Circulating Exosomal MicroRNA-1307-5p as a Predictor for Metastasis in Patients with Hepatocellular Carcinoma.
Circulating Exosomal MicroRNA-1307-5p as a Predictor for Metastasis in Patients with Hepatocellular Carcinoma.
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DOI：
10.3390/cancers12123819
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发表时间：
2020-12-18
期刊：
影响因子：
5.2
通讯作者：
Cheong JY
中科院分区：
文献类型：
--
作者：
Eun JW;Seo CW;Baek GO;Yoon MG;Ahn HR;Son JA;Sung S;Kim DW;Kim SS;Cho HJ;Cheong JY
外泌体microRNAs （exo-miRs）显著促进癌症转移。然而，尽管最近液体活检技术取得了进展，但很少有研究调查外泌体在肝细胞癌（HCC）中作为转移介质的作用。我们旨在通过对血浆exo-miR测序数据和公开可用的RNA表达数据集的全面和系统的综合分析，确定可能预测HCC转移发生的促转移循环外显子miRs，并由此提出促转移子miRs的潜在作用机制，包括促进上皮-间质转化（EMT）。我们发现循环exo-miR-1307-5p是HCC患者转移的预测标志物，通过SEC14L2和ENG下调促进EMT可能是miR-1307-5p的潜在下游途径。我们认为我们的研究对文献有重大贡献，因为我们的发现为循环外显子mirs在HCC发病和进展中的作用提供了新的见解，并表明外显子mirs是HCC的潜在治疗靶点。外泌体microRNAs （exo-miRs）有助于癌症转移。为了鉴定肝细胞癌（HCC）的促转移循环外显子mir，分析了14例HCC患者（8例非转移性和6例随访1年内发生转移）的下一代基于测序的血浆外显子mir谱。转移性HCC患者中有61例miRs显著过表达。通过对两个不同的公共表达数据集GSE67140和The Cancer Genome Atlas liver hepatellular carcinoma （TCGA_LIHC）进行综合分析，选择候选miRs。综合分析显示，61个miRs中的3个（miR-106b-5p， miR-1307-5p和miR-340-5p）在转移和血管侵袭组中普遍过表达，具有预后意义。使用储存的150例HCC患者的血液样本进行验证。验证分析显示，循环exo-miR-1307-5p在转移组以及血管侵袭组和肿瘤复发组中均显著过表达（p = 0.04）。循环exo-miR-1307-5p表达与肿瘤分期进展显著相关（p < 0.0001）。使用TargetScan和Ingenuity Pathway Analysis预测miR-1307的下游信号通路。综合生物信息学分析，miR-1307-5p促进上皮-间质转化（EMT）的下游通路显示SEC14L2和ENG下调。我们的研究结果表明，在HCC中循环的exo-miR-1307-5p促进转移并有助于预测转移，而SEC14L2和ENG是miR-1307促进EMT的靶抑癌基因。
Exosomal microRNAs (exo-miRs) significantly contribute to cancer metastasis. However, few studies have investigated the role of exosomes as metastasis mediators in hepatocellular carcinoma (HCC) despite recent advancements in liquid biopsy. We aimed to identify pro-metastatic circulating exo-miRs potentially predicting metastasis onset in HCC through comprehensive and systematic integrative analyses of plasma exo-miR sequencing data and publicly available RNA expression datasets, and accordingly propose a potential mechanism of action of pro-metastatic miRs, including promoting epithelial–mesenchymal transition (EMT). We found that circulating exo-miR-1307-5p is a predictive marker for metastasis in patients with HCC, and EMT promotion through SEC14L2 and ENG downregulation could be the potential downstream pathway of miR-1307-5p. We believe that our study makes a significant contribution to the literature because our findings provide novel insights into the role of circulating exo-miRs in the pathogenesis and progression of HCC and suggest that exo-miRs are a potential treatment target in HCC. Exosomal microRNAs (exo-miRs) contribute to cancer metastasis. To identify pro-metastatic circulating exo-miRs in hepatocellular carcinoma (HCC), next-generation sequencing-based plasma exo-miR profiles of 14 patients with HCC (eight non-metastatic and six with metastasis within 1 year of follow-up) were analyzed. Sixty-one miRs were significantly overexpressed among patients with metastatic HCC. Candidate miRs were selected through integrative analyses of two different public expression datasets, GSE67140 and The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA_LIHC). Integrative analyses revealed 3 of 61 miRs (miR-106b-5p, miR-1307-5p, and miR-340-5p) commonly overexpressed both in metastasis and vascular invasion groups, with prognostic implications. Validation was performed using stored blood samples of 150 patients with HCC. Validation analysis showed that circulating exo-miR-1307-5p was significantly overexpressed in the metastasis group (p = 0.04), as well as in the vascular invasion and tumor recurrence groups. Circulating exo-miR-1307-5p expression was significantly correlated with tumor stage progression (p < 0.0001). Downstream signaling pathways of miR-1307 were predicted using TargetScan and Ingenuity Pathway Analysis. On comprehensive bioinformatics analysis, the downstream pathway of miR-1307-5p, promoting epithelial–mesenchymal transition (EMT), showed SEC14L2 and ENG downregulation. Our results show that circulating exo-miR-1307-5p promotes metastasis and helps predict metastasis in HCC, and SEC14L2 and ENG are target tumor suppressor genes of miR-1307 that promote EMT.
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