Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer.


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
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

404-421

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Auteurs

Changhao Chen (C)

Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.

Yuming Luo (Y)

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.
Department of Pancreatobiliary Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.

Wang He (W)

Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.

Yue Zhao (Y)

Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Yao Kong (Y)

Department of Ultrasound and.

Hongwei Liu (H)

Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.

Guangzheng Zhong (G)

Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.

Yuting Li (Y)

Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.

Jun Li (J)

Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.

Jian Huang (J)

Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.

Rufu Chen (R)

Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.

Tianxin Lin (T)

Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, State Key Laboratory of Oncology in South China, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China.

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Classifications MeSH