OSCC Exosomes Regulate miR-210-3p Targeting EFNA3 to Promote Oral Cancer Angiogenesis through the PI3K/AKT Pathway
OSCC Exosomes Regulate miR-210-3p Targeting EFNA3 to Promote Oral Cancer Angiogenesis through the PI3K/AKT Pathway
复制标题
OSCC 外泌体调节 miR-210-3p 靶向 EFNA3 通过 PI3K/AKT 途径促进口腔癌血管生成
DOI：
10.1155/2020/2125656
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发表时间：
2020-07-09
影响因子：
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通讯作者：
Shang, Zhengjun
中科院分区：
文献类型：
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作者：
Wang, Hui;Wang, Lin;Shang, Zhengjun
本研究旨在探讨口腔鳞状细胞癌（oral squamous cell carcinoma，OSCC）中miR-210- 3 p的表达对HUVECs血管生成的调控作用，并探讨miR-210- 3 p与其靶蛋白的关系及其调控血管生成的可能机制。检测miR-210- 3 p在口腔鳞癌组织和口腔鳞癌组织（JCT）中的表达，分析miR-210- 3 p与微血管密度（MVD）及组织病理学特征的关系。收集OSCC细胞系CAL 27的条件培养基（CM）以刺激人脐静脉内皮细胞（HUVECs），并测量HUVECs的miR-210- 3 p水平和管形成能力。改变miR-210- 3 p的靶蛋白水平，检测HUVECs中PI 3 K/AKT通路的激活情况。在从CAL 27 CM分离的外来体中测试miR-210- 3 p，并且验证miR-210- 3 p从OSCC外来体向HUVEC的转移。OSCC组织中miR-210- 3 p的表达水平高于JCT组织，且miR-210- 3 p的表达水平与MVD、肿瘤分级呈正相关。CAL 27 CM能够提高HUVEC中的miR-210- 3 p水平并促进管形成。EFNA 3是miR-210- 3 p的靶基因，ephrinA 3蛋白水平能够影响HUVEC的迁移和增殖。当ephrinA 3下调时，HUVECs中磷酸化AKT的水平增加，并且ephrinA 3的上调导致PI 3 K/AKT通路的抑制。从CAL 27细胞的CM分离的exosomes中检测到miR-210- 3 p，并且HUVECs吸收OSCC exosomes后miR-210- 3 p水平升高。总之，miR-210- 3 p在OSCC组织中比在JCT中更过表达。OSCC细胞分泌的exosomes能够上调HUVEC中miR-210- 3 p的表达，降低ephrinA 3的表达，并通过PI 3 K/AKT信号通路促进管形成。
This study is aimed at determining how oral squamous cell carcinoma (OSCC) regulates the angiogenesis of HUVECs through miR-210-3p expression and exploring the relationship among miR-210-3p, its target protein, and the possible mechanism of angiogenesis regulation. miR-210-3p expression was detected in OSCC tissues and juxta cancerous tissues (JCT), and the relationship among miR-210-3p, microvessel density (MVD), and histopathologic features was analyzed. A conditioned medium (CM) of the OSCC cell line CAL27 was collected to stimulate human umbilical vein endothelial cells (HUVECs), and the miR-210-3p levels and tube formation capability of HUVECs were measured. The target protein level of miR-210-3p was altered; then, PI3K/AKT pathway activation in HUVECs was detected. miR-210-3p was tested in exosomes separated from CAL27 CM, and the transfer of miR-210-3p from OSCC exosomes to HUVECs was verified. Then, we found that the OSCC tissues had higher miR-210-3p levels than the JCT, and miR-210-3p level was positively correlated with MVD and tumor grade. CAL27 CM was able to elevate miR-210-3p levels in HUVECs and promoted tube formation. EFNA3 was the target gene of miR-210-3p, and ephrinA3 protein level was able to influence the migration and proliferation of HUVECs. The levels of phosphorylated AKT in the HUVECs increased when ephrinA3 was downregulated, and the upregulation of ephrinA3 resulted in the suppression of the PI3K/AKT pathway. miR-210-3p was detected in exosomes isolated from the CM of CAL27 cells, and miR-210-3p level in the HUVECs was elevated after absorbing the OSCC exosomes. In conclusion, miR-210-3p was more overexpressed in OSCC tissues than in the JCT. The exosomes secreted by OSCC cells were able to upregulate miR-210-3p expression and reduce ephrinA3 expression in HUVECs and promoted tube formation through the PI3K/AKT signaling pathway.