Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis
Wang He, Guangzheng Zhong, Ning Jiang, Bo Wang, Xinxiang Fan, Changhao Chen, Xu Chen, Jian Huang, Tianxin Lin
Wang He, Guangzheng Zhong, Ning Jiang, Bo Wang, Xinxiang Fan, Changhao Chen, Xu Chen, Jian Huang, Tianxin Lin
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Research Article Oncology

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

Abstract

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.

Authors

Wang He, Guangzheng Zhong, Ning Jiang, Bo Wang, Xinxiang Fan, Changhao Chen, Xu Chen, Jian Huang, Tianxin Lin

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Figure 3

BLACAT2 overexpression promotes lymphangiogenesis in vitro and in vivo.

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BLACAT2 overexpression promotes lymphangiogenesis in vitro and in vivo. ...
(A) Representative images of intratumoral and peritumoral microlymphatic vessels stained with anti-LYVE1 (left panel) and histogram of the quantification of microlymphatic vessel density (right panel) (n = 12). BLACAT2 expression levels were confirmed by ISH. Scale bars: 50 μm. (B and C) Representative images (left panels) and histogram quantification (right panels) of the Matrigel tube formation assay with HLECs. HLECs were cultured with conditioned medium derived from bladder cancer cells that were treated as indicated. Scale bars: 200 μm. All experiments in vitro were performed with at least 3 biological replicates. The error bars indicate the SD of the mean. Statistical significance was assessed using 2-tailed Student’s t test (A and B) and 1-way ANOVA followed by Dunnett’s tests for multiple comparisons (C). **P < 0.01.