Abstract:

Patients with bladder cancer (BCa) with clinical lymph node (LN) metastasis have 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 demonstrated that BCa cell-secreted exosomes-mediated lymphangiogenesis promoted LN metastasis in BCa, which was in a VEGF-C-independent manner. We identified an exosomal long noncoding RNA (lncRNA), termed lymph node metastasis-associated transcript 2 (LNMAT2), stimulated 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.

推薦理由：

1、外泌體來源的長鏈非編碼RNA  LNMAT2刺激了HLEC管的形成和遷移，并在體外增強了腫瘤淋巴管生成和淋巴結(jié)轉(zhuǎn)移,LNMAT2通過與hnRNPA2B1直接相互作用而被加載到膀胱癌細胞分泌的外泌體上。隨后，外泌體來源的LNMAT2被HLEC內(nèi)化，并通過募集hnRNPA2B1并增加PROX1啟動子中的H3K4三甲基化水平，表觀遺傳上調(diào)了PROX1的表達，最終導致淋巴管生成和淋巴轉(zhuǎn)移.

2、外泌體和lncrna都是本課題組的研究方向，這篇文章將研究了外泌體來源的lncrna，對我們有較好的啟發(fā)效果。