The Graduate School of Second Military Medical University, Shanghai, China.
Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
J Transl Med. 2020 Aug 28;18(1):326. doi: 10.1186/s12967-020-02494-7.
Liver cancer is among the most common malignancy worldwide. Hepatocellular carcinoma (HCC), the principal histological subtype of liver cancer, is globally the third most common cause of cancer-related mortality. The high rates of recurrence and metastasis contribute to the poor prognosis of HCC patients. In recent years, increasing evidence has shown that microRNAs (miRNAs) are involved in the tumorigenesis, progression, and prognosis of HCC.
To screen for key candidate miRNAs in HCC, three microarray datasets were downloaded from Gene Expression Omnibus (GEO). The sole common differentially expressed miRNA (DEmiR) observed in the above three datasets using a Venn diagram was microRNA-211-5p (miR-211-5p). The expression of miR-211-5p from HCC tissues was measured in several HCC cell lines. Additionally, using Kaplan-Meier plots, the potential prognostic value of miR-211-5p in HCC was analyzed. Cell counting kit-8 (CCK-8) and transwell assays examined the ability of miR-211-5p to induce cell proliferation, migration, and invasion in HCC cultures. The interaction of miR-211-5p and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) was assessed both theoretically and using a luciferase reporter assay. Finally, the ability of miR-211-5p to modulate tumorigenesis in HCC in vivo was assessed after establishing a xenograft model.
qRT-PCR demonstrated that the relative expression of miR-211-5p was considerably down-regulated in HCC tissues and cell lines compared with normal tissue. Kaplan-Meier plots indicated that HCC patients with decreased expression of miR-211-5p had poor overall survival. Upregulation of miR-211-5p in vitro consistently suppressed cell proliferation, migration, and invasion. In contrast, enhanced expression of ACSL4 promoted a malignant phenotype in HCC cells. Importantly, we discovered that ACSL4 was a direct downstream target of miR-211-5p in HCC, and that miR-211-5p suppressed the malignant phenotype by inhibition of ACSL4 expression. Furthermore, miR-211-5p overexpression impaired tumorigenesis and growth of HCC in vivo.
Targeting miR-211-5p and the downstream gene ACSL4 will possibly provide novel insight and represents a promising approach to future therapy of HCC patients.
肝癌是全球最常见的恶性肿瘤之一。肝细胞癌（HCC）是肝癌的主要组织学亚型，是全球癌症相关死亡的第三大主要原因。高复发和转移率导致 HCC 患者预后不良。近年来，越来越多的证据表明 microRNAs（miRNAs）参与 HCC 的发生、发展和预后。
为了筛选 HCC 中的关键候选 miRNA，从基因表达综合数据库（GEO）下载了三个 miRNA 芯片数据集。使用 Venn 图观察到上述三个数据集之间唯一的共同差异表达 miRNA（DEmiR）是 microRNA-211-5p（miR-211-5p）。在几种 HCC 细胞系中测量 HCC 组织中 miR-211-5p 的表达。此外，使用 Kaplan-Meier 图分析 miR-211-5p 在 HCC 中的潜在预后价值。细胞计数试剂盒-8（CCK-8）和 Transwell 分析检测 miR-211-5p 在 HCC 培养物中诱导细胞增殖、迁移和侵袭的能力。通过理论和荧光素酶报告基因检测评估 miR-211-5p 与酰基辅酶 A 合成酶长链家族成员 4（ACSL4）之间的相互作用。最后，在建立异种移植模型后，评估 miR-211-5p 在体内调节 HCC 肿瘤发生的能力。
qRT-PCR 表明，与正常组织相比，miR-211-5p 在 HCC 组织和细胞系中的相对表达明显下调。Kaplan-Meier 图表明，miR-211-5p 表达降低的 HCC 患者总生存期较差。体外上调 miR-211-5p 一致抑制细胞增殖、迁移和侵袭。相反，ACSL4 的过表达促进 HCC 细胞的恶性表型。重要的是，我们发现 ACSL4 是 HCC 中 miR-211-5p 的直接下游靶标，miR-211-5p 通过抑制 ACSL4 表达抑制恶性表型。此外，miR-211-5p 的过表达可损害 HCC 体内的肿瘤发生和生长。
靶向 miR-211-5p 和下游基因 ACSL4 可能为 HCC 患者的未来治疗提供新的见解，并代表一种有前途的方法。
