Hypoxic bone marrow mesenchymal cell-extracellular vesicles containing miR-328-3p promote lung cancer progression via the NF2-mediated Hippo axis.
Hypoxic bone marrow mesenchymal cell-extracellular vesicles containing miR-328-3p promote lung cancer progression via the NF2-mediated Hippo axis.
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含miR-328-3p的缺氧骨髓间充质细胞胞外囊泡通过NF2介导的Hippo轴促进肺癌进展
DOI：
10.1111/jcmm.15865
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发表时间：
2021-01
影响因子：
5.3
通讯作者：
Yu T
中科院分区：
文献类型：
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作者：
Liu X;Jiang F;Wang Z;Tang L;Zou B;Xu P;Yu T
肺癌是全球范围内最具侵袭性的肿瘤。据报道，细胞外囊泡（EV）递送的microRNAs （miRs）在癌症发展中起着关键作用。目前的研究旨在探讨含miR - 328 - 3p的缺氧骨髓间充质细胞（BMSC）衍生的ev在肺癌中的作用。RT - qPCR检测miR‐328‐3p在一组肺癌组织中的表达。用慢病毒介导的miR - 328 - 3p敲低感染骨髓间充质干细胞，然后在常氧或缺氧条件下培养，随后分离ev。在肺癌细胞中进行异位表达和缺失实验后，采用CCK‐8法、流式细胞术和Transwell法分析miR‐328‐3p的生物学功能。裸鼠进行异种移植，以测试缺氧BMSC来源的ev传递miR - 328 - 3p对肺癌肿瘤生长的体内影响。最后，在肺癌患者血清中检测循环miR - 328 - 3p的表达。miR‐328‐3p在缺氧骨髓间充质干细胞衍生的ev中高度表达。miR - 328 - 3p通过缺氧BMSC来源的ev传递到肺癌细胞，从而促进肺癌细胞的增殖、侵袭、迁移和上皮-间质转化。miR‐328‐3p靶向NF2灭活Hippo通路。此外，EV -递送的miR - 328 - 3p可促进体内肿瘤生长。此外，循环miR‐328‐3p在肺癌患者的血清中具有生物活性。综上所述，我们的研究结果表明，缺氧BMSC衍生的ev可以将miR‐328‐3p传递给肺癌细胞，miR‐328‐3p靶向NF2基因，从而抑制Hippo通路，最终促进肺癌的发生和进展。
Lung cancer is the most aggressive tumour afflicting patients on a global scale. Extracellular vesicle (EV)‐delivered microRNAs (miRs) have been reported to play critical roles in cancer development. The current study aimed to investigate the role of hypoxic bone marrow mesenchymal cell (BMSC)‐derived EVs containing miR‐328‐3p in lung cancer. miR‐328‐3p expression was determined in a set of lung cancer tissues by RT‐qPCR. BMSCs were infected with lentivirus‐mediated miR‐328‐3p knock‐down and then cultured in normoxic or hypoxic conditions, followed by isolation of EVs. Following ectopic expression and depletion experiments in lung cancer cells, the biological functions of miR‐328‐3p were analysed using CCK‐8 assay, flow cytometry and Transwell assay. Xenograft in nude mice was performed to test the in vivo effects of miR‐328‐3p delivered by hypoxic BMSC‐derived EVs on tumour growth of lung cancer. Finally, the expression of circulating miR‐328‐3p was detected in the serum of lung cancer patients. miR‐328‐3p was highly expressed in EVs derived from hypoxic BMSCs. miR‐328‐3p was delivered to lung cancer cells by hypoxic BMSC‐derived EVs, thereby promoting lung cancer cell proliferation, invasion, migration and epithelial‐mesenchymal transition. miR‐328‐3p targeted NF2 to inactivate the Hippo pathway. Moreover, EV‐delivered miR‐328‐3p increased tumour growth in vivo. Additionally, circulating miR‐328‐3p was bioactive in the serum of lung cancer patients. Taken together, our results demonstrated that hypoxic BMSC‐derived EVs could deliver miR‐328‐3p to lung cancer cells and that miR‐328‐3p targets the NF2 gene, thereby inhibiting the Hippo pathway to ultimately promote the occurrence and progression of lung cancer.
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