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

Changhao Chen, Wang He, Jian Huang, Bo Wang, Hui Li, Qingqing Cai, Feng Su, Junming Bi, Hongwei Liu, Bin Zhang, Ning Jiang, Guangzheng Zhong, Yue Zhao, Wen Dong and Tianxin Lin ()
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Changhao Chen: Sun Yat-sen Memorial Hospital
Wang He: Sun Yat-sen Memorial Hospital
Jian Huang: Sun Yat-sen Memorial Hospital
Bo Wang: Sun Yat-sen Memorial Hospital
Hui Li: University of Virginia
Qingqing Cai: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China
Feng Su: Sun Yat-sen Memorial Hospital
Junming Bi: Sun Yat-sen Memorial Hospital
Hongwei Liu: Sun Yat-sen Memorial Hospital
Bin Zhang: Sun Yat-sen Memorial Hospital
Ning Jiang: Sun Yat-sen Memorial Hospital
Guangzheng Zhong: Sun Yat-sen Memorial Hospital
Yue Zhao: Sun Yat-sen University First Affiliated Hospital
Wen Dong: Sun Yat-sen Memorial Hospital
Tianxin Lin: Sun Yat-sen Memorial Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06152-x

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