Queen Mary School, Medical Department, Nanchang University, Nanchang, P.R. China.
Department of Hepatobillary Surgery, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, P.R. China.
Bioengineered. 2022 Mar;13(3):5737-5755. doi: 10.1080/21655979.2021.2023792.
Metastasis and chemoresistance are the leading causes of death in patients with hepatocellular carcinoma (HCC). microRNAs (miRNAs or miRs) may be useful as diagnostic, therapeutic and prognostic markers for HCC. In this study, we set out to investigate the possible role of miR-381 in HCC development and chemoresistance along with the related mechanism. Microarray-based gene expression profiling was carried out to analyze the expression of SET domain bifurcated 1 (SETDB1) and histone methyltransferase enhancer of zeste homolog 2 (EZH2) followed by validation in clinical HCC tissues and cells. The potential binding between miR-381 and SETDB1 was found and verified. Then, the role of SETDB1 in HCC in relation to miR-381 and protein kinase B (AKT) pathway was explored through gain- and loss-of-function approaches. After expression determination of EZH2, SETDB1, miR-381, and AKT pathway-related factors, their reactions were analyzed and their functional roles in HCC progression and chemoresistance were investigated and . SETDB1 was aberrantly upregulated in clinical HCC tissues and cells. This upregulation activated AKT pathway by promoting its tri-methylation on K64. SETDB1 promoted the proliferation, migration and chemoresistance through the AKT pathway in HCC cells. In a xenograft mouse model, SETDB1 promoted HCC cell tumorigenesis by activating the AKT pathway. Furthermore, EZH2 suppressed miR-381 by catalyzing the activity of H3K27me3 on its promoter region. In conclusion, EZH2 suppressed miR-381 expression by promoting H3K27me3 activity on its promoter region to facilitate SETDB1 expression, thereby activating the AKT pathway to promote hepatocarcinogenesis and chemoresistance.
转移和化疗耐药是肝细胞癌（HCC）患者死亡的主要原因。 microRNAs（miRNAs 或 miRs）可用作 HCC 的诊断、治疗和预后标志物。在这项研究中，我们旨在研究 miR-381 在 HCC 发展和化疗耐药中的可能作用及其相关机制。通过基于微阵列的基因表达谱分析，分析 SET 域分叉 1（SETDB1）和组蛋白甲基转移酶增强子的 zeste 同源物 2（EZH2）的表达，随后在临床 HCC 组织和细胞中进行验证。发现并验证了 miR-381 与 SETDB1 之间的潜在结合。然后，通过增益和失活功能方法探索了 SETDB1 在 HCC 中与 miR-381 和蛋白激酶 B（AKT）通路的关系。确定 EZH2、SETDB1、miR-381 和 AKT 通路相关因子的表达后，分析了它们的反应，并研究了它们在 HCC 进展和化疗耐药中的功能作用。SETDB1 在临床 HCC 组织和细胞中异常上调。这种上调通过促进其在 K64 上的三甲基化来激活 AKT 通路。SETDB1 通过在 HCC 细胞中激活 AKT 通路促进增殖、迁移和化疗耐药。在异种移植小鼠模型中，SETDB1 通过激活 AKT 通路促进 HCC 细胞肿瘤发生。此外，EZH2 通过催化其启动子区域上 H3K27me3 的活性来抑制 miR-381 的表达。总之，EZH2 通过促进 H3K27me3 活性抑制 miR-381 的表达，从而促进 SETDB1 的表达，激活 AKT 通路，促进肝癌发生和化疗耐药。
