Abstract：
BACKGROUND: Distant metastases are the primary cause of therapy failure and mortality in patients with papillary thyroid carcinomas (PTCs). However, the underlying mechanism responsible for the initiation of tumor cell dissemination and metastasis in PTCs has rarely been investigated.
OBJECTIVE: The aim of this study was to investigate effects and underlying molecular mechanisms of circulating exosomal microRNAs (miRNAs) in distant metastatic PTCs.
METHODS: The most relevant circulating exosomal miRNA to distant metastatic PTCs were verified between distant metastatic PTCs and nondistant metastatic PTCs by miRNA microarray, quantitative real-time polymerase chain reaction (qRT-PCR) assays and receiver operating characteristic (ROC) curves. The parental and recipient cells of that circulating exosomal miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of circulating exosomal miRNAs that contribute to the development of distant metastases.
RESULTS: We determined that PTC-derived exosomal miR-519e-5p was significantly upregulated in the circulatory system in distant metastatic PTCs. Further tests demonstrated that PTC cells can acquire a more malignant phenotype via hnRNPA2B1-mediated sorting of tumor suppressor miR-519e-5p into exosomes to activate Wnt signaling pathway via upregulating PLAGL2. Furthermore, miR-519e-5p included in PTC-derived exosomes can be transferred to recipient CD8+ T cells and aid in tumor immune escape in distant organs through inhibiting Notch signaling pathway by downregulating NOTCH2.
CONCLUSIONS: Our findings highlight the dual role of PTC-derived exosomal miR-519e-5p in distant metastasis, which may improve our understanding of exosome-mediated distant metastatic mechanisms.
OBJECTIVE: The aim of this study was to investigate effects and underlying molecular mechanisms of circulating exosomal microRNAs (miRNAs) in distant metastatic PTCs.
METHODS: The most relevant circulating exosomal miRNA to distant metastatic PTCs were verified between distant metastatic PTCs and nondistant metastatic PTCs by miRNA microarray, quantitative real-time polymerase chain reaction (qRT-PCR) assays and receiver operating characteristic (ROC) curves. The parental and recipient cells of that circulating exosomal miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of circulating exosomal miRNAs that contribute to the development of distant metastases.
RESULTS: We determined that PTC-derived exosomal miR-519e-5p was significantly upregulated in the circulatory system in distant metastatic PTCs. Further tests demonstrated that PTC cells can acquire a more malignant phenotype via hnRNPA2B1-mediated sorting of tumor suppressor miR-519e-5p into exosomes to activate Wnt signaling pathway via upregulating PLAGL2. Furthermore, miR-519e-5p included in PTC-derived exosomes can be transferred to recipient CD8+ T cells and aid in tumor immune escape in distant organs through inhibiting Notch signaling pathway by downregulating NOTCH2.
CONCLUSIONS: Our findings highlight the dual role of PTC-derived exosomal miR-519e-5p in distant metastasis, which may improve our understanding of exosome-mediated distant metastatic mechanisms.
摘要：
背景：远处转移是甲状腺乳头状癌（PTCs）患者治疗失败和死亡的主要原因。然而,很少研究引起肿瘤细胞在PTC中扩散和转移的潜在机制。
目的：本研究的目的是研究循环外泌体microRNAs（miRNAs）在远处转移性PTC中的作用和潜在的分子机制。
方法：通过miRNA微阵列在远处转移性PTC和非远处转移性PTC之间验证了与远处转移性PTC最相关的循环外泌体miRNA，定量实时聚合酶链反应（qRT-PCR）测定和受试者工作特征（ROC）曲线。然后探索该循环外泌体miRNA的亲本和受体细胞。进一步进行体外和体内实验以阐明循环外泌体miRNA的功能和潜在机制，这些miRNA有助于远处转移的发展。
结果：我们发现，在远处转移性PTC中，PTC来源的外泌体miR-519e-5p在循环系统中显著上调。进一步的实验表明，PTC细胞可以通过hnRNPA2B1介导的肿瘤抑制因子miR-519e-5p分选为外泌体，通过上调PLAGL2激活Wnt信号通路，从而获得更恶性的表型。此外，包含在PTC衍生的外泌体中的miR-519e-5p可以转移到受体CD8+T细胞，并通过下调NOTCH2抑制Notch信号通路来帮助远处器官中的肿瘤免疫逃逸。
结论：我们的发现强调了PTC来源的外泌体miR-519e-5p在远处转移中的双重作用，这可能会提高我们对外泌体介导的远处转移机制的理解。
目的：本研究的目的是研究循环外泌体microRNAs（miRNAs）在远处转移性PTC中的作用和潜在的分子机制。
方法：通过miRNA微阵列在远处转移性PTC和非远处转移性PTC之间验证了与远处转移性PTC最相关的循环外泌体miRNA，定量实时聚合酶链反应（qRT-PCR）测定和受试者工作特征（ROC）曲线。然后探索该循环外泌体miRNA的亲本和受体细胞。进一步进行体外和体内实验以阐明循环外泌体miRNA的功能和潜在机制，这些miRNA有助于远处转移的发展。
结果：我们发现，在远处转移性PTC中，PTC来源的外泌体miR-519e-5p在循环系统中显著上调。进一步的实验表明，PTC细胞可以通过hnRNPA2B1介导的肿瘤抑制因子miR-519e-5p分选为外泌体，通过上调PLAGL2激活Wnt信号通路，从而获得更恶性的表型。此外，包含在PTC衍生的外泌体中的miR-519e-5p可以转移到受体CD8+T细胞，并通过下调NOTCH2抑制Notch信号通路来帮助远处器官中的肿瘤免疫逃逸。
结论：我们的发现强调了PTC来源的外泌体miR-519e-5p在远处转移中的双重作用，这可能会提高我们对外泌体介导的远处转移机制的理解。
