LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment

Nat Commun. 2018 Sep 20;9(1):3826. doi: 10.1038/s41467-018-06152-x.

Abstract

Tumor-associated macrophages (TAMs) are the most abundant inflammatory infiltrates in the tumor microenvironment and contribute to lymph node (LN) metastasis. However, the precise mechanisms of TAMs-induced LN metastasis remain largely unknown. Herein, we identify a long noncoding RNA, termed Lymph Node Metastasis Associated Transcript 1 (LNMAT1), which is upregulated in LN-positive bladder cancer and associated with LN metastasis and prognosis. Through gain and loss of function approaches, we find that LNMAT1 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. Mechanistically, LNMAT1 epigenetically activates CCL2 expression by recruiting hnRNPL to CCL2 promoter, which leads to increased H3K4 tri-methylation that ensures hnRNPL binding and enhances transcription. Furthermore, LNMAT1-induced upregulation of CCL2 recruits macrophages into the tumor, which promotes lymphatic metastasis via VEGF-C excretion. These findings provide a plausible mechanism for LNMAT1-modulated tumor microenvironment in lymphatic metastasis and suggest that LNMAT1 may represent a potential therapeutic target for clinical intervention in LN-metastatic bladder cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism*
  • DNA, Neoplasm / metabolism
  • Gene Expression Regulation, Neoplastic
  • Histones / metabolism
  • Humans
  • Lymphangiogenesis
  • Lymphatic Metastasis / genetics*
  • Lymphatic Metastasis / pathology
  • Lysine / metabolism
  • Macrophages / metabolism*
  • Methylation
  • Mice
  • Neoplasm Invasiveness
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Neoplasm / metabolism
  • Ribonucleoproteins / metabolism
  • Up-Regulation / genetics
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology*

Substances

  • CCL2 protein, human
  • Chemokine CCL2
  • DNA, Neoplasm
  • HNRNPL protein, human
  • Histones
  • RNA, Long Noncoding
  • RNA, Neoplasm
  • Ribonucleoproteins
  • Lysine