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.

中文翻译：

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外泌体长非编码RNA LNMAT2促进膀胱癌的淋巴转移

患有临床淋巴结转移的膀胱癌患者的预后极差。已经证明VEGF-C在BCa的LN转移中起重要作用。但是，约有20％的伴有LN转移的BCa表现出低的VEGF-C表达，这表明VEGF-C依赖性的BCa的LN转移机制。本文中，我们证明了BCa细胞分泌的外来体介导的淋巴管生成以VEGF-C独立的方式促进了BCa中的LN转移。我们确定了一种外泌体长非编码RNA（lncRNA），称为淋巴结转移相关转录本2（LNMAT2），其在体外刺激人淋巴管内皮细胞（HLEC）的管形成和迁移，并增强了体内肿瘤淋巴管生成和LN转移。机械上，LNMAT2通过与异质核核糖核蛋白A2B1（hnRNPA2B1）直接相互作用，将其加载到BCa细胞分泌的外来体上。随后，HLECs将外泌体LNMAT2内化，并通过招募hnRNPA2B1并增加PROX1启动子中的H3K4三甲基化水平，表观遗传上调Prospero同源盒1（PROX1）的表达，最终导致淋巴管生成和淋巴结转移。因此，我们的发现突出了外泌体lncRNA介导的LN转移的VEGF-C独立机制，并确定LNMAT2是BCa中LN转移的治疗靶标。