Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1
Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1
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DOI：
10.1182/blood-2014-05-576116
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发表时间：
2014-12-11
期刊：
影响因子：
20.3
通讯作者：
Ohyashiki, Junko H.
中科院分区：
文献类型：
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作者：
Umezu, Tomohiro;Tadokoro, Hiroko;Ohyashiki, Junko H.
外泌体是内体衍生的小囊泡，含有广泛的功能蛋白质、mRNA和miRNA。来自癌细胞的外泌体miRNA有助于调节微环境。在多发性骨髓瘤（MM）中，恶性浆细胞的大量增殖导致缺氧。迄今为止，大多数癌细胞的体外缺氧研究使用急性缺氧暴露（3-24小时）。因此，我们试图通过使用在慢性缺氧下体外连续生长的MM细胞（耐缺氧MM [HR-MM]细胞）来阐明MM衍生的外泌体在缺氧骨髓中的作用。在常氧或急性缺氧条件下，HR-MM细胞比亲本细胞产生更多的外泌体，并且miR-135 b在HR-MM细胞的外泌体中显著上调。外泌体miR-135 b直接抑制内皮细胞中其靶因子抑制性缺氧诱导因子1（FIH-1）。最后，来自HR-MM细胞的外泌体miR-135 b通过HIF-FIH信号通路增强缺氧下的内皮管形成。这种体外HR骨髓瘤细胞模型将有助于研究缺氧条件下MM细胞-内皮细胞相互作用，这可能模拟体内骨髓微环境。虽然肿瘤血管生成受多种因素调节，但外泌体miR-135 b可能是控制MM血管生成的靶点。
Exosomes are small endosome-derived vesicles containing a wide range of functional proteins, mRNA, and miRNA. Exosomal miRNA from cancer cells helps modulate the microenvironment. In multiple myeloma (MM), the massive proliferation of malignant plasma cells causes hypoxia. To date, the majority of in vitro hypoxia studies of cancer cells have used acute hypoxic exposure (3-24 hours). Thus, we attempted to clarify the role of MM-derived exosomes in hypoxic bone marrow by using MM cells grown continuously in vitro under chronic hypoxia (hypoxia-resistant MM [HR-MM] cells). The HR-MM cells produced more exosomes than the parental cells under normoxia or acute hypoxia conditions, and miR-135b was significantly upregulated in exosomes from HR-MM cells. Exosomal miR-135b directly suppressed its target factor-inhibiting hypoxiainducible factor 1 (FIH-1) in endothelial cells. Finally, exosomal miR-135b from HR-MM cells enhanced endothelial tube formation under hypoxia via the HIF-FIH signaling pathway. This in vitro HR myeloma cell model will be useful for investigating MM cell-endothelial cell interactions under hypoxic conditions, which may mimic the in vivo bone marrow microenvironment. Although tumor angiogenesis is regulated by various factors, exosomal miR-135b may be a target for controlling MM angiogenesis.