Eun Jung Woo, Seo Chul Won, Baek Geum Ok, Yoon Moon Gyeong, Ahn Hye Ri, Son Ju A, Sung Suna, Kim Do Wan, Kim Soon Sun, Cho Hyo Jung, Cheong Jae Youn
Department of Gastroenterology, Ajou University School of Medicine, Suwon 16499, Korea.
Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Korea.
Cancers (Basel). 2020 Dec 18;12(12):3819. doi: 10.3390/cancers12123819.
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 ( = 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 ( < 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.
外泌体微小RNA(外泌体miR)促进癌症转移。为了鉴定肝细胞癌(HCC)中促转移的循环外泌体miR,对14例HCC患者(8例无转移,6例在随访1年内发生转移)基于下一代测序的血浆外泌体miR谱进行了分析。在转移性HCC患者中,61种miR显著过表达。通过对两个不同的公共表达数据集GSE67140和癌症基因组图谱肝细胞癌(TCGA_LIHC)进行综合分析来选择候选miR。综合分析显示,61种miR中的3种(miR-106b-5p、miR-1307-5p和miR-340-5p)在转移组和血管侵犯组中均普遍过表达,具有预后意义。使用150例HCC患者的储存血样进行验证。验证分析表明,循环外泌体miR-1307-5p在转移组(P = 0.04)以及血管侵犯组和肿瘤复发组中均显著过表达。循环外泌体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显示,miR-1307-5p促进上皮-间质转化(EMT)的下游通路表现为SEC14L2和ENG下调。我们的结果表明,循环外泌体miR-1307-5p促进HCC转移并有助于预测转移,SEC14L2和ENG是miR-1307促进EMT的靶肿瘤抑制基因。