Open Access

Long non‑coding RNA MIR22HG inhibits glioma progression by downregulating microRNA‑9/CPEB3

  • Authors:
    • Yanli He
    • Haiyan Nan
    • Linfeng Yan
    • Tao Ma
    • Minghao Man
    • Bo Tian
    • Shaochun Guo
    • Xingye Zhang
  • View Affiliations

  • Published online on: December 31, 2020     https://doi.org/10.3892/ol.2020.12418
  • Article Number: 157
  • Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Glioma is one of the most common and aggressive malignant intracranial tumors worldwide. Recently, non‑coding RNAs have been found to play critical roles in the development of glioma. However, the exact mechanisms have not been fully elucidated. In the present study, reverse transcription‑quantitative PCR was used to determine the expression level of the long non‑coding RNA MIR22HG and microRNA (miR)‑9, while western blot analysis was used to detect the protein expression level of CPEB3. The potential binding sites were predicted using the StarBase v2.0 online tool and the hypothesis was verified using a luciferase reporter assay. A Cell Counting Kit‑8 assay was used to assess cell viability, while wound healing and Matrigel assays were used to determine the migration and invasion ability of glioma cancer cells. The results showed that MIR22HG expression level was decreased but miR‑9 expression level was elevated in glioma tissues and cell lines. Furthermore, MIR22HG was found to sponge miR‑9, while CPEB3 was the direct target of miR‑9 in the glioma cell line. Functionally, MIR22HG regulated the proliferation, invasion and migration of the glioma cell line by targeting miR‑9. CPEB3 may be involved in the progression of the glioma cell line. Taken together, these findings confirmed that MIR22HG suppressed glioma development by inhibiting the miR‑9/CPEB3 axis and provides a novel therapeutic strategy for glioma treatment.

Introduction

Glioma is one of the most aggressive and common malignant intracranial tumors (13) and is characterized by a high invasive ability and a high lethality rate. In 2014, 56,000 patients died as a result of glioma in China (46). According to the morphological characteristics of glioma, it can be classified as either astrocytoma, glioblastoma, oligodendroglioma, mixed oligoastrocytomas or ependymoma (7). Despite the development of active therapies (including surgery, radiotherapy, and chemotherapy), the prognosis of patients with glioma is still poor (8). A previous study reported that the median survival time for patients with high-grade glioma does not exceed 15 months (9). Therefore, elucidating the underlying mechanism of glioma pathogenesis is beneficial for diagnosis and treatment.

Long non-coding (lnc)RNAs are defined as a group of RNAs, with a total length of >200 nucleotides and a lack of protein-coding ability (10). lncRNAs, as tumor suppressor genes or oncogenes, play essential roles in vital cell functions, such as cell growth, proliferation, and invasion (11,12). Currently, increasing evidence suggests that lncRNAs function as competitive endogenous RNAs in cancer progression by sponging and inhibiting the expression of microRNAs (miRNA/miR) (13). For example, the lncRNA MIR503HG inhibited cell migration and invasion by sponging miR-103 in triple-negative breast cancer (14), while the lncRNA MEG3 repressed cell growth in glioma by modulating the expression level of miR-96-5p (15). For colorectal cancer (CRC), the lncRNA MFI2-AS1 facilitated CRC cell proliferation, migration and invasion by sponging miR-574-5p (16).

The lncRNA MIR22HG is located in the 17p13.3 region; it primarily exists in the cytoplasm and is frequently hypermethylated and degraded (17). It has been hypothesized that the lncRNA MIR22HG could be involved in the development and progression of different types of tumor, including hepatocellular carcinoma (18). Previous research has shown that the lncRNA MIR22HG contributed to the inhibition of gastric cancer by attenuating NOTCH2 signaling (19). In endometrial carcinoma, the apoptosis of endometrial carcinoma cells was strengthened by MIR22HG, which negatively regulated miR-141-3p and enhanced death-associated protein kinase 1 protein expression (20). In addition, the lncRNA MIR22HG plays a tumor suppressor role in lung cancer by downregulating the oncogenes, Y-box binding protein 1, MET proto-oncogene receptor tyrosine kinase, and p21 (21).

The cytoplasmic polyadenylation element-binding protein (CPEB) family includes RNA-binding proteins that mediate translation through cytoplasmic polyadenylation (22,23). The CPEB family typically consists of four members, CPEB-1, −2, −3 and −4 in vertebrates (24). CPEB3 primarily exists in the cytoplasm and plays a vital role in synaptic plasticity and memory (25,26). In recent years, it has been reported that CPEB3 participates in regulating various types of cancer (27,28). In CRC, the lncRNA SUMO1P3 induced cell proliferation and the cell cycle, and restricted apoptosis by epigenetically silencing CPEB3 (29).

Recently, the upregulation of CPEB3 was found to inhibit cell proliferation and growth in a glioma cell line (30). Furthermore, miR-9 was found to be a positive regulator in glioma tumorigenesis and angiogenesis (31). However, the association between miR-9 and CPEB3 is unclear. In addition, previous findings indicated that the lncRNA MIR22HG participated in the development of a variety of different cancers including prostate cancer, colorectal cancer and glioma (3234). However, the exact role and detailed mechanism of the lncRNA MIR22HG in the development of glioma is unclear.

In the present study, we aimed to explore the expression of lncRNA MIR22HG, miR-9 and CPEB3. We tried to investigate the effect of MIR22HG in the progression of glioma and elucidate the underlying molecular. Our study intended to uncover the molecular pathological mechanism and provided potential therapeutic targets for glioma.

Materials and methods

Clinical specimens

All tissues, including 25 human glioma tissues and 15 normal brain tissues (tissues from patients with traumatic brain injury) were obtained from patients who underwent surgical excision at the Neurosurgery Department of Tangdu Hospital from January 2017 to January 2018. The mean ages of the patients with glioma and control patients were 48.5 and 46.8 years, respectively. Patients with glioma composed of 14 males and 11 females. The control patients composed of eight males and 7 females. All tissue samples were pathologically evaluated by senior pathologist according to the fourth edition of the World Health Organization classification of tumors of the central nervous system (2016) (35) and stored in liquid nitrogen at −80°C. The study protocol was approved by the Ethical Committee of Tangdu Hospital of the Fourth Military Medical University, and written informed consent was provided from all the patients.

Cell culture

The human glioma cell lines U251 (TCHu 58), U87 (TCHu138; glioblastoma of unknown origin) and the HA1800 normal human astrocyte cell line (JNO171-101) were purchased from the Cell Resource Center of the Shanghai Institute of Biological Sciences. To confirm the identity of the cells over long culture periods, the U87 cell line was genotyped using short tandem repeat analysis and the cells were confirmed to be the U87MG cell line from American Type Culture Collection. All the cell lines were cultured in DMEM, supplemented with 10% FBS and 100 U/ml penicillin/streptomycin at 37°C in a humidified incubator with 5% CO2.

Starbase and TargetScan analysis

The relationship between MIR22HG and miR-9 was analyzed using online software Starbase (http://starbase.sysu.edu.cn/). The miRNA-LncRNA tool was utilized to analyze the relationship. The target miRNA was miR-9 and the predicted lncRNAs were listed in the software. Similarly, the relationship between miR-9 and CPEB3 was also analyzed using TargetScan (http://www.targetscan.org/mamm_31/). The method we used was miRNA- tool and the target miRNA was also miR-9.

Reverse transcription-quantitative PCR (RT-qPCR)

Total RNA from glioma tissues or cell lines was extracted using TRIzol® (Invitrogen; Thermo Fisher Scientific, Inc.). The isolated RNA was reverse transcribed into complementary dNA using a PrimeScript™ RT master mix (Takara Biotechnology, Inc.) and TaqMan advanced miRNA assay kit (Thermo Fisher Scientific, Inc.) at 42°C for 15 min. A 20-µl reaction system was used: 0.5 µl Sense and antisense primers, 50 ng RT product and 10 µl 2X SYBR TransStar Green PCR Super mix (cat. no. B21202; http://www.bimake.com/product/sybr-green-qpcr-master-mix.html) in an IQ™ 5 Real-Time PCR Detection system (Bio-Rad Laboratories, Inc.). The thermocycling conditions were: 95°C For 4 min for denaturation, followed by 40 cycles for 23 sec, and annealing for 28 sec at 60°C and extension at 72°C for 35 sec. miR-103 and GAPDH served as normalizing controls and the 2−ΔΔCq method was used for quantification (36,37). The sequences of the primers were as follows: MIR22HG forward, 5′-CGGACGCAGTGATTTGCT-3′ and reverse, 5′-GCTTTAGCTGGGTCAGGACA-3′; miR-9 forward, 5′-GAGGCCCGTTTCTCTCTTTG-3′ and reverse, 5′-AGCTTTATGACGGCTCTGTG-3′; CPEB3 forward, 5′-TCAACACAACGACATTGACAAA-3′ and reverse, 5′-CCCTGACACTCGTCACACAT-3′; GAPDH forward, 5′-AAATCCCATCACCATCTTCCAG-3′ and reverse, 5′-TGATGACCCTTTTGGCTCCC-3′; miR-103 forward, 5′-GCCGAGCTGCCTTGTGGAATC-3′ and reverse, 5′-CTGCCTTGTGGAATCACAT-3′.

Cell transfection

The pcDNA3 empty vector and pcDNA3-MIR22HG overexpression vector, and the miR-9 mimic and negative control (NC) mimic were constructed by Shanghai GenePharma, Co., Ltd.. The cells were transfected with 3 µg control or overexpression vector in one well of 6-well plate. The working concentration of miR-9 mimic was 50 nM. Then, according to the manufacturer's instructions, the U87 and U251 cell lines were transfected with the pcDNA3 empty vector, pcDNA3-MIR22HG, miR-9 mimic, or NC mimic using Lipofectamine® 2000 (Invitrogen; Thermo Fisher Scientific, Inc.). After transfection for 48 h, the cells were used for subsequent experiments.

Luciferase reporter assay

The luciferase reporter assay was used to determine the association between miR-9 and MIR22HG, and CPEB3. Wild-type (WT) and mutant (MUT) MIR22HG or CPEB3 3′-untranslated region sequences were inserted into the pmirGLO luciferase reporter vectors (Promega Corporation) to construct a luciferase reporter vector. In total, 50 ng WT and MUT luciferase vectors or 50 nM miR-9 mimic were transfected into U87 or U251 cells using Lipofectamine® 2000 (Invitrogen; Thermo Fisher Scientific, Inc.) for 20 min at room temperature. After 48 h, the luciferase activities were detected using a dual-luciferase reporter assay kit (Promega Corporation). The firefly luciferase was normalized using Renilla luciferase as the internal control.

Western blot assay

The collected cells was lysed in the RIPA lysis buffer (Beyotime Institute of Biotechnology) on the ice for 30 min. Total protein was extracted from the glioma cell lines and the protein concentration was determined using a BCA protein concentration kit (Beyotime Institute of Biotechnology). Then, 20 µg protein was separated per lane using 10% SDS-PAGE and transferred to PVDF membranes (EMD Millipore). Following which, the PVDF membranes were blocked with 5% skimmed milk for 2 h, at room temperature, then incubated with anti-CPEB3 (cat. no. ab10883, 1:1,000 dilution) and β-actin antibodies (cat. no. ab8226, 1:2,000 dilution both from Abcam,) overnight at 4°C. The membranes were washed with TBST for 5 min three times at room temperature. After washing with 1X TBST, the membranes were then incubated with HRP-conjugated goat anti-rabbit IgG H&L (cat. no. as014) or goat anti-mouse IgG H&L secondary antibodies (cat. no. as003; 1:5,000) (both ABclonal Biotech Co., Ltd.) for 2 h at room temperature. The signals were visualized using an enhanced chemiluminescence kit (EMD Millipore).

Cell Counting Kit-8 (CCK-8) assay

The kit was used according the instruction of the manufacturer. U87 and U251 cells transfected with MIR22HG or/and miR-9 were seeded in a 96-well plate, at a density of 5,000 cells/well. In total, 10 µl CCK-8 solution (Beyotime Institute of Biotechnology) was added to each well according to the manufacturer's instructions. The absorbance was examined at 450 nm in Multiskan™ FC microplate reader with Skan It software 2.4.2 (both Thermo Fisher Scientific, Inc.).

Matrigel assay

The diluted Matrigel was used to cover the upper chamber of the Transwell inserts for 5 h at 37°C. Then, 200 µl serum-free medium containing 3×104 U87 or U251 cells was added into the upper chamber of the Transwell inserts, while 500 µl 10% FBS-containing complete medium was added to the lower chamber. The cells were incubated for 24 h (at 37°C in a humidified incubator with 5% CO2,). After 24 h, the cells were fixed with 4% paraformaldehyde for 0.5 h at room temperature, then stained with crystal violet staining solution for 0.5 h at room temperature. The number of stained cells in five random fields of view was counted using a light phase contrast microscope with ×10 magnification.

Wound healing assay

The U87 and U251 cell lines were plated in a 6-well plate until they had reached 90% confluence. The glioma cells were scraped using a 20-µl pipette tip to generate a wound. Then, the cells were washed three times with PBS and cultured with serum-free culture medium for 24 h. Cell migration was observed using a light phase contrast microscope at ×10 magnification. Images were captured and analyzed with FL Color Cell Imaging systems version 1.4. (Thermo Fisher Scientific, Inc.).

Statistical analysis

An unpaired Student's t-test was used to analyze differences between two groups, while one-way ANOVA followed by Tukey's post hoc test to determine the differences between three or more groups. SPSS v19.0 (SPSS, Inc.) was used for the analysis. The data are presented as the mean ± SEM of at least three different experiments. P<0.05 was considered to indicate a statistically significant difference.

Results

MIR22HG is downregulated and miR-9 is increased in human glioma tissues and glioma cell lines

To determine the role of MIR22HG in human glioma tissues, the expression level of MIR22HG was measured using RT-qPCR and the results showed that the expression level of MIR22HG significantly decreased in human glioma tissues compared with that in adjacent normal tissues (Fig. 1A). However, the expression level of miR-9 was increased in human glioma tissues, which suggested that MIR22HG may be associated with miR-9 (Fig. 1B). Therefore there may be a regulatory relationship between them. Furthermore, the expression level of MIR22HG and miR-9 in the glioma cell lines was also detected using RT-qPCR and the results showed that the expression level of MIR22HG was decreased in the glioma cell lines compared with that in the normal human astrocytes (Fig. 1C). Conversely, miR-9 expression level was also increased in the glioma cell lines compared with that in the normal cell lines (Fig. 1D).

MIR22HG sponges miR-9 in the glioma cell lines

Previous studies have confirmed that lncRNAs could act as sponges to regulate miRNAs (3840). It was found that MIR22HG contained a potential binding site for miR-9 using the bioinformatics database StarBase v2.0 (Fig. 2A). To further investigate whether MIR22HG could directly bind to miR-9 in the glioma cell lines, the U251 or U87 cells were co-transfected with miR-9 mimic and WT or MUT MIR22HG. The effect of miR-9 mimic in the U87 and U251 cells was confirmed (Fig. S1A and B). Then, the luciferase activity of the cells was detected. The results indicated that the luciferase activity was significantly reduced when U87 or U251 cells were transfected with the miR-9 mimic and MIR22HG-WT. In contrast, the luciferase activity did not significantly change when U87 or U251 cells were transfected with the miR-9 mimic and MIR22HG-MUT (Fig. 2B and C). These results verified that miR-9 was a direct target of MIR22HG. Furthermore, MIR22HG was overexpressed in the U87 and U251 cell lines and the expression level of miR-9 was detected using RT-qPCR. The results confirmed that MIR22HG was increased when transfected with pcDNA-MIR22HG (Fig. S1C and D). Furthermore, upregulating MIR22HG expression suppressed the expression level of miR-9 in the glioma cell lines (Fig. 2D).

CPEB3 is the target molecule of miR-9 in the glioma cell lines

The present study revealed that miR-9 is the direct target of MIR22HG in the glioma cell lines; however, the potential regulatory mechanisms remain unclear. The target gene of miR-9 was predicted using bioinformatics tools (TargetScan) (Fig. 3A). CPEB3 was identified as the downstream target of miR-9. The luciferase reporter assay showed that the luciferase activity was significantly decreased in CPEB3-WT, while there was no significant difference for CPEB3-MUT (Fig. 3B and C). Then, the mRNA and protein expression levels of CPEB3 were determined using RT-qPCR and western blot analysis, respectively. Transfection with MIR22HG overexpression vector increased the mRNA and protein expression level of CPEB3, while the mRNA and protein expression levels of CPEB3 was reduced when the U87 and U251 cell lines were co-transfected with miR-9 mimic and MIR22HG overexpression vector (Fig. 3D and E). In summary, CPEB3 was a direct target of miR-9, and MIR22HG regulated the expression of CPEB3 via miR-9.

MIR22HG regulates the proliferation, invasion and migration of the glioma cells through miR-9

It has been reported that MIR22HG is a tumor suppressor in a variety of different cancer types (33,41,42). However, the role of MIR22HG in glioma is unknown. To investigate the function of MIR22HG in the glioma cell lines, MIR22HG overexpressing vector was transfected into the cell lines with or without miR-9 mimic. The CCK-8 assay showed that upregulated MIR22HG expression restricted glioma cell proliferation, but the miR-9 mimic reversed the inhibitory effects of MIR22HG overexpression (Fig. 4A and B). In addition, the overexpression of MIR22HG repressed glioma cell migration and invasion and the effects were abrogated by transfection with the miR-9 mimic (Fig. 4C-I). In summary, the aforementioned data suggested that MIR22HG regulated the proliferation, invasion and migration of glioma cells through miR-9.

Discussion

Glioma is a malignant brain tumor with high incidence rates, that can immensely impair public health (43). Despite improvements in glioma therapy, the 5-year survival rate of patients is <6% in 2016 (44). Therefore, clarifying the detailed molecular mechanisms of glioma would assist with discovering novel therapeutic targets. As showed in Fig. 5, it was found that MIR22HG expression level was decreased while miR-9 expression level was increased in glioma tissues and cell lines. Then, MIR22HG was proven to directly bind to and negatively regulate miR-9 in the glioma cell lines. Furthermore, it was found that CPEB3 was the target molecule of miR-9. Functionally, MIR22HG negatively regulated glioma cell proliferation, invasion and migration by modulating the miR-9/CPEB3 axis.

In the present study, we identified that MIR22HG expression level was significantly decreased in human glioma tissues compared with that in adjacent normal tissues. In contrast, the expression level of miR-9 was increased. It has been reported that the lncRNA MIR22HG functions as an antioncogene (45) and the expression level was decreased in multiple types of cancer. For example, the expression level of the lncRNA MIR22HG was decreased in lung cancer tissues, and was associated with poor patient survival (21). In thyroid cancer, decreased MIR22HG expression level was associated with the degree of malignancy of tumors, which indicated that MIR22HG could be a new diagnostic marker for thyroid cancer (46). miR-9 has been found to be an oncogene or a tumor suppressor in several types of cancer. In prostate cancer cell lines, miR-9 inhibitor transfection could suppress cell proliferation, invasion and migration (47). Furthermore, a previous research showed that miR-9 expression level was increased in glioma tissues and cell lines (48).

Then, the association between MIR22HG and miR-9 was investigated. The bioinformatics database StarBase v2.0 showed that MIR22HG contained a potential binding site for miR-9. A luciferase reporter assay was used to confirm that MIR22HG directly regulated miR-9 in the glioma cell lines. Next, we investigated the target gene of miR-9 using TargetScan. CPEB3 was found to be the downstream target of miR-9 and the luciferase activity confirmed that CPEB3 was the target molecule of miR-9 in the glioma cell lines. Moreover, MIR22HG was proved to regulate the and protein expression level of CPEB3 via miR-9. CPEB3, a member of the CPEB family, was discovered to monitor cell translation by adjusting cytoplasmic polyadenylation. It has also been reported that CPEB3 was aberrantly expressed in several types of cancer (23,30,49). In a study of ovarian cancer cells, miR-301b-3p increased cell invasion and migration by targeting CPEB3 (50). In addition, CPEB3 plays a crucial role in glioma pathogenesis. The protein level of CPEB3 was increased by the lncRNA HCG11, which inhibited glioma cell proliferation and arrested the cell cycle (30). Thus, MIR22HG and miR-9 may regulate the development of glioma via targeting CPEB3.

However, the effect of MIR22HG in glioma remains unclear. To investigate the effect of MIR22HG in the glioma cell lines, a CCK-8 assay was used to measure cell proliferation. The results showed that upregulated MIR22HG expression restricted glioma cell proliferation, but miR-9 mimic reversed the inhibitory effects of MIR22HG. In addition, the overexpression of MIR22HG reduced cell migration and invasion. The MIR22HG-induced effects were abrogated by transfection with miR-9 mimic. It has been demonstrated that MIR22HG interacts with multiple signaling pathways and affects the progression of multiple tumors, including thyroid cancer, gastric cancer, and hepatocellular carcinoma (19,46,51). The results from the present study indicated that MIR22HG inhibited the progression of glioma via negatively modulating the downstream target miR-9.

MIR22HG was decreased in glioma tissue and cell lines in the present study, and that the miR-9/CPEB3 axis was the downstream pathway. However, little is known how MIR22HG expression level is reduced in glioma. Circular (circ)RNAs have been reported to regulate the expression of lncRNAs and function as a diagnostic or prognostic biomarker in laryngeal squamous cell carcinoma and bladder cancer (52,53). In glioma, it is unknown whether MIR22HG is modulated by circRNAs, and it also remains unknown which circRNA directly regulates MIR22HG. This will be investigated in future studies.

In summary, it was found that MIR22HG expression level and CPEB3 were reduced while miR-9 expression level was increased in glioma tissues and cell lines. Then, MIR22HG was found to negatively modulate miR-9 in the glioma cell lines. In addition, CPEB3 was proven to be the target molecule of miR-9 in the glioma cell lines. In addition, upregulated MIR22HG expression level inhibited the proliferation, invasion and migration of glioma cells by inhibiting miR-9 expression level. The present study indicated that MIR22HG regulated the proliferation, invasion and migration of glioma cells through miR-9 and that CPEB3 is involved in this mechanism.

Supplementary Material

Supporting Data

Acknowledgements

Not applicable.

Funding

This study was supported by National Natural Science Foundation Project (grant no. 81571656).

Availability of data and materials

All the data generated and/or analyzed during the present study are included in this published article.

Author's contributions

XZ and YH conceived and designed the experiments. YH, HN, LY, TM, MM, BT and SG performed the experiments. YH, HN and LY collected and analyzed the data. XZ and YH interpreted the results and wrote the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

This study was performed in accordance with standard guide-lines and was approved by the Ethics Committee of The Second Affiliated Hospital of the Fourth Military Medical University. All patients provided written informed consent prior to the study.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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February-2021
Volume 21 Issue 2

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Spandidos Publications style
He Y, Nan H, Yan L, Ma T, Man M, Tian B, Guo S and Zhang X: Long non‑coding RNA MIR22HG inhibits glioma progression by downregulating microRNA‑9/CPEB3. Oncol Lett 21: 157, 2021
APA
He, Y., Nan, H., Yan, L., Ma, T., Man, M., Tian, B. ... Zhang, X. (2021). Long non‑coding RNA MIR22HG inhibits glioma progression by downregulating microRNA‑9/CPEB3. Oncology Letters, 21, 157. https://doi.org/10.3892/ol.2020.12418
MLA
He, Y., Nan, H., Yan, L., Ma, T., Man, M., Tian, B., Guo, S., Zhang, X."Long non‑coding RNA MIR22HG inhibits glioma progression by downregulating microRNA‑9/CPEB3". Oncology Letters 21.2 (2021): 157.
Chicago
He, Y., Nan, H., Yan, L., Ma, T., Man, M., Tian, B., Guo, S., Zhang, X."Long non‑coding RNA MIR22HG inhibits glioma progression by downregulating microRNA‑9/CPEB3". Oncology Letters 21, no. 2 (2021): 157. https://doi.org/10.3892/ol.2020.12418