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

J Clin Invest. 2018 Feb 1;128(2):861-875. doi: 10.1172/JCI96218. Epub 2018 Jan 22.

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.

Keywords: Cancer; Oncogenes; Oncology; Urology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lymphangiogenesis
  • Lymphatic Metastasis*
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms / metabolism
  • Prognosis
  • RNA, Long Noncoding / genetics*
  • Snail Family Transcription Factors / metabolism
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / metabolism
  • Vascular Endothelial Growth Factor C / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • RNA, Long Noncoding
  • SNAI2 protein, human
  • Snail Family Transcription Factors
  • Vascular Endothelial Growth Factor C
  • WDR5 protein, human
  • Histone-Lysine N-Methyltransferase
  • MMP9 protein, human
  • Matrix Metalloproteinase 9