A concise review on the role of MIR100HG in human disorders

Abstract MIR100HG is a long non‐coding RNA (lncRNA) encoded by a locus on chr11:122,028,203‐122,556,721. This gene can regulate cell proliferation, apoptosis, cell cycle transition and cell differentiation. MIR100HG was firstly identified through a transcriptome analysis and found to regulate differentiation of human neural stem cells. It is functionally related with a number of signalling pathways such as TGF‐β, Wnt, Hippo and ERK/MAPK signalling pathways. Dysregulation of MIR100HG has been detected in a diversity of cancers in association with clinical outcomes. Moreover, it has a role in the pathophysiology of dilated cardiomyopathy, intervertebral disk degeneration and pulmonary fibrosis. The current study summarizes the role of these lncRNAs in human disorders.


| INTRODUC TI ON
Long noncoding RNAs (lncRNAs) are transcripts with sizes more than 200 nucleotides that do not encode proteins. These transcripts play critical regulatory role in numerous biological events through various mechanisms, including regulation of chromatin structure, interaction with other RNA molecules, sequestering miRNAs and serving as scaffolds for establishment of protein complexes. 1 Genes encoding lncRNAs can be categorized according to their relation with other genes in the genome. MicroRNA-host-gene-derived lncRNAs (MIRHGs) are a group of lncRNAs derived from miRNA host genes as a result of pre-miRNA processing. 2 About 17% of miRNAs are estimated to be produced by MIRHGs. 3 The processing of MIRHGs is functionally related with synthesis of the encoded miRNAs. Notably, MIRHGs have been shown to play important functions in fundamental cellular events and pathogenesis of diseases. 2 The molecular crosstalk between lncRNAs and miRNAs plays a fundamental role in the development of a number of diseases mainly through lncRNA/miRNA sponging mechanisms. The sponging effect of lncRNAs on miRNAs attenuates the repression of mRNAs by miRNAs. 4 These effects have been best studied in cancer where lncRNA-miRNA axes regulate apoptosis and autophagy. Moreover, these axes influence tumour metastases through regulation of epithelial-mesenchymal transition (EMT) and expression of matrix metalloproteinase. 5 MIR100HG, alternatively named as Mir-100-Let-7a-2-Mir-125b-1 Cluster Host Gene, is encoded by a gene located on chr11:122,028,203-122,556,721 ( Figure 1). The gene encoding this lncRNA has 17 exons. The intronic coding region in this lncRNA has a role as a pro-apoptotic element. This role is exerted through influencing the caspase-dependent mitochondrial apoptotic axis. 6 Alternative splicing events can give rise to more than 100 transcripts for MIR100HG with sizes ranging from 242 to 7061 bp. 7 The main locus of MIR100HG is the nucleus with also being detected in the cytoplasm. 8 This gene produces lncRNAs that regulate cell proliferation.
MIR100HG was firstly identified through a transcriptome analysis 9 and found to be a crucial regulator of differentiation of human neural stem cells. 10 Several transcript variants are produced from this gene through alternative promoter usage and splicing. Notably, some of these variants have a role in promotion of cell growth, while others are negative regulators of cell division.
A number of spliced and stable lncRNAs that are produced by MIR100HG exhibit up-regulation during the G1 phase of the cell cycle. It has been shown that depletion of these lncRNAs in human cells leads to abnormalities in the progression of cell cycle without changing the expression amounts of MIR100HG-encoded miRNAs.

F I G U R E 1
The schematic diagram represented the chromosomal location of the MIR100HG, which is encoded by a gene located on chromosome 11q24.1. From the NCBI database (http://www.ncbi.nlm.nih.gov/gene/399959), the genomic context of the MIR100HG was extracted.
The absence of significant alterations in the expression of mature MIR100HG-encoded miRNAs during the cell cycle might be explained by their enhanced stability. However, the nuclear-restricted MIR100HG has a dynamic expression pattern and differential stability during the cell cycle. These findings indicate MIR100HGencoded lncRNAs might contribute in cell cycle progression. 11 Functional studies have shown interaction between MIR100HG and HuR/ELAVL1 as well as numerous HuR-target transcripts. 11 The current study summarizes the role of these lncRNAs in human disorders.

| Cell line studies
MIR100HG has been shown to be over-expressed in acute megakaryoblastic leukaemia (AMKL) blasts. MIR100HG transcripts are principally localized in the nucleus parallel with miRNA cluster.
MIR100HG silencing has obstructed leukaemic growth of AMKL cell lines. This study has indicated the role of MIR100HG in the haematopoiesis and its oncogenic effect in the evolution of myeloid leukaemia. 12 In order to evaluate function of MIR100HG in AMKL, this lncRNA has been down-regulated in a human cell line derived from this type of malignancy (M-07e) using antisense LNA GapmeRs. This study have indicated that suppression of MIR100HG can inhibit proliferation of M-07e cells, induce apoptosis and necrosis and enhance expression of TGFβ. 13 An experiment in bladder cancer cells has shown that up- Besides, forced over-expression of β-catenin has led to lessening of the enrichment of H3K27Ac on this promoter. Besides, HDAC6 recruitment on the MIR100HG promoter has led to reduction of H3K27Ac enrichment through a β-catenin-dependent route. Upregulation of MIR100HG has led to G0-G1 arrest and suppression of cell proliferation through increasing p57 levels. Cumulatively, ectopic β-catenin can repress transcription of MIR100HG via HDAC6mediated histone modifications. 15 Another study in colorectal cancer cells has shown that the interplay between MIR100HG and hnRNPA2B1 can increase m (6)A-dependent stability of TCF7L2 transcripts and facilitate progression of colorectal cancer. 16 In the context of gastric cancer, CXXC finger protein 4 has been shown to inhibit the CDK18-ERK1/2 axis to inhibit the immune escape through modulation of ELK1/MIR100HG pathway. 17 MIR100HG silencing has been shown to attenuate progression of hepatocellular carcinoma through modulation of miR-146b-5p/ CBX6 axis. 18 In laryngeal squamous cell carcinoma, MIR100HG exerts its oncogenic effects via down-regulating expression of miR-204-5p. 19 In osteosarcoma cells, expression of MIR100HG has been shown to be induced by ELK1. This lncRNA enhances progression of osteosarcoma through decreasing expressions of LATS1 and LATS2 via epigenetical mechanisms. 20 MIR100HG expression has been found to be induced by TGFβ in different cancer types. MIR100HG silencing has decreased activity of TGFβ signalling and reduced expression of TGFβ-target genes.
Besides, MIR100HG silencing has suppressed motility of both normal and cancer cells and increased the cytotoxic effects of cytostatic drugs. 21 Table 1 shows the impact of MIR100HG in the cancer cell lines.

| Animal studies
While a single animal study has shown that up-regulation of MIR100HG reduces growth of colorectal cancer cells in nude mice, 15 another in vivo animal study has revealed that upregulation of MIR100HG can promote migration and invasion of colorectal carcinoma and development of liver metastasis in mice. 23 Consistent with the latter study, MIR100HG silencing in colorectal cancer cells has reduced lung metastases and enhanced survival of animals in another in vivo study. 16 (Table 2).

TA B L E 1 (Continued)
not in adjacent non-cancerous tissues. 19 Table 3 reviews the role of MIR100HG in carcinogenesis based on the results of expression assays in clinical samples.

| Non-malignant disorders
MIR100HG has been shown to be a crucial regulator of differentiation of human neural stem cells. 10 It is involved in the pathology of bipolar disorder. LncRNA-mRNA co-expression network analysis has shown that MIR100HG is a driver gene of key modules in this disorder. 35 Moreover, it has been among m6A-methylated lncRNAs whose down-regulation might be involved in the development of neural tube defect. 36 MIR100HG has also been found to exert a role in the pathophysiology of dilated cardiomyopathy, intervertebral disk degeneration and pulmonary fibrosis (Table 4) has been found to be over-expressed in bleomycin-induced lung fibrogenesis and TGF-β1-stimulated MLE 12 cells. This lncRNA can affect TGF-β1-associated fibrotic alterations in type II alveolar epithelial cells and, therefore, can be a target for treatment of pulmonary fibrosis. 37 The role MIR100HG in the pathogenesis of dilated cardiomyopathy has been indicated by a microarray study of lncRNA profiles.
MIR100HG has been among eight hub lncRNAs in this module.
Being located in the cytoplasm, MIR100HG has been predicted to act as a competing endogenous RNA. 38 MIR100HG has also been among important lncRNAs that are linked with oxidative stress in the contetx of intervertebral disc degeneration. 39

| DISCUSS ION
MIR100HG is a miRNA host gene whose roles in the development of diverse disorders, principally cancers, are being clarified.  ↓stimulating effect of TGF-β1 on DNA synthesis and migration, ↓TGF-β1-induced changes (TGF-β1-associated alterations: ↑ α-SMA, collagen I, vimentin and ↓E-cadherin) 37 F I G U R E 3 Schematic illustration representing the up-regulation of MIR100HG in mouse type II alveolar epithelial cells triggered by TGF-1 and bleomycin (BLM)-induced pulmonary fibrosis, respectively. MIR100HG, which functions as a sponge for miR-29a-3p, has been shown to have an effect on the expression of TGF-activated kinase 1/MAP3K7 binding protein 1 (TAB1) and cause fibrogenesis.

FU N D I N G I N FO R M ATI O N
Not applicable.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare they have no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Not applicable.