Becker Vivien, Yuan Xu, Boewe Anne S, Ampofo Emmanuel, Ebert Elke, Hohneck Johannes, Bohle Rainer M, Meese Eckart, Zhao Yingjun, Menger Michael D, Laschke Matthias W, Gu Yuan
Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany.
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Mol Ther Nucleic Acids. 2023 Jan 27;31:421-436. doi: 10.1016/j.omtn.2023.01.015. eCollection 2023 Mar 14.
The tumor microenvironment stimulates the angiogenic activity of endothelial cells (ECs) to facilitate tumor vascularization, growth, and metastasis. The involvement of microRNA-186-5p (miR-186) in regulating the aberrant activity of tumor-associated ECs has so far not been clarified. In the present study, we demonstrated that miR-186 is significantly downregulated in ECs microdissected from human non-small cell lung cancer (NSCLC) tissues compared with matched non-malignant lung tissues. analyses of primary human dermal microvascular ECs (HDMECs) exposed to different stimuli indicated that this miR-186 downregulation is triggered by hypoxia via activation of hypoxia-inducible factor 1 alpha (HIF1α). Transfection of HDMECs with miR-186 mimic (miR-186m) significantly inhibited their proliferation, migration, tube formation, and spheroid sprouting. In contrast, miR-186 inhibitor (miR-186i) exerted pro-angiogenic effects. , endothelial miR-186 overexpression inhibited the vascularization of Matrigel plugs and the initial growth of tumors composed of NSCLC cells (NCI-H460) and HDMECs. Mechanistic analyses revealed that the gene encoding for protein kinase C alpha (PKCα) is a target of miR-186. Activation of this kinase significantly reversed the miR-186m-repressed angiogenic activity of HDMECs. These findings indicate that downregulation of miR-186 in ECs mediates hypoxia-stimulated NSCLC angiogenesis by upregulating PKCα.
肿瘤微环境刺激内皮细胞（ECs）的血管生成活性，以促进肿瘤血管形成、生长和转移。迄今为止，微小RNA-186-5p（miR-186）在调节肿瘤相关ECs异常活性中的作用尚未明确。在本研究中，我们证明，与配对的非恶性肺组织相比，从人非小细胞肺癌（NSCLC）组织中显微切割得到的ECs中，miR-186显著下调。对暴露于不同刺激的原代人真皮微血管内皮细胞（HDMECs）的分析表明，这种miR-186下调是由缺氧通过激活缺氧诱导因子1α（HIF1α）触发的。用miR-186模拟物（miR-186m）转染HDMECs可显著抑制其增殖、迁移、管形成和球体发芽。相反，miR-186抑制剂（miR-186i）发挥促血管生成作用。此外，内皮细胞miR-186过表达抑制了基质胶栓的血管形成以及由NSCLC细胞（NCI-H460）和HDMECs组成的肿瘤的初始生长。机制分析显示，编码蛋白激酶Cα（PKCα）的基因是miR-186的一个靶标。该激酶的激活显著逆转了miR-186m抑制的HDMECs的血管生成活性。这些发现表明，ECs中miR-186的下调通过上调PKCα介导缺氧刺激的NSCLC血管生成。
