Exosomal Metastasis-Associated Lung Adenocarcinoma Transcript 1 Promotes Angiogenesis and Predicts Poor Prognosis in Epithelial Ovarian Cancer
Exosomal Metastasis-Associated Lung Adenocarcinoma Transcript 1 Promotes Angiogenesis and Predicts Poor Prognosis in Epithelial Ovarian Cancer
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DOI：
10.7150/ijbs.28048
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发表时间：
2018-01-01
影响因子：
9.2
通讯作者：
Hua, Ke-Qin
中科院分区：
文献类型：
--
作者：
Qiu, Jun-Jun;Lin, Xiao-Jing;Hua, Ke-Qin
外泌体通过转移其分子货物（包括长非编码RNA（IncRNA））来介导癌症进展中的细胞-细胞串扰。转移相关肺腺癌转录本1（MALAT 1）是一种与肿瘤血管生成和转移相关的IncRNA。然而，MALAT 1在外泌体中的存在以及外泌体MALAT 1在上皮性卵巢癌（EOC）中的作用和临床价值仍然未知。本研究主要探讨外泌体MALAT 1介导的EOC细胞与内皮细胞间的相互作用，探讨外泌体和外泌体MALAT 1在EOC血管生成中的作用，以及血清外泌体MALAT 1在EOC中的临床意义和预后预测价值。我们观察到MALAT 1在转移性EOC细胞及其分泌的外泌体中均增加。将来自EOC细胞的外泌体MALAT 1通过外泌体转移至受体人脐静脉内皮细胞（HUVEC）。在体外和体内实验表明，MALAT 1敲低损害外泌体介导的促血管生成活性的HUVECs通过某些关键的血管生成相关基因。临床上，血清外泌体MALAT 1升高与EOC的晚期和转移表型高度相关，并且是EOC总生存期（OS）的独立预测因素。此外，我们构建的预后诺模图模型显示，根据c指数（0.751，95%置信区间[CI]=0.691-0.811）和校准曲线，EOC患者3年OS的概率有很好的预测。总的来说，我们的数据提供了一种新的机制，通过这种机制，EOC细胞通过外泌体将MALAT 1转移到受体HUVEC，并通过刺激血管生成相关基因表达来影响HUVEC，最终促进血管生成。此外，循环外泌体MALAT 1可以作为EOC预后的有希望的基于血清的非侵入性预测生物标志物。
Exosomes mediate cell-cell crosstalk in cancer progression by transferring their molecular cargos, including long noncoding RNAs (IncRNAs). Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a well-known IncRNA associated with cancer angiogenesis and metastasis. However, the presence of MALAT1 in exosomes and the roles and clinical values of exosomal MALAT1 in epithelial ovarian cancer (EOC) remain unknown. The present study focused on the crosstalk between EOC cells and endothelial cells mediated by exosomal MALAT1 and aimed to explore the roles of exosomes and exosomal MALAT1 in EOC angiogenesis and to reveal the clinical relevance and prognostic predictive value of serum exosomal MALAT1 in EOC. We observed that MALAT1 was increased in both metastatic EOC cells and their secreted exosomes. Exosomal MALAT1 derived from EOC cells was transferred to recipient human umbilical vein endothelial cells (HUVECs) via exosomes. In vitro and in vivo experiments demonstrated that MALAT1 knockdown impaired the exosome-mediated proangiogenic activity of HUVECs through certain key angiogenesis-related genes. Clinically, elevated serum exosomal MALAT1 was highly correlated with an advanced and metastatic phenotype of EOC and was an independent predictive factor for EOC overall survival (OS). Moreover, a prognostic nomogram model we constructed showed a good prediction of the probability of 3-year OS of EOC patients according to the c-index (0.751, 95% confidence interval [CI]=0.691-0.811) and calibration curve. Collectively, our data provide a novel mechanism by which EOC cells transfer MALAT1 via exosomes to recipient HUVECs and influence HUVECs by stimulating angiogenesis-related gene expression, eventually promoting angiogenesis. Additionally, circulating exosomal MALAT1 can serve as a promising serum-based, noninvasive predictive biomarker for EOC prognosis.