The prognosis for bladder cancer patients with lymph node (LN) metastasis is dismal and only minimally improved by current treatment modalities. Elucidation of the molecular mechanisms that underlie LN metastasis may provide clinical therapeutic strategies for LN-metastatic bladder cancer. Here, we report that a long noncoding RNA LINC00958, which we have termed bladder cancer–associated transcript 2 (BLACAT2), was markedly upregulated in LN-metastatic bladder cancer and correlated with LN metastasis. Overexpression of BLACAT2 promoted bladder cancer–associated lymphangiogenesis and lymphatic metastasis in both cultured bladder cancer cell lines and mouse models. Furthermore, we demonstrate that BLACAT2 epigenetically upregulated VEGF-C expression by directly associating with WDR5, a core subunit of human H3K4 methyltransferase complexes. Importantly, administration of an anti–VEGF-C antibody inhibited LN metastasis in BLACAT2-overexpressing bladder cancer. Taken together, these findings uncover a molecular mechanism in the lymphatic metastasis of bladder cancer and indicate that BLACAT2 may represent a target for clinical intervention in LN-metastatic bladder cancer.

中文翻译：

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长链非编码 RNA BLACAT2 促进膀胱癌相关淋巴管生成和淋巴转移

伴有淋巴结 (LN) 转移的膀胱癌患者的预后很差，目前的治疗方式只能轻微改善。阐明 LN 转移的分子机制可能为 LN 转移性膀胱癌提供临床治疗策略。在这里，我们报告了一种长链非编码 RNA LINC00958，我们称之为膀胱癌相关转录物 2 (BLACAT2)，在 LN 转移性膀胱癌中显着上调，并与 LN 转移相关。在培养的膀胱癌细胞系和小鼠模型中，BLACAT2 的过表达促进了膀胱癌相关淋巴管生成和淋巴转移。此外，我们证明 BLACAT2 通过直接与人类 H3K4 甲基转移酶复合物的核心亚基 WDR5 相关联来表观遗传上调 VEGF-C 表达。重要的是，施用抗 VEGF-C 抗体可抑制 BLACAT2 过表达膀胱癌的 LN 转移。总之，这些发现揭示了膀胱癌淋巴转移的分子机制，并表明 BLACAT2 可能代表 LN 转移性膀胱癌临床干预的靶点。