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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 1 Pg. 404-421 (01 02 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 31593555 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heterogeneous-Nuclear Ribonucleoprotein Group A-B
• Homeodomain Proteins
• RNA, Long Noncoding
• RNA, Neoplasm
• Tumor Suppressor Proteins
• VEGFC protein, human
• Vascular Endothelial Growth Factor C
• hnRNP A2
• prospero-related homeobox 1 protein

Topics

• Animals
• Cell Line, Tumor
• Exosomes (genetics, metabolism, pathology)
• Female
• Heterogeneous-Nuclear Ribonucleoprotein Group A-B (genetics, metabolism)
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Lymphatic Metastasis
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• RNA, Long Noncoding (genetics, metabolism)
• RNA, Neoplasm (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)
• Vascular Endothelial Growth Factor C (genetics, metabolism)