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

作者：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, Tianxin Lin · 发表于：Nature Communications · 年份：2018 · DOI：10.1038/s41467-018-06152-x · 被引用次数：525 · 研究领域：Cancer-related molecular mechanisms research、Immune cells in cancer、Epigenetics and DNA Methylation

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.