Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer.
Animals
Cell Line, Tumor
Exosomes
/ genetics
Female
Heterogeneous-Nuclear Ribonucleoprotein Group A-B
/ genetics
Homeodomain Proteins
/ genetics
Humans
Lymphatic Metastasis
Male
Mice
Mice, Inbred BALB C
Mice, Nude
RNA, Long Noncoding
/ genetics
RNA, Neoplasm
/ genetics
Tumor Suppressor Proteins
/ genetics
Urinary Bladder Neoplasms
/ genetics
Vascular Endothelial Growth Factor C
/ genetics
Lymph
Noncoding RNAs
Oncology
Urology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
02 01 2020
02 01 2020
Historique:
received:
06
06
2019
accepted:
02
10
2019
pubmed:
9
10
2019
medline:
22
7
2020
entrez:
9
10
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31593555
pii: 130892
doi: 10.1172/JCI130892
pmc: PMC6934220
doi:
pii:
Substances chimiques
Heterogeneous-Nuclear Ribonucleoprotein Group A-B
0
Homeodomain Proteins
0
RNA, Long Noncoding
0
RNA, Neoplasm
0
Tumor Suppressor Proteins
0
VEGFC protein, human
0
Vascular Endothelial Growth Factor C
0
hnRNP A2
0
prospero-related homeobox 1 protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
404-421Références
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