Details

Autor(en) / Beteiligte

• 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

Titel

Hypoxia-induced downregulation of microRNA-186-5p in endothelial cells promotes non-small cell lung cancer angiogenesis by upregulating protein kinase C alpha

Ist Teil von

• Molecular therapy. Nucleic acids, 2023-03, Vol.31, p.421-436

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. In vitro 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. In vivo, 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 bona fide 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. [Display omitted] The present study demonstrates that miR-186 is downregulated in tumor endothelial cells of human NSCLC patients. This endothelial miRNA potently inhibits multiple mechanisms of blood vessel formation via directly targeting protein kinase C alpha. Accordingly, endothelial miR-186 represents a potential therapeutic target for the future anti-angiogenic treatment of NSCLC.