA诱导的淋巴管生成中起重要作用。此外，利用siRNA抑制，我们发现LPA诱导的体外淋巴管生成和IL-8的产生是通过LPA受体介导的。最后，使用人类前哨传入淋巴管外植体，我们证明了LPA上调淋巴管内皮细胞中IL-8的产生。这些研究提供了LPA促进淋巴管生成和诱导LECs产生IL-8的第一个证据；我们还揭示了LPA在促进不同癌症类型的肿瘤进展和转移中可能发挥的新作用。(Am J Pathol2012,180：2170-2181；doi：10.1016/j.ajpath.2012.03.003)
The bioactive phospholipid lysophosphatidic acid (LPA) and its receptors LPA(1-3) are aberrantly expressed in many types of human cancer. LPA has been reported to induce tumor cell proliferation, migration, and cytokine production. However, whether LPA exerts an effect on lymphatic endothelial cells (LECs) or on lymphangiogenesis, a process of new lymphatic vessel formation that is associated with increased metastasis and poor prognosis in cancer patients, has been unknown. Here, we show that LPA induces cell proliferation, survival, migration, and tube formation, and promotes lymphangiogenesis in vitro in human dermal LECs. In addition, LPA induces IL-8 expression by enhancing IL-8 promoter activity via activation of the NF-kappa B pathway in LECs. Using IL-8 siRNA and IL-8 neutralizing antibody, we revealed that IL-8 plays an important role in LPA-induced lymphangiogenesis in vitro. Moreover, using siRNA inhibition, we discovered that LPA-induced lymphangiogenesis in vitro and IL-8 production are mediated via the LPA, receptor in LECs. Finally, using human sentinel afferent lymphatic vessel explants, we demonstrated that LPA up-regulates IL-8 production in the LECs of lymphatic endothelia. These studies provide the first evidence that LPA promotes lymphangiogenesis and induces IL-8 production in LECs; we also reveal a possible new role of LPA in the promotion of tumor progression, as well as metastasis, in different cancer types. (Am J Pathol 2012, 180:2170-2181; DOI: 10.1016/j.ajpath.2012.03.003)