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

C Chen, W He, J Huang, B Wang, H Li, Q Cai… - Nature …, 2018 - nature.com
C Chen, W He, J Huang, B Wang, H Li, Q Cai, F Su, J Bi, H Liu, B Zhang, N Jiang, G Zhong…
Nature communications, 2018nature.com
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 …
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.
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