Identification and Functional Characterization of Long Non-coding RNA MIR22HG as a Tumor Suppressor for Hepatocellular Carcinoma.
Identification and Functional Characterization of Long Non-coding RNA MIR22HG as a Tumor Suppressor for Hepatocellular Carcinoma.
复制标题
长非编码 RNA MIR22HG 作为肝细胞癌肿瘤抑制因子的鉴定和功能表征
作者：
Zhang DY;Zou XJ;Cao CH;Zhang T;Lei L;Qi XL;Liu L;Wu DH
长链非编码RNA（lncRNAs）最近被确定为肿瘤发生和发展的关键调节因子。然而，lncRNAs在人类肝细胞癌（HCC）中的功能在很大程度上仍然未知。我们的研究旨在探索lncRNA MIR22HG在HCC中的生物学功能和临床意义。
方法：我们在52例患者、145例患者、癌症基因组图谱（TCGA）以及基因表达综合数据库（GSE14520）中的HCC队列中评估了MIR22HG的表达。从增殖、侵袭和转移方面，在体外和体内分析了MIR22HG对HCC的影响。通过生物信息学、荧光素酶报告基因以及RNA免疫沉淀分析探索了MIR22HG作用的机制。
结果：与对照组相比，MIR22HG在4个独立的HCC队列中的表达显著下调。其低表达与HCC患者的肿瘤进展和不良预后相关。在HCC细胞中强制表达MIR22HG在体外和体内显著抑制增殖、侵袭和转移。从机制上讲，MIR22HG产生miR - 22 - 3p以靶向高迁移率族蛋白B1（HMGB1），从而使HMGB1下游通路失活。此外，MIR22HG直接与HuR相互作用并调节其亚细胞定位。MIR22HG竞争性结合人抗原R（HuR），导致HuR稳定的癌基因（如β - 连环蛋白）表达减弱。此外，miR - 22 - 3p的抑制、HuR或HMGB1的过表达挽救了由MIR22HG过表达引起的抑制作用。
结论：我们的研究结果表明，MIR22HG通过抑制肿瘤细胞的增殖、侵袭和转移在肿瘤进展中起关键作用，提示其在HCC中作为肿瘤抑制因子和预后生物标志物的潜在作用。
Long non-coding RNAs (lncRNAs) have recently been identified as critical regulators in tumor initiation and development. However, the function of lncRNAs in human hepatocellular carcinoma (HCC) remains largely unknown. Our study was designed to explore the biological function and clinical implication of lncRNA MIR22HG in HCC. Methods: We evaluated MIR22HG expression in 52-patient, 145-patient, TCGA, and GSE14520 HCC cohorts. The effects of MIR22HG on HCC were analyzed in terms of proliferation, invasion, and metastasis, both in vitro and in vivo. The mechanism of MIR22HG action was explored through bioinformatics, luciferase reporter, and RNA immunoprecipitation analyses. Results: MIR22HG expression was significantly down-regulated in 4 independent HCC cohorts compared to that in controls. Its low expression was associated with tumor progression and poor prognosis of patients with HCC. Forced expression of MIR22HG in HCC cells significantly suppressed proliferation, invasion, and metastasis in vitro and in vivo. Mechanistically, MIR22HG derived miR-22-3p to target high mobility group box 1 (HMGB1), thereby inactivating HMGB1 downstream pathways. Additionally, MIR22HG directly interacted with HuR and regulated its subcellular localization. MIR22HG competitively bound to human antigen R (HuR), resulting in weakened expression of HuR-stabilized oncogenes, such as β-catenin. Furthermore, miR-22-3p suppression, HuR or HMGB1 overexpression rescued the inhibitory effects caused by MIR22HG overexpression. Conclusion: Our findings revealed that MIR22HG plays a key role in tumor progression by suppressing the proliferation, invasion, and metastasis of tumor cells, suggesting its potential role as a tumor suppressor and prognostic biomarker in HCC.