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Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2020 Jan 02; Vol. 130 (1), pp. 404-421. - Publication Year :
- 2020
-
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.
- Subjects :
- Animals
Cell Line, Tumor
Exosomes genetics
Exosomes pathology
Female
Heterogeneous-Nuclear Ribonucleoprotein Group A-B genetics
Heterogeneous-Nuclear Ribonucleoprotein Group A-B metabolism
Homeodomain Proteins genetics
Homeodomain Proteins metabolism
Humans
Lymphatic Metastasis
Male
Mice
Mice, Inbred BALB C
Mice, Nude
RNA, Long Noncoding genetics
RNA, Neoplasm genetics
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins metabolism
Urinary Bladder Neoplasms genetics
Urinary Bladder Neoplasms pathology
Vascular Endothelial Growth Factor C genetics
Vascular Endothelial Growth Factor C metabolism
Exosomes metabolism
RNA, Long Noncoding metabolism
RNA, Neoplasm metabolism
Urinary Bladder Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 130
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 31593555
- Full Text :
- https://doi.org/10.1172/JCI130892