Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer
Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer
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外泌体长链非编码RNA LNMAT2促进膀胱癌淋巴转移
DOI：
10.1172/jci130892
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发表时间：
2020-01-01
影响因子：
15.9
通讯作者：
Lin, Tianxin
中科院分区：
文献类型：
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作者：
Chen, Changhao;Luo, Yuming;Lin, Tianxin
膀胱癌（BCa）合并临床淋巴结（LN）转移的患者预后极差。VEGF-C已被证明在BCa的LN转移中起重要作用。然而，大约20%伴有淋巴结转移的BCa表现出低VEGF-C表达，这表明BCa的淋巴结转移机制不依赖于VEGF-C。在这里，我们证明了BCa细胞分泌的外泌体介导的淋巴管生成以不依赖vegf - c的方式促进了BCa的LN转移。我们发现了一种外泌体长链非编码RNA (lncRNA)，称为淋巴结转移相关转录物2 (LNMAT2)，它在体外刺激人淋巴内皮细胞（HLEC）管的形成和迁移，并在体内增强肿瘤淋巴管生成和淋巴结转移。机制上，LNMAT2通过直接与异质核核糖核蛋白A2B1 （hnRNPA2B1）相互作用被装载到BCa细胞分泌的外泌体上。随后，外泌体LNMAT2被HLECs内化，并通过募集hnRNPA2B1和增加PROX1启动子中的H3K4三甲基化水平，表观遗传上调PROX1的表达，最终导致淋巴管生成和淋巴转移。因此，我们的研究结果强调了vegf - c介导的外泌体lncrna介导的LN转移的不依赖机制，并确定LNMAT2是BCa LN转移的治疗靶点。
Patients with bladder cancer (BCa) with clinical lymph node (LN) metastasis have an extremely poor prognosis. VEGF-C has been demonstrated to play vital roles in LN metastasis in BCa. However, approximately 20% of BCa with LN metastasis exhibits low VEGF-C expression, suggesting a VEGF-C-independent mechanism for LN metastasis of BCa. Herein, we demonstrate that BCa cell-secreted exosome-mediated lymphangiogenesis promoted LN metastasis in BCa in a VEGF-C-independent manner. We identified an exosomal long noncoding RNA (lncRNA), termed lymph node metastasis-associated transcript 2 (LNMAT2), that stimulated human lymphatic endothelial cell (HLEC) tube formation and migration in vitro and enhanced tumor lymphangiogenesis and LN metastasis in vivo. Mechanistically, LNMAT2 was loaded to BCa cell-secreted exosomes by directly interacting with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1). Subsequently, exosomal LNMAT2 was internalized by HLECs and epigenetically upregulated prospero homeobox 1 (PROX1) expression by recruitment of hnRNPA2B1 and increasing the H3K4 trimethylation level in the PROX1 promoter, ultimately resulting in lymphangiogenesis and lymphatic metastasis. Therefore, our findings highlight a VEGF-C-independent mechanism of exosomal lncRNA-mediated LN metastasis and identify LNMAT2 as a therapeutic target for LN metastasis in BCa.