Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer
Changhao Chen, Yuming Luo, Wang He, Yue Zhao, Yao Kong, Hongwei Liu, Guangzheng Zhong, Yuting Li, Jun Li, Jian Huang, Rufu Chen, Tianxin Lin
Changhao Chen, Yuming Luo, Wang He, Yue Zhao, Yao Kong, Hongwei Liu, Guangzheng Zhong, Yuting Li, Jun Li, Jian Huang, Rufu Chen, Tianxin Lin
View: Text | PDF
Research Article Oncology

Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer

Abstract

Patients with bladder cancer (BCa) with clinical lymph node (LN) metastasis have an 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 demonstrate that BCa cell–secreted exosome-mediated lymphangiogenesis promoted LN metastasis in BCa in a VEGF-C–independent manner. We identified an exosomal long noncoding RNA (lncRNA), termed lymph node metastasis-associated transcript 2 (LNMAT2), that stimulated human lymphatic endothelial cell (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.

Authors

Changhao Chen, Yuming Luo, Wang He, Yue Zhao, Yao Kong, Hongwei Liu, Guangzheng Zhong, Yuting Li, Jun Li, Jian Huang, Rufu Chen, Tianxin Lin

×

Figure 1

LNMAT2 overexpression is associated with BCa lymphatic metastasis.

Options: View larger image (or click on image) Download as PowerPoint
LNMAT2 overexpression is associated with BCa lymphatic metastasis. (A) ...
(A) qRT-PCR analysis of LNMAT2 expression in a cohort of 266 BCa patients according to LN status. Groups were compared using the nonparametric Mann-Whitney U test. GAPDH was used as an internal control. The OS (B) and DFS (C) of patients with BCa with lower vs. higher LNMAT2 expression were estimated using Kaplan-Meier curves. The median expression was used as the cut-off value. Representative ISH images (D) and percentages (E) of LNMAT2 expression (blue) in paraffin-embedded NAT and BCa tissue with or without LN metastasis (n = 266). Scale bars: 50 μm. Statistical significance was assessed by χ2 test. Representative images (F) and correlation analysis (G and H) of ISH and IHC staining showing positive correlation between LNMAT2 expression and lymphatic vessel density indicated by anti–LYVE-1 staining, and that LNMAT2 expression was not correlated with VEGF-C levels in the BCa tissues (n = 266). Scale bars: 50 μm. *P < 0.05; **P < 0.01.