circEHBP1 promotes lymphangiogenesis and lymphatic metastasis of bladder cancer via miR-130a-3p/TGFβR1/VEGF-D signaling.
circEHBP1 promotes lymphangiogenesis and lymphatic metastasis of bladder cancer via miR-130a-3p/TGFβR1/VEGF-D signaling.
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circEHBP1通过miR-130a-3p/TGF beta R1/VEGF-D信号促进膀胱癌的淋巴管生成和淋巴转移
DOI：
10.1016/j.ymthe.2021.01.031
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发表时间：
2021-05-05
期刊：
影响因子：
--
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Zhu J;Luo Y;Zhao Y;Kong Y;Zheng H;Li Y;Gao B;Ai L;Huang H;Huang J;Li Z;Chen C
淋巴结转移是膀胱癌复发和死亡的主要原因。越来越多的证据表明，淋巴管生成是引发淋巴转移的必要条件。然而，对具体机制知之甚少。在本研究中，我们揭示了参与膀胱癌淋巴转移的途径，其中环状RNA（circRNA）以血管内皮生长因子C（VEGF-C）非依赖性方式促进淋巴管生成。新的circRNA circEHBP 1在膀胱癌中显著上调，并与膀胱癌患者的淋巴结转移和不良预后呈正相关。circEHBP 1通过与miR-130 a-3 p物理结合并拮抗miR-130 a-3 p对TGF-β受体1（TGF-β R 1）3′ UTR区的抑制作用，上调TGF-β R 1的表达。随后，circEHBP 1介导的TGFβR1过表达激活TGF-β/SMAD 3信号通路，从而促进VEGF-D的分泌，并驱动膀胱癌中的淋巴管生成和淋巴转移。重要的是，施用VEGF-D中和抗体显著阻断了体内circEHBP 1诱导的淋巴管生成和淋巴转移。我们的研究结果表明，circEHBP 1/miR-130 a-3 p/TGFβR1/VEGF-D轴在膀胱癌淋巴管生成和淋巴转移中的作用不依赖于VEGF-C，这可能导致circEHBP 1成为膀胱癌淋巴转移的潜在生物标志物和有希望的治疗靶点。淋巴结转移是膀胱癌复发和死亡的主要原因。Zhu及其同事发现，circEHBP 1/miR-130 a-3 p/TGFβR1/VEGF-D轴与膀胱癌的淋巴转移有关，不依赖于VEGF-C。这将circEHBP 1确定为膀胱癌淋巴转移的新生物标志物和有前途的治疗靶点。
Lymphatic metastasis constitutes a leading cause of recurrence and mortality in bladder cancer. Accumulating evidence indicates that lymphangiogenesis is indispensable to trigger lymphatic metastasis. However, the specific mechanism is poorly understood. In the present study, we revealed a pathway involved in lymphatic metastasis of bladder cancer, in which a circular RNA (circRNA) facilitated lymphangiogenesis in a vascular endothelial growth factor C (VEGF-C)-independent manner. Novel circRNA circEHBP1 was markedly upregulated in bladder cancer and correlated positively with lymphatic metastasis and poor prognosis of patients with bladder cancer. circEHBP1 upregulated transforming growth factor beta receptor 1 (TGFBR1) expression through physically binding to miR-130a-3p and antagonizing the suppression effect of miR-130a-3p on the 3′ UTR region of TGFBR1. Subsequently, circEHBP1-mediated TGFβR1 overexpression activated the TGF-β/SMAD3 signaling pathway, thereby promoting the secretion of VEGF-D and driving lymphangiogenesis and lymphatic metastasis in bladder cancer. Importantly, administration of VEGF-D neutralizing antibodies remarkably blocked circEHBP1-induced lymphangiogenesis and lymphatic metastasis in vivo. Our findings highlighted that the circEHBP1/miR-130a-3p/TGFβR1/VEGF-D axis contributes to lymphangiogenesis and lymphatic metastasis of bladder cancer independent of VEGF-C, which might lead to the development of circEHBP1 as a potential biomarker and promising therapeutic target for lymphatic metastasis in bladder cancer. Lymphatic metastasis constitutes a leading cause of recurrence and mortality in bladder cancer. Zhu and colleagues discovered that the circEHBP1/miR-130a-3p/TGFβR1/VEGF-D axis is implicated in lymphatic metastasis of bladder cancer, independent of VEGF-C. This identified circEHBP1 as a novel biomarker and promising therapeutic target for lymphatic metastasis of bladder cancer.
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