Identification and Functional Characterization of Long Non-coding RNA<i> MIR22HG</i> as a Tumor Suppressor for Hepatocellular Carcinoma

Abstract

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 <i>MIR22HG</i> in HCC. <b>Methods:</b> We evaluated <i>MIR22HG</i> expression in 52-patient, 145-patient, TCGA, and GSE14520 HCC cohorts. The effects of <i>MIR22HG</i> on HCC were analyzed in terms of proliferation, invasion, and metastasis, both <i>in vitro</i> and <i>in vivo</i>. The mechanism of <i>MIR22HG</i> action was explored through bioinformatics, luciferase reporter, and RNA immunoprecipitation analyses. <b>Results:</b><i>MIR22HG</i> 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 <i>MIR22HG</i> in HCC cells significantly suppressed proliferation, invasion, and metastasis <i>in vitro</i> and <i>in vivo</i>. Mechanistically, <i>MIR22HG</i> derived miR-22-3p to target high mobility group box 1 (HMGB1), thereby inactivating HMGB1 downstream pathways. Additionally, <i>MIR22HG</i> directly interacted with HuR and regulated its subcellular localization. <i>MIR22HG</i> 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. <b>Conclusion:</b> Our findings revealed that <i>MIR22HG</i> 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.