Dopamine agonist resistance-related endocan promotes angiogenesis and cells viability of prolactinomas
Dopamine agonist resistance-related endocan promotes angiogenesis and cells viability of prolactinomas
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多巴胺激动剂耐药相关的内切酶促进泌乳素瘤的血管生成和细胞活力。
DOI：
10.1007/s12020-015-0824-2
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发表时间：
2016-06-01
期刊：
影响因子：
3.7
通讯作者：
Wu, Zhe Bao
中科院分区：
文献类型：
--
作者：
Cai, Lin;Leng, Zhi Gen;Wu, Zhe Bao
多巴胺激动剂（DAs）是泌乳素瘤的一线治疗药物。它们通过肿瘤细胞中的多巴胺2受体（D2R）发挥作用。内皮细胞特异性分子 - 1（ESM1），也称为内康（Endocan），被描述为新生血管生成的标志物。然而，ESM1是否会促进泌乳素瘤对多巴胺激动剂治疗的耐药性在很大程度上尚不清楚。在我们的研究中，根据对溴隐亭的临床反应，将25例泌乳素瘤患者分为耐药组和敏感组。我们发现耐药性泌乳素瘤的ESM1 - 微血管密度显著高于敏感型泌乳素瘤（47.9 ± 11.6，n = 8，对比13.1 ± 2.8，n = 17，p = 0.0006），这表明ESM1是一个与多巴胺激动剂耐药相关的基因。免疫染色显示ESM1在肿瘤血管和散在的肿瘤细胞中表达，并且在肿瘤血管中ESM1与平滑肌肌动蛋白（SMA）和血管性血友病因子（VWF）有重叠。在体外，沉默ESM1显著抑制了GH3和MMQ细胞的活力，并且进一步显著提高了GH3和MMQ细胞对多巴胺激动剂治疗的敏感性。此外，沉默ESM1下调了血管生成相关基因，如血管内皮生长因子受体2（VEGFR2）、成纤维细胞生长因子2（FGF2）、CD34、CD31、血管性血友病因子（VWF）和表皮生长因子受体（EGFR）。敲低ESM1减少了人脐静脉内皮细胞（HUVECs）的内皮管形成，并显著提高了人脐静脉内皮细胞对阿瓦斯汀治疗的敏感性。因此，我们首次证明与多巴胺激动剂耐药相关的ESM1促进了泌乳素瘤的血管生成和肿瘤细胞生长，这表明ESM1可能是泌乳素瘤的一个新的治疗靶点。
Dopamine agonists (DAs) are the first-line treatment of prolactinomas. They function through the dopamine 2 receptor (D2R) in the tumor cells. Endocan, also called endothelial cell-specific molecule-1 (ESM1), has been described as a marker of neoangiogenesis. However, whether ESM1 promotes the resistance of prolactinomas to DA therapy is largely unknown. In our study, 25 patients with prolactinomas were divided into resistant- and sensitive- groups according to the clinical response to bromocriptine. We found that ESM1-microvessel density of resistant prolactinomas was significantly higher than that of sensitive prolactinomas (47.9 ± 11.6,n= 8, vs 13.1 ± 2.8,n= 17,p= 0.0006), indicating that ESM1 was a DA resistance-related gene. Immunostaining showed that ESM1 was expressed in tumor vessels and sporadic tumor cells, and ESM1 was overlapped with the Smooth Muscle Actin (SMA) and von Willebrand Factor (VWF) in the tumor vessels. Silencing of ESM1 markedly suppressed the viability of GH3 and MMQ cells in vitro, and furthermore, significantly increased the sensitivity of GH3 and MMQ cells to DA treatment. Additionally, silencing of ESM1 down-regulated the angiogenesis-associated genes, such as VEGFR2, FGF2, CD34, CD31, VWF, and EGFR. Knockdown of ESM1 decreased endothelial tube formation of HUVECs, and significantly increased the sensitivity of HUVECs to Avastin treatment. Therefore, we first demonstrate that DA resistance-related ESM1 promotes the angiogenesis and tumor cells growth of prolactinomas, suggesting that ESM1 may be a novel therapeutic target for prolactinomas.