Epac increases melanoma cell migration by a heparan sulfate-related mechanism
Epac increases melanoma cell migration by a heparan sulfate-related mechanism
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DOI：
10.1152/ajpcell.00129.2009
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发表时间：
2009-10-01
影响因子：
5.5
通讯作者：
Ishikawa, Yoshihiro
中科院分区：
文献类型：
--
作者：
Baljinnyam, Erdene;Iwatsubo, Kousaku;Ishikawa, Yoshihiro
[10]李文，李文. Epac通过硫酸乙酰肝素相关机制增加黑色素瘤细胞迁移。美国生理学杂志细胞生理学297：C802-C813，2009年。首次发表于2009年8月5日; doi：10.1152/ajpcell.00129.2009。黑色素瘤是人类皮肤癌中最恶性的一种，由于其转移能力强，预后差。最近证实，Epac，cAMP的效应分子，参与调节细胞迁移;然而，Epac在黑色素瘤细胞迁移中的作用仍不清楚。因此，我们研究了Epac是否调节黑色素瘤的细胞迁移和转移。通过特异性激动剂或过表达Epac激活Epac，增加黑色素瘤细胞迁移。用小干扰RNA删除内源性Epac降低了基底黑色素瘤细胞的迁移。这些数据表明Epac在黑色素瘤细胞迁移中的主要作用。epac诱导的细胞迁移是由细胞表面硫酸乙酰肝素蛋白聚糖syndecan-2易位到脂筏介导的。这种多配体蛋白聚糖-2易位通过Epac/磷酸肌醇-3激酶途径由微管蛋白聚合调节。epac诱导的细胞迁移也受到硫酸乙酰肝素（一种主要的细胞外基质）的调节。Epac诱导的硫酸乙酰肝素的产生是由于N-脱乙酰基酶/N-磺基转移酶-1（NDST-1）的表达增加，并伴随着NDST-1翻译速率的增加。最后，Epac过表达增强小鼠黑色素瘤细胞的肺定植。总之，这些数据表明Epac主要通过多配体蛋白聚糖-2易位和硫酸乙酰肝素产生来调节黑素瘤细胞迁移/转移。
Baljinnyam E, Iwatsubo K, Kurotani R, Wang X, Ulucan C, Iwatsubo M, Lagunoff D, Ishikawa Y. Epac increases melanoma cell migration by a heparan sulfate-related mechanism. Am J Physiol Cell Physiol 297: C802-C813, 2009. First published August 5, 2009; doi:10.1152/ajpcell.00129.2009.-Melanoma, the most malignant form of human skin cancer, has a poor prognosis due to its strong metastatic ability. It was recently demonstrated that Epac, an effector molecule of cAMP, is involved in regulating cell migration; however, the role of Epac in melanoma cell migration remains unclear. We thus examined whether Epac regulates cell migration and metastasis of melanoma. Epac activation, by either specific agonist or overexpression of Epac, increased melanoma cell migration. Deletion of endogenous Epac with small interfering RNA decreased basal melanoma cell migration. These data suggested a major role of Epac in melanoma cell migration. Epac-induced cell migration was mediated by translocation of syndecan-2, a cell-surface heparan sulfate proteoglycan, to lipid rafts. This syndecan-2 translocation was regulated by tubulin polymerization via the Epac/phosphoinositol-3 kinase pathway. Epac-induced cell migration was also regulated by the production of heparan sulfate, a major extracellular matrix. Epac-induced heparan sulfate production was attributable to the increased expression of N-deacetylase/N-sulfotransferase-1 (NDST-1) accompanied by an increased NDST-1 translation rate. Finally, Epac overexpression enhanced lung colonization of melanoma cells in mice. Taken together, these data indicate that Epac regulates melanoma cell migration/metastasis mostly via syndecan-2 translocation and heparan sulfate production.