Department of Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.
Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.
Int J Med Sci. 2021 Aug 25;18(15):3556-3564. doi: 10.7150/ijms.57504. eCollection 2021.
MiRNAs are pivotal regulators involved in proliferation, apoptosis, invasion, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, drug resistance and autophagy in hepatocellular carcinoma (HCC). The aim of this study was to investigate the influence of miR-139-5p and its target genes on the outcomes of HCC. Survival analysis of miR-139-5p in HCC was conducted in Kaplan-Meier plotter. Target genes of miR-139-5p were identified in TargetScan, miRTarBase and starBase. Gene Expression Omnibus (GEO) series were used for the validation of miR-139-5p target genes. Cox proportional regression model was also established. In Kaplan-Meier plotter, 163 HCC patients were included. MiR-139-5p downregulation was significantly associated with unfavorable overall survival (OS) and disease-free survival (DFS) in HCC patients (all < 0.001). MiR-139-5p was significantly downregulated in HCC tumors and human hepatoma cell lines (all < 0.05). As a target gene of miR-139-5p, CCT5 was overexpressed in HCC tumor tissues and peripheral blood mononuclear cells (all < 0.05). A negative correlation between CCT5 and miR-139-5p was found in TCGA dataset. CCT5 overexpression was significantly associated with worse OS in HCC patients ( < 0.001), which was validated in the GSE14520 dataset ( = 0.017). CCT5 mRNA was significantly overexpressed in HCC patients with alpha-fetoprotein (AFP) > 300 ng/ml, BCLC staging B-C, TNM staging III and main tumor size > 5 cm (all < 0.05). According to the Cox regression model of CCT5-interacting genes, HCC patients with high risk had poor OS compared to those with low risk in the TCGA dataset ( < 0.001), with the 1-year, 3-year, and 5-year ROC curves of an area under the curve (AUC) equal to 0.704, 0.662, and 0.631, respectively. MiR-139-5p suppresses HCC tumor aggression and conversely correlated with CCT5. The miR-139-5p/CCT5 axis might perform crucial functions in the development of HCC.
miRNAs 是参与肝癌（HCC）增殖、凋亡、侵袭、转移、上皮间质转化（EMT）、血管生成、耐药和自噬的关键调节因子。本研究旨在探讨 miR-139-5p 及其靶基因对 HCC 结局的影响。在 Kaplan-Meier plotter 中进行 HCC 中 miR-139-5p 的生存分析。在 TargetScan、miRTarBase 和 starBase 中鉴定 miR-139-5p 的靶基因。使用基因表达综合数据库（GEO）系列验证 miR-139-5p 的靶基因。还建立了 Cox 比例风险回归模型。在 Kaplan-Meier plotter 中，纳入了 163 例 HCC 患者。miR-139-5p 下调与 HCC 患者的不良总生存期（OS）和无病生存期（DFS）显著相关（均<0.001）。miR-139-5p 在 HCC 肿瘤和人肝癌细胞系中均显著下调（均<0.05）。作为 miR-139-5p 的靶基因，CCT5 在 HCC 肿瘤组织和外周血单核细胞中均过表达（均<0.05）。在 TCGA 数据集发现 CCT5 与 miR-139-5p 之间存在负相关。CCT5 过表达与 HCC 患者的 OS 较差显著相关（<0.001），在 GSE14520 数据集得到验证（=0.017）。在 AFP>300ng/ml、BCLC 分期 B-C、TNM 分期 III 和主肿瘤大小>5cm 的 HCC 患者中，CCT5mRNA 均显著过表达（均<0.05）。根据 CCT5 相互作用基因的 Cox 回归模型，在 TCGA 数据集中，高危 HCC 患者的 OS 明显低于低危患者（<0.001），其 1 年、3 年和 5 年 AUC 的 ROC 曲线分别为 0.704、0.662 和 0.631。miR-139-5p 抑制 HCC 肿瘤侵袭，与 CCT5 呈负相关。miR-139-5p/CCT5 轴可能在 HCC 的发展中发挥关键作用。
