MiR-323 Inhibits Prostate Cancer Vascularization Through Adiponectin Receptor
MiR-323 Inhibits Prostate Cancer Vascularization Through Adiponectin Receptor
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MiR-323 通过脂联素受体抑制前列腺癌血管化
DOI：
10.1159/000430313
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发表时间：
2015-01-01
影响因子：
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通讯作者：
Zheng, Junhua
中科院分区：
文献类型：
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作者：
Gao, Qiruo;Yao, Xudong;Zheng, Junhua
背景/目标：目前的治疗方法未能为侵袭性前列腺癌（PC）提供令人满意的治愈效果。因此，对 PC 转移的进一步理解对于提高治疗水平非常重要。我们之前已经表明，脂联素可能通过 AMPK/mTor 信号传导降低 PC 中血管内皮生长因子 A (VEGF-A) 的水平，从而抑制肿瘤相关的新生血管形成。在这里，我们研究了 PC 中脂联素信号传导的调节。方法：我们分析了 PC 样本中脂联素受体 1 (AdipoR1) 和 microRNA-323 (miR-323) 的水平和相关性，并与配对的正常前列腺组织进行比较。我们分别通过生物信息学分析和荧光素酶报告基因测定分析了 miR-323 与 AdipoR1 mRNA 3'UTR 的结合及其对 AdipoR1 翻译的影响。我们修改了 PC 细胞中的 miR-323 水平，并检查了其对 AdipoR1 和 VEGF-A 表达的影响，以及对人脐静脉内皮细胞 (HUVEC) Transwell 胶原凝胶测定中血管形成的影响。结果：我们在 PC 样本中检测到 AdipoR1 水平显着降低，而 miR-323 水平显着升高。此外，AdipoR1 和 miR-323 的水平呈负相关。此外，还发现 miR-323 与 AdipoR1 mRNA 的 3'UTR 结合，抑制其翻译。 PC 细胞中 miR-323 的过表达会降低 AdipoR1 蛋白水平，而抑制 miR-323 会增加 AdipoR1 蛋白水平，而不影响 AdipoR1 转录本。此外，miR-323的过表达增加了VEGF-A的水平和HUVEC的血管形成，而抑制miR-323则降低了VEGF-A的水平和HUVEC的血管形成。结论：我们的数据表明，miR-323 可能通过抑制 AdipoR1 来增加 PC 细胞中 VEGF-A 介导的癌症血管化。
Background/Aims: The current treatments fail to provide satisfactory cure for aggressive prostate cancers (PCs). Hence, further comprehension of PC metastasis is highly appreciated for improving the levels of therapy. We have previously shown that Adiponectin reduces the levels of vascular endothelial growth factor A (VEGF-A) in PCs to suppress tumor-associated neovascularization, possibly through AMPK/mTor signaling. Here, we studied the regulation of Adiponectin signaling in PCs. Methods: We analyzed the levels and correlation of Adiponectin receptor 1 (AdipoR1) and microRNA-323 (miR-323) in the PC specimen, compared to the paired normal prostate tissue. We analyzed the binding of miR-323 to the 3'UTR of AdipoR1 mRNA and its effects on AdipoR1 translation by bioinformatics analysis and by luciferase-reporter assay, respectively. We modified miR-323 levels in PC cells, and examined the effects on the expression of AdipoR1 and VEGF-A, as well as on vessel formation in a human umbilical vein endothelial cells (HUVECs) transwell collagen gel assay. Results: We detected significantly lower levels of AdipoR1 and significantly higher levels of miR-323 in PC specimen. Moreover, the levels of AdipoR1 and miR-323 are inversely correlated. Moreover, miR-323 was found to bind to the 3'UTR of AdipoR1 mRNA to inhibit its translation. Overexpression of miR-323 in PC cells decreased AdipoR1 protein levels, whereas inhibition of miR-323 increased AdipoR1 protein levels, without affecting AdipoR1 transcripts. Moreover, overexpression of miR-323 increased the levels of VEGF-A and the vessel formation by HUVECs, while inhibition of miR-323 decreased the levels of VEGF-A and the vessel formation by HUVECs. Conclusion: Our data demonstrate that miR-323 may increase VEGF-A-mediated cancer vascularization in PC cells through AdipoR1 suppression.