Background: B-cell-specific moloney leukemia virus insertion site 1 (Bmi-1) plays important roles in various cancers, but its regulation through microRNAs (miRNAs) and its functions in hepatocellular carcinoma (HCC) remains unclear. Methods: We evaluated the expression and prognostic significance of Bmi-1 in HCC by using tissue samples and The Cancer Genome Atlas (TCGA) data sets. The relationship between miRNAs and Bmi-1 was verified by bioinformatics prediction and immunofluorescence. Colony formation and apoptosis assays were used to reveal the effect of miR-203 on radiosensitivity. Results: The Bmi-1 mRNA and protein were upregulated in HCC tissues. Cox regression multivariate analyses showed that Bmi-1 overexpression was an independent prognostic parameter for HCC patients. The expression level of Bmi-1 was negatively associated with miR-203 levels in HCC tissues. Dual-luciferase reporter assays showed that miR-203 could target the 3′ untranslated region (3′-UTR) of Bmi-1 directly. Overexpression of miR-203 in HepG2 and Smmc-7721 cells increases their sensitivity to ionizing radiation in vitro and in vivo. Moreover, the improved cell radiosensitivity induced by miR-203 could be rescued by restoration of Bmi-1 expression. Conclusions: Bmi-1 could improve the predictive accuracy for HCC patients’ survival. Moreover, miR-203 enhance cell radiosensitivity in vitro and in vivo by targeting Bmi-1 in HCC.

中文翻译：

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MicroRNA-203通过直接靶向肝细胞癌中的Bmi-1增加细胞放射敏感性

背景：B细胞特异性单株白血病病毒插入位点1（Bmi-1）在各种癌症中起着重要作用，但其通过microRNA（miRNA）的调控及其在肝细胞癌（HCC）中的功能仍不清楚。方法：我们通过使用组织样本和癌症基因组图谱（TCGA）数据集评估了Bmi-1在肝癌中的表达和预后意义。通过生物信息学预测和免疫荧光验证了miRNA与Bmi-1之间的关系。使用菌落形成和凋亡测定法来揭示miR-203对放射敏感性的影响。结果：肝癌组织中Bmi-1 mRNA和蛋白上调。Cox回归多元分析表明，Bmi-1过表达是HCC患者的独立预后参数。Bmi-1的表达水平与肝癌组织中的miR-203水平呈负相关。双重荧光素酶报告基因测定表明，miR-203可以直接靶向Bmi-1的3'非翻译区（3'-UTR）。miR-203在HepG2和Smmc-7721细胞中的过表达增加了它们在体外和体内对电离辐射的敏感性。此外，可以通过恢复Bmi-1表达来挽救miR-203诱导的改善的细胞放射敏感性。结论：Bmi-1可以提高肝癌患者生存的预测准确性。而且，miR-203通过靶向HCC中的Bmi-1增强体外和体内细胞的放射敏感性。miR-203在HepG2和Smmc-7721细胞中的过表达增加了它们在体外和体内对电离辐射的敏感性。此外，可以通过恢复Bmi-1表达来挽救miR-203诱导的改善的细胞放射敏感性。结论：Bmi-1可以提高肝癌患者生存的预测准确性。而且，miR-203通过靶向HCC中的Bmi-1增强体外和体内细胞的放射敏感性。miR-203在HepG2和Smmc-7721细胞中的过表达增加了它们在体外和体内对电离辐射的敏感性。此外，可以通过恢复Bmi-1表达来挽救miR-203诱导的改善的细胞放射敏感性。结论：Bmi-1可以提高肝癌患者生存的预测准确性。而且，miR-203通过靶向HCC中的Bmi-1增强体外和体内细胞的放射敏感性。