Emerging impact of the long noncoding RNA MIR22HG on proliferation and apoptosis in multiple human cancers

One of the most well-characterized mechanisms of lncRNAs is functioning as a ceRNA or “sponge” for miRNAs. ceRNAs are involved in posttranscriptional regulation, as they compete with miRNAs through the same miRNA sequence during RNA transcription to regulate the expression of downstream target genes [32‐34]. Mounting evidence has demonstrated that ceRNAs play a vital role in cancer progression [35‐37].

More recently, MIR22HG has also emerged as exhibiting ceRNA functions in many cancer types, such as thyroid carcinoma (TC), endometrial carcinoma (EC) and hepatocellular carcinoma (HCC) (Fig. 2). Chen et al. revealed that MIR22HG was downregulated in TC tumor tissues compared with nontumor tissues using 40 pairs of papillary thyroid carcinoma tissues through qRT-PCR detection. Further biological function studies have demonstrated that MIR22HG suppresses the growth, migration and invasion of TC cells. Systematically, MIR22HG acts as a ceRNA to upregulate p27kip1 by directly binding with miR-24-3p, which inhibits the malignant phenotype of TC cells [21] (Fig. 2a). Moreover, the authors reported that low MIR22HG expression was related to tumor size (P = 0.015), TNM stage (P = 0.022) and poor overall survival (P = 0.030) by qRT-PCR detection. Another study by Qin et al. verified these findings. They reported that the downregulation of MIR22HG was significantly related to the lymph node metastasis status (P < 0.01), the residual tumor status (P < 0.05), N stage (P < 0.05), tumor grade (P < 0.001) and T stage (P < 0.001) while high MIR22HG expression was significantly correlated with the disease recurrence rate (P < 0.01), overall survival time (P = 0.0665) and disease-free survival time (P < 0.05) in TC by analyzing TCGA, GSE29265, GSE33630, and GSE55091 public database. Coexpression, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that MIR22HG was involved in regulating apoptosis, transcription, the cell cycle, and Hippo signaling [22].

Wu et al. found that MIR22HG was significantly decreased in 120 HCC tissues compared with adjacent nontumor liver tissues by employing qRT-PCR. Furthermore, low MIR22HG expression was associated with short overall survival (P = 0.045) and poor disease-free survival (P = 0.036). These results implicated the potential role of MIR22HG as a diagnostic and prognostic biomarker to improve HCC patient outcomes. Functional experiments demonstrated that the knockdown of MIR22HG promoted the growth, migration and invasion of HCC cells. It has also been reported that miR-10a functions as an oncogene or tumor suppressor depending on the context [38‐41]. Mechanistically, miR-10a-5p can be a downstream target of MIR22HG. By acting in this manner as a ceRNA, MIR22HG directly binds to miR-10a-5p and increases NCOR2 expression to inhibit the proliferation, migration and invasion of HCC cells [23] (Fig. 2b).

Not coincidentally, Cui’s team confirmed the critical role by which MIR22HG acts as a ceRNA to modulate the proliferation, apoptosis and cell cycle of EC cells [25] (Fig. 2c). MIR22HG overexpression significantly reduced miR-141-3p expression in EC cells. Subsequently, MIR22HG increased DAPK1 expression by targeting miR-141-3p, thus inhibiting cell proliferation via G1 arrest of the cell cycle and promoting the apoptosis of EC cells. In summary, the MIR22HG-regulated miR-141-3p/DAPK1 axis may be a new therapeutic target for the treatment and prevention of EC.

Signaling pathways coordinate communication to enable cells to respond to intracellular or extracellular stimuli. There are many different signaling pathways that contribute to development and cellular homeostasis [42‐44]. In diseases, especially cancer, aberrant signaling has been identified as a key mechanism of cancer progression and metastasis [45]. Growing evidence suggests that the MIR22HG-mediated dysregulation of signaling pathways is central to many different types of cancer (Fig. 3).

Another common mechanism by which lncRNAs mediate their functions is through interactions with proteins. LncRNAs can function as protein decoys to recruit or sequester proteins or act as scaffolds linking different proteins, either coordinately or in a complex [77]. LncRNA-protein interactions exert essential functions in posttranscriptional gene regulation, such as splicing, translation, and signaling, thus participating in the progression of various diseases, including cancer [78, 79].

Su et al. analyzed Seo, TCGA and UM RNA-Seq datasets and found that MIR22HG was significantly downregulated in lung adenocarcinoma (LUAD) tissues compared to normal lung tissues. In addition, a high expression level of MIR22HG was significantly correlated with favorable patient outcomes in two independently published LUAD microarray datasets: Okayama et al. (P = 0.02) and Shedden et al. (P = 0.02). The authors employed RT-qPCR to confirm that MIR22HG expression levels were significantly lower in LUAD tissues than in normal lung tissues (P < 0.001) and that low MIR22HG expression was correlated with poor patient survival (P = 0.003) in an independent UM cohort including 101 LUAD tissues and 27 normal lung tissues. MIR22HG overexpression suppresses cell proliferation and invasion and induces cell cycle arrest in non-small cell lung cancer (NSCLC) cells. Mechanistically, MIR22HG interacts with and stabilizes YBX1. The MIR22HG-YBX1 complex can bind to the promoter of MET and promote MET expression at both the mRNA and protein levels and inhibit the expression of p21, a potential target of YBX1, leading to the inhibition of proliferation and promotion of apoptosis (Fig. 4a). The dual role of p21 in the progression of cancer may depend on the cell type, p21 location and p53 status [80‐82]. Therefore, in different tumors, p21 may have divergent functions. Upregulated p21 is associated with poor survival in patients with glioma and prostate, cervical, ovarian, and esophageal cancers. However, the opposite is observed in other tumors, such as breast, gastric, and ovarian cancers [30]. In this study, the authors revealed the biological role of p21 as a potent oncogene that promotes tumor growth in NSCLC and shed light on a new therapeutic strategy for the regulatory mechanism of p21 mediated by lncRNA-protein interactions [30].

Zhang’s team measured MIR22HG levels in a 52-patient cohort by qRT-PCR (P < 0.001), analyzed TCGA and the GSE14520 cohorts (P < 0.001 for both cohorts) and revealed that MIR22HG was comparatively expressed at low levels in HCC tissues. Kaplan-Meier analysis of overall survival and disease-free survival (log-rank) in the 145-patient cohort and the TCGA cohort revealed that patients with high MIR22HG expression exhibited better overall survival (145-patient cohort: P = 0.001; TCGA cohort: P = 0.015) and disease-free survival (145-patient cohort: P = 0.042; TCGA cohort: P = 0.003) than those with low MIR22HG expression. Functionally, biological studies have revealed that the overexpression of MIR22HG dramatically inhibits cell proliferation, migration and invasion in vitro. Moreover, the overexpression of MIR22HG significantly inhibits tumor growth and metastasis in vivo according to mouse subcutaneous xenograft models and a lung metastasis mouse model. Conversely, the silencing of MIR22HG promotes cell proliferation both in vitro and in vivo. Mechanistically, MIR22HG can interact with the human antigen R (HuR) protein, an RNA-binding protein positively associated with malignant aggressiveness [83‐85]. This lncRNA-protein interaction increases MIR22HG stability and regulates the subcellular localization of HuR, resulting in the decreased expression of HuR-stabilized oncogenes such as β-catenin, CCNB1 (encoding cyclin B1), HIF1A (encoding hypoxia-inducible factor-1α), BCL2 (encoding apoptosis regulator Bcl2), COX2 (encoding cyclooxygenase COX2), and C-FOS (encoding the nuclear phospho-protein c-Fos) and thereby inhibiting the proliferation, invasion and migration of HCC (Fig. 4b). Importantly, their investigation may help identify potential biomarkers that can improve the diagnosis and treatment of HCC [24].

The regulatory relationship between miRNAs and their host genes provides another mechanism for lncRNA-mediated gene expression. A previous study described MIR22HG as a host gene of miR-22 [86]. Two independent studies examined whether MIR22HG functions as the host gene of miR-22 in cancer progression (Fig. 5). Han et al. revealed that the expression of MIR22HG was higher in glioblastoma (GBM) and glioma stem-like cells than in normal neural stem cells and that increased MIR22HG was correlated with poor overall survival (P < 0.0001) in an analysis of a TCGA dataset. Silencing MIR22HG inhibited GBM cell proliferation and invasion in vitro. In vivo studies in which mouse subcutaneous xenograft and brain orthotopic xenograft models were used have revealed that MIR22HG inhibits tumor growth and metastasis. A mechanistic analysis revealed that MIR22HG, as a host gene of miR-22, is strongly associated with the expression of miR-22-3p and miR-22-5p. Rescue experiments showed that the overexpression of miR-22 is sufficient to restore the MIR22HG depletion-induced inhibition of GBM cell proliferation and invasion. Silencing MIR22HG resulted in the loss of miR-22-3p and miR-22-5p, which upregulated the expression of their direct targets SFRP2 and PCDH15, leading to the inhibition of GBM progression. AC1L6JTK, a specific small-molecule inhibitor, efficiently suppresses tumor growth in vivo by blocking the processing of pre-miR-22 into mature miR-22. These data indicate that the interplay between miR-22 and its host gene MIR22HG might be a potential target for patients with GBM through pharmacological blockade [31] (Fig. 5a). Another independent study confirmed the important role of this interaction in cancer. In addition to its interaction with HuR, Zhang et al. also found that increased MIR22HG could markedly upregulate miR-22-3p expression levels. Additionally, MIR22HG drives miR-22-3p to target HMGB1, leading to the deactivation of HMGB1 signaling. These data demonstrate that miR-22-3p and its host gene MIR22HG are coexpressed and functionally coordinated in HCC [24] (Fig. 5b).