Breast cancer cell-derived exosomal miR-20a-5p promotes the proliferation and differentiation of osteoclasts by targeting SRCIN1
Breast cancer cell-derived exosomal miR-20a-5p promotes the proliferation and differentiation of osteoclasts by targeting SRCIN1
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DOI：
10.1002/cam4.2454
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发表时间：
2019-08-06
期刊：
影响因子：
4
通讯作者：
Cui, Hujun
中科院分区：
文献类型：
--
作者：
Guo, Ling;Zhu, Ye;Cui, Hujun
乳腺癌的骨转移使患者遭受疼痛、骨折、脊髓压迫和高钙血症，几乎无法治愈。虽然乳腺癌骨转移的机制已被深入研究，但新的特异性靶点将有助于乳腺癌新的治疗策略的发展。因此，我们将重点放在肿瘤细胞来源的exosomes的microRNA上，以研究骨微环境与肿瘤细胞之间的通讯。通过qRT-PCR评估原代鼠骨髓巨噬细胞（BMSCs）、MCF-10A、MCF-7和MDA-MB-231细胞系以及细胞来源的外泌体中miR-20 a-5 p的表达。使用Transwell测定来评估miR-20 a-5 p对肿瘤细胞迁移和侵袭的影响。Western Blot检测外泌体标志物CD 63和TSG 101的表达。流式细胞仪分析细胞周期分布。3-UTR荧光素酶报告基因测定用于验证miR-20 a-5 p和SRCIN 1之间的推定结合。miR-20 a-5 p在乳腺癌组织和MDA-MB-231细胞的exosomes中高表达。MiR-20 a-5 p促进MDA-MB-231细胞的迁移和侵袭以及破骨细胞的增殖和分化。MDA-MB-231细胞来源的exosomes将miR-20 a-5 p转移到Bctin，并通过靶向SRCIN 1促进破骨细胞生成。本研究为从乳腺癌细胞来源的exosomes中转移的miR-20 a-5 p通过靶向SRCIN 1促进破骨细胞的增殖和分化提供了证据，为开发exosomes或miR-20 a-5 p靶向乳腺癌进展的治疗干预提供了科学依据。
Bone metastasis of breast cancer makes patients suffer from pain, fractures, spinal cord compression, and hypercalcemia, and is almost incurable. Although the mechanisms of bone metastasis in breast cancers have been studied intensively, novel specific target will be helpful to the development of new therapeutic strategy of breast cancer. Herein, we focused on the microRNA of tumor cell-derived exosomes to investigate the communication between the bone microenvironment and tumor cells. The expression of miR-20a-5p in the primary murine bone marrow macrophages (BMMs), MCF-10A, MCF-7, and MDA-MB-231 cell lines, as well as the cell-derived exosomes were assessed by qRT-PCR. Transwell assays were used to evaluate the effects of miR-20a-5p on tumor cell migration and invasion. The expression of exosomes marker including CD63and TSG101 was detected by Western Blot. Cell cycle distribution of BMMs was analyzed by flow cytometry. 3-UTR luciferase reporter assays were used to validate the putative binding between miR-20a-5p and SRCIN1. MiR-20a-5p was highly expressed in breast tumor tissues and the exosomes of MDA-MB-231 cells. MiR-20a-5p promoted migration and invasion in MDA-MB-231 cells, and the proliferation and differentiation of osteoclasts. MDA-MB-231 cell-derived exosomes transferred miR-20a-5p to BMMs and facilitated the osteoclastogenesis via targeting SRCIN1. The present work provides evidence that miR-20a-5p transferred from breast cancer cell-derived exosomes promotes the proliferation and differentiation of osteoclasts by targeting SRCIN1, providing scientific foundations for the development of exosome or miR-20a-5p targeted therapeutic intervention in breast cancer progression.