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
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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

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Figure 10

Exosomal LNMAT2 is associated with BCa lymphatic metastasis.

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Exosomal LNMAT2 is associated with BCa lymphatic metastasis. Representat...
Representative images (A) and percentages (B) of BCa tissues (n = 206) with high and low LYVE-1 levels in the intratumoral and peritumoral lymphatic vessels in patients with different expression of LNMAT2. Scale bars: 50 μm. Statistical significance was assessed by χ2 test. (C) qRT-PCR analysis of LNMAT2 expression in a 206-patient cohort of urinary-EXO from BCa patients with or without LN metastasis. GAPDH was used as an internal control. Groups were compared using the nonparametric Mann-Whitney U test. Kaplan-Meier curves of OS (D) and DFS (E) of patients with BCa according to the relative urinary exosomal LNMAT2 expression. The median expression was used as the cut-off value (n = 206). ROC curve analyses for evaluating the diagnostic potential of urinary exosomal LNMAT2 for BCa (F) and LN metastasis (G). (H) Proposed model of BCa cell–secreted exosomal LNMAT2-mediated PROX1 activation in HLECs for promoting lymphangiogenesis and LN metastasis. *P < 0.05; **P < 0.01.