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 February 1, 2018
Citation Information: J Clin Invest. 2018;128(2):861-875. https://doi.org/10.1172/JCI96218.
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Categories: 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 1

BLACAT2 overexpression correlates with LN metastasis and poor prognosis of bladder cancer.

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BLACAT2 overexpression correlates with LN metastasis and poor prognosis ...
(A) Unsupervised hierarchical clustering of lncRNAs that are differentially expressed in MIBC and paired normal adjacent tissues (NAT) (fold changes > 2.0, P < 0.05). The red color scale (log2 fold change) represents a higher expression level, and the green color scale represents a lower expression level. (B) RT-qPCR analysis of BLACAT2 expression in a 140-case cohort of freshly collected human bladder cancer samples with or without LN metastasis. The nonparametric Mann-Whitney U test was used to compare the expression levels of the 2 groups. (C) Negative correlation between BLACAT2 expression and survival in the patient cohort referred to in B. The Kaplan-Meier method was used to estimate survival for the 2 groups. Median BLACAT2 expression was used as a cutoff value. (D and E) Representative images (left panels) and percentages (right panels) of tissue specimens with high and low levels of LYVE1-positive intratumoral (D) and peritumoral (E) microlymphatic vessels in 140 cases of bladder cancer with low or high expression of BLACAT2. BLACAT2 expression levels were quantified by ISH, and microlymphatic vessel density was quantified by immunohistochemistry using the anti-LYVE1 antibody. Two representative cases are shown. Statistical significance was assessed by χ2 test. Scale bars: 50 μm (D and E). **P < 0.01.