Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis
Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis
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长非编码RNA BLACAT2促进膀胱癌相关淋巴管生成和淋巴转移
DOI：
10.1172/jci96218
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发表时间：
2018-02-01
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：
He, Wang;Zhong, Guangzheng;Lin, Tianxin
伴有淋巴结转移的膀胱癌患者预后不佳，目前的治疗方式仅能轻微改善预后。阐明LN转移的分子机制可能为LN转移性膀胱癌的临床治疗提供策略。在这里，我们报道了一种长链非编码RNA LINC00958，我们将其命名为膀胱癌相关转录本2 (BLACAT2)，在LN转移性膀胱癌中显著上调，并与LN转移相关。在培养的膀胱癌细胞系和小鼠模型中，过表达BLACAT2促进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WDR5（人类H3K4甲基转移酶复合物的核心亚基）相关，从表观遗传上上调VEGF-C的表达。重要的是，抗vegf - c抗体可抑制blacat2过表达膀胱癌的LN转移。综上所述，这些发现揭示了膀胱癌淋巴转移的分子机制，并表明BLACAT2可能是ln转移性膀胱癌临床干预的靶点。
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.