Non-small cell lung cancer cell-derived exosomal miR-17-5p promotes osteoclast differentiation by targeting PTEN
Non-small cell lung cancer cell-derived exosomal miR-17-5p promotes osteoclast differentiation by targeting PTEN
复制标题
非小细胞肺癌细胞来源的外泌体 miR-17-5p 通过靶向 PTEN 促进破骨细胞分化。
DOI：
10.1016/j.yexcr.2021.112834
复制
发表时间：
2021-09-25
影响因子：
3.7
通讯作者：
Wang, Lin
中科院分区：
文献类型：
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作者：
Wang, Mengyan;Zhao, Mingna;Wang, Lin
骨吸收破骨细胞活性异常在骨质疏松症和癌症骨转移的发生发展中起关键作用。新靶点的发现将有助于肺癌骨转移新的治疗策略的发展。在这里，我们检测了肿瘤细胞来源的外切体中的microRNAs，以研究骨环境和肿瘤细胞之间的通讯。TCGA数据库分析显示，非小细胞肺癌组织中miR-17-5p的表达水平高于非小细胞肺癌组织。为探讨外切体在诱导破骨细胞生成中的作用，将破骨细胞前体与非小细胞肺癌细胞系分离的外切体以及核因子-kB配体受体激活剂和M-CSF共同孵育诱导破骨细胞生成。我们发现外体miR-17-5p在一个有骨转移的非小细胞肺癌细胞系中较原始细胞系上调。过表达miR-17-5p可促进RAW264.7细胞的破骨细胞分化。PTEN被认为是miR-17-5p的直接靶点，对破骨细胞的形成具有负性作用。重要的是，LY294002(一种PI3K/Akt通路的抑制剂)的治疗减弱了miR-17-5p介导的破骨细胞生成作用。综上所述，我们的研究结果表明miR-17-5p通过靶向PTEN，通过PI3K/Akt途径在肺癌中促进破骨细胞的形成。
Aberrant activity of bone resorbing osteoclasts plays a key role in the development of osteoporosis and cancer bone metastasis. The identification of novel and specific targets will be helpful for the development of new therapeutic strategies for bone metastasis in lung cancer. Herein, we examined microRNAs in tumor cell-derived exosomes to investigate the communication between the bone environment and tumor cells. TCGA database analysis showed that the level of miR-17-5p increased in non-small cell lung cancer tissues compared with non-tumor tissues. To investigate the function of exosomes in inducing osteoclastogenesis, osteoclast precursors were incubated with exosomes isolated from non-small cell lung cancer cell line, as well as receptor activator of NF-KB ligand and M-CSF to induce osteoclastogenesis. We found that exosomal miR-17-5p is upregulated in a non-small cell lung cancer cell line with bone metastasis compared with the original cell line. Overexpression of miR-17-5p enhanced the osteoclastogenesis of RAW264.7 cells. PTEN was identified as a direct target of miR-17-5p and showed negative effects on osteoclastogenesis. Importantly, treatment of LY294002 (an inhibitor of the PI3K/Akt pathway) attenuated miR-17-5p-mediated osteoclastogenesis effects. Taken together, our findings demonstrated that miR-17-5p promotes osteoclastogenesis through the PI3K/Akt pathway via targeting PTEN in lung cancer.