Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 1, Pages 404-421Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI130892
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Funding
- National Key Research and Development Program of China [2018YFA0902803]
- National Natural Science Foundation of China [81825016, 81802530, 81830082, 81772719, 81772728, 91740119]
- Guangdong Medical Research Foundation [A2018330]
- Medical Scientific Research Foundation of Guangdong Province [A201947]
- Science and Technology Program of Guangzhou [201604020156, 201604020177, 201707010116, 2017B020227007]
- National Natural Science Foundation of Guangdong [2018A030313564, 2018A030310250, 2016A030313321]
- Yixian Youth project of Sun Yat-sen Memorial Hospital [YXQH201812]
- Key Areas Research and Development Program of Guangdong [2018B010109006]
- Guangdong Province Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme
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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.
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