Gu Yuan, Pais Gianni, Becker Vivien, Körbel Christina, Ampofo Emmanuel, Ebert Elke, Hohneck Johannes, Ludwig Nicole, Meese Eckart, Bohle Rainer M, Zhao Yingjun, Menger Michael D, Laschke Matthias W
Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany.
Institute of Pathology, Saarland University, 66421 Homburg/Saar, Germany.
Mol Ther Nucleic Acids. 2021 Oct 8;26:849-864. doi: 10.1016/j.omtn.2021.10.003. eCollection 2021 Dec 3.
MicroRNAs (miRNAs) expressed in endothelial cells (ECs) are powerful regulators of angiogenesis, which is essential for tumor growth and metastasis. Here, we demonstrated that miR-22 is preferentially and highly expressed in ECs, while its endothelial level is significantly downregulated in human non-small cell lung cancer (NSCLC) tissues when compared to matched nontumor lung tissues. This reduction of endothelial miR-22 is possibly induced by NSCLC cell-secreted interleukin-1β and subsequently activated transcription factor nuclear factor-κB. Endothelial miR-22 functions as a potent angiogenesis inhibitor that inhibits all of the key angiogenic activities of ECs and consequently NSCLC growth through directly targeting sirtuin 1 and fibroblast growth factor receptor 1 in ECs, leading to inactivation of AKT/mammalian target of rapamycin signaling. These findings provide insight into the molecular mechanisms of NSCLC angiogenesis and indicate that endothelial miR-22 represents a potential target for the future antiangiogenic treatment of NSCLC.
在内皮细胞（ECs）中表达的微小RNA（miRNAs）是血管生成的有力调节因子，而血管生成对于肿瘤生长和转移至关重要。在此，我们证明miR-22在内皮细胞中优先且高表达，而与匹配的非肿瘤肺组织相比，其在内皮中的水平在人类非小细胞肺癌（NSCLC）组织中显著下调。内皮miR-22的这种减少可能是由NSCLC细胞分泌的白细胞介素-1β诱导的，随后激活转录因子核因子-κB。内皮miR-22作为一种有效的血管生成抑制剂，通过直接靶向内皮细胞中的沉默调节蛋白1和成纤维细胞生长因子受体1，抑制内皮细胞的所有关键血管生成活性，从而抑制NSCLC生长，导致AKT/雷帕霉素哺乳动物靶标信号失活。这些发现为NSCLC血管生成的分子机制提供了见解，并表明内皮miR-22代表了未来NSCLC抗血管生成治疗的潜在靶点。
