Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion
Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion
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卡利他汀通过下调VEGF-C表达和分泌抑制胃癌淋巴管生成和淋巴转移
DOI：
10.1007/s10120-017-0787-5
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发表时间：
2018-07-01
期刊：
影响因子：
7.4
通讯作者：
Yang, Xia
中科院分区：
文献类型：
--
作者：
Ma, Caiqi;Luo, Chuanghua;Yang, Xia
背景肿瘤诱导的淋巴管生成和淋巴道转移是多种肿瘤转移的主要途径。然而，平衡肿瘤淋巴管生成和淋巴转移的内源性抑制剂尚未得到很好的评价。卡利斯他汀已被认为是一种内源性血管生成抑制剂。方法和结果我们最近的研究首次表明，卡利斯他汀过表达转基因小鼠的肺和胃切片中的淋巴管密度（LVD）降低。Kallistatin通过抑制人淋巴管内皮细胞（hLEC）的增殖、迁移和管形成来表达抗淋巴管生成活性。因此，本研究主要探讨胃癌组织中Kalistatin的表达变化与淋巴管生成和淋巴道转移的关系及其可能机制。我们的研究结果显示，胃癌患者的癌组织、转移淋巴结和血浆中的激肽释放酶抑制剂的表达显著下调，并且血浆中的激肽释放酶抑制剂水平与淋巴结转移的时间呈负相关。此外，用激肽释放酶抑制剂重组蛋白治疗降低了裸鼠胃移植瘤的LVD和淋巴结转移。结论Kalistatin通过LRP 6/IKK/I κ B B/NF-κ B B信号通路下调胃癌细胞VEGF-C的表达和分泌，从而抑制胃癌淋巴管生成和淋巴道转移。
BackgroundTumor-induced lymphangiogenesis and lymphatic metastasis are predominant during the metastasis of many types of cancers. However, the endogenous inhibitors that counterbalance the lymphangiogenesis and lymphatic metastasis of tumors have not been well evaluated. Kallistatin has been recognized as an endogenous angiogenesis inhibitor.Methods and resultsOur recent study showed for the first time that the lymphatic vessel density (LVD) was reduced in lung and stomach sections from kallistatin-overexpressing transgenic mice. Kallistatin expresses anti-lymphangiogenic activity by inhibiting the proliferation, migration, and tube formation of human lymphatic endothelial cells (hLECs). Therefore, the present study focuses on the relationships of changes in kallistatin expression with the lymphangiogenesis and lymphatic metastasis of gastric cancer and its underlying mechanisms. Our results revealed that the expression of kallistatin in cancer tissues, metastatic lymph nodes, and plasma of gastric cancer patients was significantly downregulated and that the plasma level of kallistatin was negatively associated with the phase of lymph node metastasis. Furthermore, treatment with kallistatin recombinant protein decreased LVD and lymph node metastases in the implanted gastric xenograft tumors of nude mice. Mechanically, kallistatin suppressed the lymphangiogenesis and lymphatic metastasis by downregulating VEGF-C expression and secretion through the LRP6/IKK/IҡB/NF-ҡB signaling pathway in gastric cancer cells.ConclusionsThese findings demonstrated that kallistatin functions as an endogenous lymphangiogenesis inhibitor and has an important part in the lymphatic metastasis of gastric cancer.