Identification and Functional Characterization of Long Non-coding RNA MIR22HG 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 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.

LncRNA MIR22HG inhibits growth, migration and invasion through regulating the miR‐10a‐5p/NCOR2 axis in hepatocellular carcinoma cells

“…LncRNA MIR22HG, which is mostly located in cytoplasm, is frequently deleted or hypermethylated, and commonly shows loss of heterozygosity in HCC . MIR22HG has previously been demonstrated to be downregulated in hepatocellular carcinoma .…”

“…MIR22HG has previously been demonstrated to be downregulated in hepatocellular carcinoma . MIR22HG repressed hepatocellular carcinoma cell invasion by deriving miR‐22 to target HMGB1 and binding with human antigen R (HuR) . Su et al revealed that MIR22HG could inhibit cell survival signaling via oncogenes YBX1, MET and p21 in lung cancer.…”

MIR22HG acts as a tumor suppressor via TGFβ/SMAD signaling and facilitates immunotherapy in colorectal cancer

“…MIR22HG was shown to competing with miRNAs with H19 and play important regulatory roles in breast cancer progression [47]. MIR22HG can also competitively bind to human antigen R (HuR), resulting in weakened expression of HuR-stabilized oncogenes, such as β-catenin in hepatocellular carcinoma cells [32]. MIR22HG was found to inhibit growth, migration and invasion through regulating the miR-10a-5p/NCOR2 axis in hepatocellular carcinoma cells [31].…”

“…1d). We found that MIR22HG is the mostly investigated one in cancer and has been show to function as a tumor suppressor in hepatocellular carcinoma [31,32], lung cancer [33] and thyroid cancer [34]. However, we are still lack of knowledge of its roles in CRC.…”

<p>MIR22HG As A Tumor Suppressive lncRNA In HCC: A Comprehensive Analysis Integrating RT-qPCR, mRNA-Seq, And Microarrays</p>

“…For example, silencing of MIR22HG triggered apoptosis in lung cancer cells, while upregulation of MIR22HG inhibited the proliferation of endometrial cancer cells. 12,13 Studies have shown that overexpression of MIR22HG could significantly suppress the malignant progression of HCC, while indicating good survival outcome of HCC patients, [14][15][16] suggesting promising prospects for the application of MIR22HG in HCC treatment. Nevertheless, these studies had shortcomings, including the use of only limited numbers of HCC specimens for examining the expression level of MIR22HG in HCC and non-cancer tissues and the lack of sufficient diversity in the methods used to evaluate the expression of MIR22HG in HCC and non-cancer tissues.…”