High‐grade bladder cancer cells secrete extracellular vesicles containing miRNA‐146a‐5p and promotes angiogenesis
High‐grade bladder cancer cells secrete extracellular vesicles containing miRNA‐146a‐5p and promotes angiogenesis
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DOI：
10.1002/jex2.47
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发表时间：
2022-08
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影响因子：
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通讯作者：
Marta Prieto-Vila;W. Usuba;Y. Yoshioka;F. Takeshita;M. Yoshiike;Hideo Sasaki;Yusuke Yamamoto;E. Kikuchi;T. Ochiya
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作者：
Marta Prieto-Vila;W. Usuba;Y. Yoshioka;F. Takeshita;M. Yoshiike;Hideo Sasaki;Yusuke Yamamoto;E. Kikuchi;T. Ochiya
复发是膀胱癌（BCa）的主要问题之一。新技术，如检测尿液中细胞外囊泡（ev）携带的microrna，已被提出作为检测BCa复发的生物标志物。虽然已经报道了微小rna在癌症患者体液中的作用，但也知道它们在癌症进展中起着至关重要的作用。我们之前提出miR - 146a - 5p作为BCa的预后标志物，因为其尿表达与分级和肿瘤深度相关。然而，miR - 146a - 5p的具体机制尚不清楚。在这里，我们展示了高级别BCa细胞分泌的miR - 146a - 5p的促血管生成作用。高级别BCa患者尿miR - 146a - 5p水平高于低级别BCa患者。同样，miR - 146a -过表达BCa细胞在小鼠体内产生的肿瘤生长迅速，血管生成水平高。BCa来源的EV处理通过抑制去甲基化酶TET2和随后增加其下游靶标c - Myc来促进内皮细胞的增殖。这些发现表明，miR - 146a - 5p的分泌通过促进血管生成来促进癌症的进展。因此，ev中的mirna不仅可能成为一种诊断工具，而且可能成为治疗的靶分子。
Abstract Recurrence is one of the major issues in bladder cancer (BCa). Novel technologies, such as the detection of microRNAs carried by extracellular vesicles (EVs) in urine, have been proposed as biomarkers for detecting recurrence in BCa. Although the usefulness of microRNAs in body fluids from cancer patients has been reported, it is also known that they play essential roles in cancer progression. We previously proposed miR‐146a‐5p as a prognostic marker in BCa, since its urinary expression was associated with grade and tumour depth. However, the specific mechanisms of miR‐146a‐5p remain unclear. Here, we show the proangiogenic effects of miR‐146a‐5p secreted by high‐grade BCa cells. The urinary miR‐146a‐5p level was higher in patients with high‐grade BCa than in those with low‐grade BCa. Similarly, tumours generated by miR‐146a‐overexpressing BCa cells in mice grew rapidly with high levels of angiogenesis. BCa‐derived EV treatment promoted the proliferation of endothelial cells via the inhibition of the demethylase TET2 and the subsequent increase in its downstream target c‐Myc. These findings demonstrate that secreted miR‐146a‐5p contributes to cancer progression by promoting angiogenesis. Therefore, miRNAs in EVs may become not only a diagnostic tool but also a target molecule for therapy.