J Clin Invest//外泌体来源的长链非编码RNA LNMAT2促进膀胱癌中的淋巴转移

Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder Cancer

Changhao Chen^1,2#, Yuming Luo^2,3#, Wang He^1,2#, Yue Zhao^4#, Yao Kong⁵

, Hongwei Liu^1,2,Guangzheng Zhong^1,2, Yuting Li⁶, Jun Li⁷, Jian Huang^1,2*, 

Rufu Chen^8*, Tianxin Lin^1,2*

J Clin Invest(IF=12.282)pub date：2019 Oct 8

DOI:10.1172/JCI130892

Abstract:

Patients with bladder cancer (BCa) with clinical lymph node (LN) metastasis have extremely poor prognosis. VEGF-C has been demonstrated to play vital roles in LN metastasis in BCa. However, approximately 20% of BCa with LN metastasis exhibits low VEGF-C expression, suggesting a VEGF-C-independent mechanism for LN metastasis of BCa. Herein, we demonstrated that BCa cell-secreted exosomes-mediated lymphangiogenesis promoted LN metastasis in BCa, which was in a VEGF-C-independent manner. We identified an exosomal long noncoding RNA (lncRNA), termed lymph node metastasis-associated transcript 2 (LNMAT2), stimulated HLEC tube formation and migration in vitro and enhanced tumor lymphangiogenesis and LN metastasis in vivo. Mechanistically, LNMAT2 was loaded to BCa cell-secreted exosomes by directly interacting with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1). Subsequently, exosomal LNMAT2 was internalized by HLECs and epigenetically upregulated prospero homeobox 1 (PROX1) expression by recruitment of hnRNPA2B1 and increasing the H3K4 trimethylation level in the PROX1 promoter, ultimately resulting in lymphangiogenesis and lymphatic metastasis. Therefore, our findings highlight a VEGF-C-independent mechanism of exosomal lncRNA-mediated LN metastasis and identify LNMAT2 as a therapeutic target for LN metastasis in BCa.

推荐理由：

1、外泌体来源的长链非编码RNA  LNMAT2刺激了HLEC管的形成和迁移，并在体外增强了肿瘤淋巴管生成和淋巴结转移,LNMAT2通过与hnRNPA2B1直接相互作用而被加载到膀胱癌细胞分泌的外泌体上。随后，外泌体来源的LNMAT2被HLEC内化，并通过募集hnRNPA2B1并增加PROX1启动子中的H3K4三甲基化水平，表观遗传上调了PROX1的表达，最终导致淋巴管生成和淋巴转移.

2、外泌体和lncrna都是本课题组的研究方向，这篇文章将研究了外泌体来源的lncrna，对我们有较好的启发效果。