MicroRNA-379 inhibits cell proliferation and invasion in glioma via targeting metadherin and regulating PTEN/AKT pathway

Retraction in: /10.3892/mmr.2022.12853

  • Authors:
    • Li Li
    • Hongqi Zhang
  • View Affiliations

  • Published online on: December 27, 2017     https://doi.org/10.3892/mmr.2017.8361
  • Pages: 4049-4056
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Abstract

Numerous microRNAs (miRNAs) are aberrantly expressed in glioma, and implicated in glioma occurrence and development. Therefore, the development of miRNAs as potential therapeutic targets for the treatment of patients with glioma has been proposed. miR‑379 has been shown to be aberrantly expressed in the progression of malignant tumours. However, the expression, biological functions and mechanism of miR‑379 in glioma are yet to be fully understood. Hence, the present study aimed to detect miR‑379 expression, investigate its functional relevance and explore its associated molecular mechanism in glioma. In this study, miR‑379 expression was significantly downregulated in glioma tissues and cell lines. Enforced miR‑379 expression markedly suppressed the cell proliferation and invasion of glioma. Metadherin (MTDH) was identified as a direct target of miR‑379 in glioma. The miR‑379 expression and MTDH mRNA levels exhibited an inverse association in glioma tissues. The restoration of the MTDH expression partially rescued the inhibitory effects of miR‑379 overexpression on glioma cell proliferation and invasion, and the upregulation of miR‑379 inhibited the activation of phosphatase and tensin homolog (PTEN)/AKT serine/threonine kinase (AKT) signaling pathway. Overall, these findings demonstrated that miR‑379 may play tumour‑suppressing roles in glioma through downregulation of MTDH and regulation of the PTEN/AKT signaling pathway, suggesting that miR‑379 might be a possible target for the treatment of patients with this malignancy.

Introduction

Glioma, the most common primary central nervous system tumour, accounts for ~80% of malignant brain tumours (1). This tumour type can be divided into four grades (I–IV) on the basis of their degree of malignancy (2). Despite remarkable improvements in treatment strategies, including surgery, chemotherapy, radiotherapy and immunotherapy, the overall survival rate of patients with glioma remains poor, with a median survival time of 9–12 months from diagnosis to death (3). The poor prognosis of patients with gliomas is mainly due to its unlimited proliferation, high tumour aggressiveness and difficulty in completing surgical excision (4,5). Undoubtedly, investigating the molecular mechanisms of glioma formation and progression is essential for the development of novel and precise therapeutic targets for patients with this disease.

MicroRNAs (miRNAs) are a large subset of single-strand and non-coding short RNAs with a length of approximately 18–24 nucleotides. They have been considered as critical regulators of gene expression through interaction with 3′-untranslated regions (3′-UTRs) of their target genes, thereby inhibiting translation or promoting degradation of the Mrna (6). Through this mechanism, miRNAs modulate >50% of all human protein-coding genes and implicated in the regulation of numerous physiological and pathological processes, including cell proliferation, cell cycle, apoptosis, differentiation and metastasis (79). However, abnormal expression of miRNAs has been observed in human malignancies, such as glioma (10), gastric cancer (11), lung cancer (12), cervical cancer (13) and bladder cancer (14). In tumourigenesis and tumour development, highly expressed miRNAs may play oncogenic roles by regulating tumour suppressor genes (15), whereas downregulated miRNAs may perform tumour-suppressing functions by directly targeting oncogenes (16). Therefore, the expression pattern, roles and associated mechanisms of miRNAs in glioma should be investigated to identify novel and efficient therapeutic methods for gliomas.

MiR-379 has been shown to be aberrantly expressed in the progression of malignant tumours (17,18). However, the expression, biological functions and mechanism of miR-379 in glioma are yet to be fully understood. Hence, this study aimed to detect miR-379 expression, investigate its functional relevance and explore its associated molecular mechanism in glioma.

Materials and methods

Tissue collection

A total of 26 pairs of glioma tissues and matched adjacent normal brain tissues were collected from patients who were undergo surgery resection at The Fourth Affiliated Hospital of Harbin Medical University between March 2014 and October 2016. All these participants were first diagnosed with glioma and had not been treated with chemotherapy, radiotherapy, or immunotherapy prior to surgery. Tissues were immediately frozen and stored in liquid nitrogen until RNA isolation. This study was approved by the Ethics Committee of The Fourth Affiliated Hospital of Harbin Medical University. Written informed consent was provided by all patients before enrollment.

Cell culture

Five human glioma cell lines (U138, U251, U343, T98 and LN229) were acquired from Chinese Academy of Sciences Cell Bank (Shanghai, China), and cultured in Dulbecco's modified Eagle medium (DMEM) containing 10% fetal bovine serum (FBS), 100 U/ml penicillin and 100 mg/ml streptomycin (all from Invitrogen, Carlsbad, CA, USA). A normal human astrocyte (NHA) cell line was purchased from ScienCell Research Laboratories (Carlsbad, CA, USA), and was grown in astrocyte medium supplemented with 1% astrocyte growth supplement (both from Sciencell Research Laboratories) and 10% FBS. All cell lines were maintained in a humidified incubator at 37°C with 5% CO2.

Cell transfection

MiR-379 mimics and miRNA mimic negative control (miR-NC) were obtained from GeneCopoeia (Guangzhou, China). Metadherin (MTDH) overexpression vector (pcDNA3.1-MTDH) and empty vector (pcDNA3.1) were chemically synthesised and their sequences confirmed by Shanghai Genechem Co., Ltd. (Shanghai, China). Cells were plated into six-well plates at a density of 5×105 cells per well and incubated at 37°C with 5% CO2 until 50% confluence was reached. Cells were transfected with miR-379 mimics, miR-NC, pcDNA3.1-MTDH or pcDNA3.1 using Lipofectamine 2000 transfection reagent (Invitrogen) following the manufacturer's instructions. The medium was subsequently replaced with fresh DMEM with 10% FBS at 8 h posttransfection.

Bioinformatic assay

The potential targets of miR-379 were predicted using the algorithms TargetScan (https://www.targetscan.org) and PicTar (http://pictar.mdc-berlin.de/).

RNA isolation and reverse transcription-quantitative polymerase chain reaction (RT-qPCR)

TRIzol Reagent (Invitrogen) was used to extract total RNA from tissues or cells. To examine miR-379 expression, reverse transcription was conducted using a TaqMan miRNA reverse transcription kit, followed by real-time PCR with a TaqMan miRNA PCR kit (both from Applied Biosystems, Foster City, CA, USA) according to the manufacturer's protocol. To quantify the mRNA expression of MTDH, cDNA was synthesised from total RNA by using a PrimeScript RT reagent kit (Takara Bio, Inc., Otsu, Japan). Quantitative PCR was also performed with SYBR® Premix Ex Taq (Takara Bio) to measure the mRNA expression of MTDH. The expression levels of miR-379 and mRNA of MTDH were normalised with U6 snRNA and GAPDH, respectively. Data were analysed using 2−ΔΔCq method (19).

Cell counting kit-8 (CCK-8) assay

CCK-8 assay (Dojindo Molecular Technologies, Inc., Kumamoto, Japan) was adopted to determine cell proliferative ability. Cells were seeded onto 96-well plates with a density of 3,000 cells per well. After overnight incubation, cell transfection or cotransfection was performed and further incubated at 37°C with 5% CO2 for 0, 1, 2 and 3 days. At each time point, CCK-8 assay was carried out according to the manufacturer's instructions. In brief, 10 µl of CCK8 reagent was added to each well and incubated at 37°C for 2 h. Afterwards, absorbance at 450 nm wavelength was detected using an automatic multi-well spectrophotometer (Bio-Rad Laboratories, Inc., Hercules, CA, USA).

Transwell invasion assay

Cellular invasion capacity was evaluated using 24-well polycarbonate membrane Transwell chambers (8 µm pore-size; Corning Inc., NY, USA) pre-coated with Matrigel (BD Biosciences, Franklin Lakes, NJ, USA). Transfected cells were collected at 48 h post-transfection and suspended in FBS-free culture medium. A total of 5×104 cells were plated in the upper chambers and the lower chambers were filled with 500 µl of DMEM containing 10% FBS. The cells were cultured at 37°C with 5% CO2 for 24 h, and non-invasive cells remaining on the upper side of the membrane were removed with a cotton swab. Invasive cells were fixed with methanol, stained with 0.1% crystal violet (Sigma, St. Louis, MO, USA) and washed with phosphate-buffered saline. Five randomly selected fields in each chamber were photographed and counted under an inverted microscope (Olympus Corp., Tokyo, Japan).

Luciferase reporter assay

The predicted 3′-UTR sequence of MTDH, containing the wild-type (Wt) or mutant (Mut) putative binding sequences for miR-379, was synthesized and inserted into the pmirGLO luciferase reporter vector (Promega Corp., Madison, WI, USA), and be named as pmirGLO-MTDH-3′-UTR Wt and pmirGLO-MTDH-3′-UTR Mut, respectively. For luciferase reporter assay, cells were plated into 24-well plates and cotransfected with miR-379 mimics or miR-NC and pmirGLO-MTDH-3′-UTR Wt or pmirGLO-MTDH-3′-UTR Mut using Lipofectamine 2000 transfection reagent. Cell lysates were harvested 48 h subsequent to transfection, and luciferase activities were detected using a Dual-Luciferase® Reporter Assay system (Promega Corp.). Renilla luciferase activity was employed as an internal control.

Western blot analysis

RIPA lysis buffer (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) was utilised to isolate total protein from tissue samples or cells. The concentration of total protein was quantified using a BCA kit (Beyotime Biotechnology, Haimen, China). Equal amounts of total protein were separated via 10% sodium dodecyl sulphate polyacrylamide gel electrophoresis and electrically transferred onto PVDF membranes (Millipore, Billerica, MA, USA). The membranes were then blocked with 5% skimmed milk at room temperature for 2 h and then incubated with primary antibodies recognizing MTDH (sc-517220), phosphatase and tensin homolog (PTEN) (sc-7974), p-AKT (sc-271966), AKT (sc-81434) or GAPDH (sc-166574) at 4°C overnight. All these primary antibodies were acquired form Santa Cruz Biotechnology. Subsequently, the membranes were probed with horseradish peroxidase-conjugated secondary antibodies (sc-2005; Santa Cruz Biotechnology) and further visualised using enhanced chemiluminescence reagents (Pierce, Rockford, IL, USA). GAPDH was used as the loading control.

Statistical analysis

All data are expressed as the mean ± SD. Statistical significance was analyzed with SPSS19.0 (IBM SPSS, Chicago, IL, USA) using Student's t-tests or one-way analysis of variance followed by the SNK multiple comparisons test. The association between MTDH mRNA and miR-379 in glioma tissues was evaluated by Spearman's correlation analysis. P<0.05was considered to indicate a statistically significant difference.

Results

MiR-379 expression is decreased in glioma tissues and cell lines

To investigate the expression pattern of miR-379 in glioma, we initially measured the miR-379 expression in 26 pairs of glioma tissues and matched adjacent normal brain tissues. The results of RT-qPCR showed that miR-379 expression was downregulated in glioma tissues compared with that in normal brain tissues (P<0.05) (Fig. 1A). Afterwards, we conducted RT-qPCR to determine the miR-379 expression in five human glioma cell lines (U138, U251, U343, T98 and LN229) and a normal NHA cell line. As shown in Fig. 1B, the miR-379 expression levels were consistently decreased in glioma cell lines compared with NHA (P<0.05). These results suggest that miR-379 may play important roles in glioma progression.

Restoration of miR-379 expression attenuates glioma cell proliferation and invasion

To explore the biological roles of miR-379 in glioma, miR-379 mimics were transfected into U251 and U343 cells, which expressed relatively lower miR-379 expression among the five glioma cell lines. RT-qPCR analysis confirmed that miR-379 was markedly upregulated in U251 and U343 cells after transfection with miR-379 mimics compared with those transfected with miR-NC (P<0.05) (Fig. 2A). Subsequently, CCK-8 assay was conducted to detect proliferation of U251 and U343 cells transfected with miR-379 mimics or miR-NC. The results showed that miR-379 upregulation prohibited the proliferation of U251 and U343 cells compared with the miR-NC group (P<0.05) (Fig. 2B). The effect of miR-379 overexpression on the cell invasion ability of U251 and U343 cells was evaluated using Transwell invasion assay. Compared with miR-NC transfected cells, U251 and U343 cells transfected with miR-379 mimics showed significantly decreased invasion capacities (P<0.05) (Fig. 2C). These results suggest that miR-379 plays tumour-suppressing roles in the progression of glioma.

MTDH is a direct target of miR-379 in glioma cells

To delineate the molecular mechanisms by which miR-379 inhibits glioma cell proliferation and invasion, we identified the targets of miR-379 in glioma. Bioinformatics analysis indicated that MTDH, which has been reported to contribute to the initiation and formation of glioma (2022), was predicted as a candidate target of miR-379 (Fig. 3A). Luciferase reporter assay was further performed to confirm whether the 3′-UTR of MTDH could be directly targeted by miR-379. MiR-379 mimics or miR-NC was transfected into U251 and U343 cells along with luciferase reporter plasmids containing Wt or Mut putative binding sequences for miR-379. As shown in Fig. 3B, miR-379 overexpression significantly decreased the luciferase activities of pmirGLO-MTDH-3′-UTR Wt (P<0.05), whereas no such inhibitory effect was observed when miR-379 mimics was cotransfected with pmirGLO-MTDH-3′-UTR Mut (P>0.05).

RT-qPCR and western blot analysis were adopted to identify how MTDH expression was altered at mRNA and protein levels upon miR-379 overexpression and to understand the regulatory effects of miR-379 on endogenous MTDH expression. The results revealed that the ectopic expression of miR-379 reduced the MTDH expression in U251 and U343 cells at mRNA (P<0.05) (Fig. 3C) and protein (P<0.05) (Fig. 3D) levels. We further measured the mRNA expression of MTDH in 26 pairs of glioma tissues and matched adjacent normal brain tissues and determined the association between the miR-379 and MTDH mRNA expression levels in glioma tissues. The RT-qPCR data indicated that the mRNA expression level of MTDH was higher in glioma tissues than in adjacent normal brain tissues (P<0.05) (Fig. 3E). Furthermore, a significant inverse association between miR-379 expression and MTDH mRNA expression was found in glioma tissues (r=−0.6408, P=0.0004) (Fig. 3F). In conclusion, MTDH may be a novel target of miR-379 in glioma.

MTDH upregulation partially rescues the suppressive effects of miR-379 on glioma cell progression and invasion

To further verify that the inhibitory effects of miR-379 on glioma cell proliferation and invasion were mediated by MTDH, we carried out a series of rescue experiments. U251 and U343 cells were cotransfected with miR-379 mimics and the MTDH overexpression vector pcDNA3.1-MTDH or the empty vector pcDNA3.1. After transfection, western blot analysis showed that cotransfection of pcDNA3.1-MTDH partially restored the decreased MTDH protein level in U251 and U343 cells that was induced by miR-379 mimics (P<0.05) (Fig. 4A). In addition, functional assays demonstrated that the restoration of MTDH expression rescued the inhibition of cell proliferation (P<0.05) (Fig. 4B) and invasion (P<0.05) (Fig. 4C) caused by miR-379 overexpression in U251 and U343 cells. These results suggest that miR-379 may serve tumour suppressive roles in glioma, at least in part, by inhibiting MTDH expression.

MiR-379 inhibits PTEN/AKT pathway in glioma

MTDH contributes to the activation of the PTEN/AKT signaling pathway (20,23,24). Hence, we investigated whether miR-379 could inhibit PTEN/AKT pathway in glioma. Western blot analysis was utilised to detect PTEN, p-AKT and AKT expression in U251 and U343 cells transfected with miR-379 mimics or miR-NC. The results demonstrated that enforced expression of miR-379 increased the expression of PTEN and reduced p-AKT, whereas the expression of total AKT was unaltered compared with the miR-NC group (Fig. 5). These results suggest that miR-379 inhibits PTEN/AKT signaling pathway in glioma.

Discussion

Numerous miRNAs are aberrantly expressed in glioma and are implicated in glioma occurrence and development (2527). Therefore, the development of miRNAs as potential therapeutic targets for the treatment of patients with glioma has been proposed. In this research, miR-379 expression was downregulated in glioma tissues and cell lines. In addition, the restoration of miR-379 expression inhibited cell proliferation and invasion of glioma. MTDH was validated as a novel target of miR-379 in glioma, and its upregulation partially rescued the suppressive effects of miR-379 on glioma cell progression and invasion. Moreover, miR-379 inhibited the activation of the PTEN/AKT pathway in glioma. These results suggested that miR-379 attenuates glioma progression by directly targeting MTDH and indirectly regulating the PTEN/AKT pathway.

MiR-379 has been reported to be downregulated in multiple types of human malignancies. For example, miR-379 is decreased in gastric cancer tissues and cell lines, and its low expression is associated with lymph node metastasis and TNM stage. Additionally, miR-379 is identified as an independent prognostic marker for the prediction of the 5-year survival of patients with gastric cancer (17). In hepatocellular carcinoma, miR-379 expression levels are low in tumour tissues and are correlated with advanced TNM stage and metastasis (18). In breast cancer, miR-379 is downregulated in tumour tissues compared with normal breast tissues. A decreased miR-379 expression is significantly correlated with tumour stage of breast cancer (28). Downregulation of miR-379 was also observed in bladder cancer (29), osteosarcoma (30), lung cancer (31), medulloblastomas (32) and pleural mesothelioma (33). These findings suggest that miR-379 may be used as a prognostic marker in these specific types of cancer.

Deregulated miR-379 expression contributes to the initiation and progression of several types of cancer. For instance, manipulation of miR-379 levels suppresses cell metastasis and epithelial-mesenchymal transition (EMT) in gastric cancer through the regulation of FAK/AKT signaling pathway (17). Chen et al reported that ectopic expression of miR-379 decreases cell migration, invasion and EMT of hepatocellular carcinoma by directly targeting FAK and regulating AKT signaling pathway (18). Khan et al found that enforced miR-379 expression inhibits breast cancer cell proliferation via the blockade of cyclin B1 (28). Wu et al showed that miR-379 upregulation attenuates cell growth and metastasis by directly targeting MDM2 (29). Li et al revealed that miR-379 targets PDK1 to reduce osteosarcoma cell proliferation, in vitro invasion and in vivo tumour growth (30). Hao et al demonstrated that miR-379 overexpression increases cisplatin chemosensitivity in non-small cell lung cancer by downregulating EIF4G2 (31). These findings suggest that miR-379 is worth investigating as a novel therapeutic target for patients with these specific types of cancer.

The direct targets of miR-379 should be identified to understand its role in tumourigenesis and tumour development. In this study, MTDH, also known as astrocyte elevated gene-1, was identified as a direct target of miR-379 in glioma. MTDH is located at chromosome 8q22 and has been reported to be regulated in various human cancers, such as hepatocellular carcinoma (34), colorectal cancer (35), gastric cancer (36), bladder cancer (37) and breast cancer (38). In glioma, MTDH was overexpressed and significantly correlated with histological grade (39). The survival time of glioma patients and with high MTDH expression was shorter than that of patients with low MTDH expression. High MTDH expression is also identified as an independent prognostic indicator of the survival of patients with gliomas (40). Previous studies demonstrated that MTDH is involved in the initiation and progression of glioma through the regulation of cell proliferation, colony formation, metastasis, EMT in vitro and decreased tumour growth in vivo (2022). Therefore, these findings suggested that MTDH could represent a possible target for the therapy of patients with this deadly disease.

In summary, miR-379 is downregulated in glioma tissues and cell lines. The restoration of miR-379 expression attenuates the proliferation and invasion of glioma cells by directly targeting MTDH and indirectly regulating the PTEN/AKT signaling pathways. These results suggest that the miR-379/MTDH signaling pathway is a potential target to treat patients with glioma.

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Li L and Li L: MicroRNA-379 inhibits cell proliferation and invasion in glioma via targeting metadherin and regulating PTEN/AKT pathway Retraction in /10.3892/mmr.2022.12853. Mol Med Rep 17: 4049-4056, 2018
APA
Li, L., & Li, L. (2018). MicroRNA-379 inhibits cell proliferation and invasion in glioma via targeting metadherin and regulating PTEN/AKT pathway Retraction in /10.3892/mmr.2022.12853. Molecular Medicine Reports, 17, 4049-4056. https://doi.org/10.3892/mmr.2017.8361
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Li, L., Zhang, H."MicroRNA-379 inhibits cell proliferation and invasion in glioma via targeting metadherin and regulating PTEN/AKT pathway Retraction in /10.3892/mmr.2022.12853". Molecular Medicine Reports 17.3 (2018): 4049-4056.
Chicago
Li, L., Zhang, H."MicroRNA-379 inhibits cell proliferation and invasion in glioma via targeting metadherin and regulating PTEN/AKT pathway Retraction in /10.3892/mmr.2022.12853". Molecular Medicine Reports 17, no. 3 (2018): 4049-4056. https://doi.org/10.3892/mmr.2017.8361