Tumor-derived exosomal BCYRN1 activates WNT5A/VEGF-C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer.
Tumor-derived exosomal BCYRN1 activates WNT5A/VEGF-C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer.
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肿瘤源性外泌体BCYRN1激活WNT5A/VEGF-C/VEGFR3前馈环驱动膀胱癌淋巴转移
DOI：
10.1002/ctm2.497
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发表时间：
2021-07
影响因子：
10.6
通讯作者：
Lin T
中科院分区：
文献类型：
--
作者：
Zheng H;Chen C;Luo Y;Yu M;He W;An M;Gao B;Kong Y;Ya Y;Lin Y;Li Y;Xie K;Huang J;Lin T
转移性膀胱癌(BCA)患者预后极差。BCA来源的外切体作为重要的生物活性载体，在引发肿瘤转移的肿瘤微环境中发挥着重要的信号转导作用。然而，外切体介导BCA中LN转移的机制尚不清楚。我们进行了高通量测序，以探索BCA患者尿外切体中长非编码RNA(LncRNA)的表达谱，并在一个更大的210例队列中进一步评估外体lncRNA BCYRN1的临床相关性。通过体外迁移和管状形成实验和体内足垫-延髓LN转移模型评价外体BCYRN1的功能作用。通过RNA下拉实验、荧光素酶实验和放线菌素实验来检测外体BCYRN1的调控机制。BCA患者尿液中LncRNA BCYRN1表达显著上调，并与BCA的LN转移有关。我们发现外体BCYRN1在体外能显著促进人淋巴管内皮细胞(HLECs)的形成和迁移，在体内能明显促进BCA淋巴管的生成和层转移。在机制上，BCYRN1通过诱导Wnt5A启动子中hnRNPA1相关的H3K4三甲基化，激活Wnt/β-catenin信号通路，促进BCA中血管内皮生长因子-C的分泌，从而上调WNT5A的表观遗传表达。此外，外体BCYRN1通过转导HLECs稳定VEGFR3mRNA，形成hnRNPA1/Wnt5A/VEGFR3前馈调控环，最终促进BCA的淋巴转移。重要的是，用特异性的阻断剂SAR131675阻断VEGFR3可显著抑制外体BCYRN1诱导的LN体内转移。临床上，外体BCYRN1与BCA患者较短的生存期呈正相关，并被认为是患者预后不良的因素。我们的结果揭示了一个新的机制，即外体BCYRN1协同增强VEGF-C/VEGFR3信号诱导的BCA的淋巴转移，表明BCYRN1可能成为BCA患者令人鼓舞的治疗靶点。膀胱癌(BCA)患者尿液外切体中LncRNA BCYRN1表达上调，与LN转移和预后不良有关。BCYRN1上调WNT5A的表达，激活WNT/β-连环蛋白途径，促进血管内皮生长因子C的分泌。外体BCYRN1能稳定HLECs中VEGFR3mRNA的表达，构成促进淋巴管生成和LN转移的前馈环。
Patients with lymph node (LN) metastatic bladder cancer (BCa) present with extremely poor prognosis. BCa‐derived exosomes function as crucial bioactive cargo carriers to mediate the signal transduction in tumor microenvironment triggering tumor metastasis. However, the mechanisms underlying exosome‐mediated LN metastasis in BCa are unclear. We conducted the high‐throughput sequencing to explore the expression profile of long noncoding RNA (lncRNA) in urinary exosomes (urinary‐EXO) from patients with BCa and further evaluated the clinical relevance of exosomal lncRNA BCYRN1 in a larger 210‐case cohort. The functional role of exosomal BCYRN1 was evaluated through the migration and tube formation assays in vitro and the footpad‐popliteal LN metastasis model in vivo. RNA pull‐down assays, luciferase assays, and actinomycin assays were conducted to detect the regulatory mechanism of exosomal BCYRN1. LncRNA BCYRN1 was substantially upregulated in urinary‐EXO from patients with BCa, and associated with the LN metastasis of BCa. We demonstrated that exosomal BCYRN1 markedly promoted tube formation and migration of human lymphatic endothelial cells (HLECs) in vitro and lymphangiogenesis and LN metastasis of BCa in vivo. Mechanistically, BCYRN1 epigenetically upregulated WNT5A expression by inducing hnRNPA1‐associated H3K4 trimethylation in WNT5A promoter, which activated Wnt/β‐catenin signaling to facilitate the secretion of VEGF‐C in BCa. Moreover, exosomal BCYRN1 was transmitted to HLECs to stabilize the VEGFR3 mRNA and thus formed an hnRNPA1/WNT5A/VEGFR3 feedforward regulatory loop, ultimately promoting the lymphatic metastasis of BCa. Importantly, blocking VEGFR3 with specific inhibitor, SAR131675 significantly impaired exosomal BCYRN1‐induced the LN metastasis in vivo. Clinically, exosomal BCYRN1 was positively associated with the shorter survival of BCa patients and identified as a poor prognostic factor of patients. Our results uncover a novel mechanism by which exosomal BCYRN1 synergistically enhances VEGF‐C/VEGFR3 signaling‐induced lymphatic metastasis of BCa, indicating that BCYRN1 may serve as an encouraging therapeutic target for patients with BCa. lncRNA BCYRN1 is upregulated in urinary exosomes from bladder cancer (BCa) patients and associated with LN metastasis and poor prognosis of patients. BCYRN1 upregulates WNT5A expression to activate WNT/β‐catenin pathway and promotes the secretion of VEGF‐C in BCa. Exosomal BCYRN1 stabilizes VEGFR3 mRNA in HLECs, constituting a feedforward loop to promote lymphangiogenesis and LN metastasis of BCa.
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