Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis
Wang He, … , Jian Huang, Tianxin Lin
Wang He, … , Jian Huang, Tianxin Lin
Published January 22, 2018
Citation Information: J Clin Invest. 2018;128(2):861-875. https://doi.org/10.1172/JCI96218.
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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 5

BLACAT2 regulates VEGF-C, SNAI2, and MMP9 expression.

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BLACAT2 regulates VEGF-C, SNAI2, and MMP9 expression. (A) Heatmap repres...
(A) Heatmap representing unsupervised hierarchical clustering of genes regulated by BLACAT2 quantified by NGS. Rows represent probe sets, and columns represent samples treated as indicated. Green, downregulation; red, upregulation. SNAI2, VEGF-C, and MMP9 are indicated by black arrows. (B and C) Bladder cancer cells were transduced with a lentivirus-based BLACAT2-overexpressing vector (B), BLACAT2 shRNAs (C), or control vectors as indicated. Transduced cells were harvested 96 hours later, and VEGF-C, SNAI2, and MMP9 mRNA expression levels were quantified by RT-qPCR. Statistical significance was assessed using 2-tailed Student’s t test (B) and 1-way ANOVA followed by Dunnett’s tests for multiple comparisons (C) (n = 3, **P < 0.01). (D) Representative image of the Western blotting analysis of VEGF-C, SNAI2, and MMP9 protein levels after BLACAT2 overexpression or depletion in UM-UC-3. (E) Representative images (left panels) and correlation analysis (right panel) of IHC staining showing that BLACAT2 expression positively correlates with VEGF-C, SNAI2, and MMP9 expression levels in the bladder cancer tissues. n = 140. Scale bars: 50 μm.