MicroRNA-194 represses glioma cell epithelial‑to‑mesenchymal transition by targeting Bmi1

  • Authors:
    • Xi Zhang
    • Chunyan Wei
    • Jin Li
    • Jiali Liu
    • Jianqiang Qu
  • View Affiliations

  • Published online on: January 17, 2017     https://doi.org/10.3892/or.2017.5376
  • Pages: 1593-1600
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Abstract

MicroRNA-194 (miR-194) is frequently dysregulated in many types of cancer. However, the function of miR-194 in glioma remains unknown. In the present study, we aimed to investigate the biological functions of miR-194 in glioma and the potential molecular mechanism of miR-194 involved in glioma progression. We found that miR-194 expression was significantly reduced in glioma specimens and cell lines, as detected by real-time quantitative polymerase chain reaction (RT-qPCR) analysis. The overexpression of miR-194 inhibited while the suppression of miR-194 promoted cell migration, invasion and epithelial mesenchymal transition (EMT) in glioma cells. Bioinformatics analysis showed that the B cell-specific moloney murine leukemia virus insertion site 1 (Bmi1) was a direct target of miR-194, which was validated by dual-luciferase reporter assay, RT-qPCR and western blot analysis. The restoration of Bmi1 expression significantly abrogated the suppressive effect of miR-194 on glioma cell EMT. Taken together, the present study suggests that miR-194 inhibits glioma cell EMT by targeting Bmi1 providing novel insights into understanding the pathogenesis of glioma. The restoration of miR-194 may be a potential therapeutic strategy for glioma treatment.

Introduction

Glioma is one of the most prevalent brain tumors, with a high yearly mortality rate worldwide (1,2). In spite of the current advances in cancer treatments, glioma is still an intractable disease due to the rapid growth, angiogenesis and metastasis of glioma cells (3,4). The overall survival has not been significantly improved during the past decades (4,5). Therefore, there is an urgent need to develop new therapies for glioma. However, the mechanism of glioma tumorigenesis is still not fully understood that hampers the development of new treatments for glioma.

In recent years, microRNAs (miRNAs), a group of small and non-coding RNA, have emerged as potential and promising tools for cancer diagnosis and treatments (6,7). miRNAs can regulate target gene expression by interacting with the 3-untranslated region (UTR) of the mRNA that inhibits translation or induces mRNA degradation (8,9). Thus, miRNAs function as native regulators of gene expression. miRNAs are capable of modulating cancer cell proliferation, apoptosis, differentiation, migration and invasion by targeting oncogenes or tumor suppressors (10). There is increasing evidence suggesting that various miRNAs are dysregulated in glioma, which function as oncogenes or tumor suppressors (11,12), highlighting their potential as novel agents for the treatment of glioma. However, the precise role of miRNAs in glioma remains largely unknown.

The B cell-specific moloney murine leukemia virus insertion site 1 (Bmi1) is a self-renewal gene that is overexpressed in multiple human cancers (13). Bmi1 is a key component of the polycomb regulatory complex-1 regulating the transcription of a variety of important genes (14,15). The inhibition of Bmi1 induces tumor cell apoptosis and increases susceptibility to chemotherapy and radiation therapy, indicating an oncogenic role of Bmi1 (16,17). Bmi1 can induce cell transformation and promote cancer proliferation in vivo and in vitro through transcriptional repression of tumor suppressor genes including p16INK4A and p14ARF (1820). The epithelial-to-mesenchymal transition (EMT) is an essential process for cancer invasion and metastasis (21). Notably, a recent study has shown that Bmi1 plays an important role in inducing EMT (2224). Bmi1 plays an important role in glioma tumorigenesis through promoting the invasion, migration, angiogenesis and proliferation of glioma cells (2528). Therefore, targeted therapy on Bmi1 may have promising and potential therapeutic values on glioma treatment.

Emerging evidence has suggested that miR-194 functions as a tumor suppressor in many types of human cancers including lung cancer (29), hepatocellular carcinoma (30) and colorectal cancer (31). However, the role of miR-194 in glioma remains unclear. In the present study, we aimed to explore the biological role of miR-194 and the underlying molecular mechanism in regulating glioma procession. We found that miR-194 expression was significantly decreased in glioma tissues and cell lines. Overexpression of miR-194 inhibited while the suppression of miR-194 promoted cell migration, invasion and EMT of glioma cells. Bioinformatic analysis indicated that Bmi1 was the direct target of miR-194 in glioma cells by which miR-194 regulated the glioma EMT process. Our findings provide a better understanding of the mechanism of glioma development and suggest that targeting Bmi1 by miR-194 may serve as an attractive treatment method for glioma.

Materials and methods

Tissue specimens and cell line

A total of 20 glioma specimens were histopathologically diagnosed at the Department of Neurosurgery, the Second Affiliated Hospital of Xi'an Jiaotong University (Xi'an, China). The specimens were resected prior to any therapeutic treatment. Normal brain tissues obtained from internal decompression patients undergoing surgical operation were used as a control. Prior written informed consent of the patients and approval were obtained from the Institutional Human Experiment and Ethic Committee of the Second Affiliated Hospital of Xi'an Jiaotong University. This study was performed in accordance with the Helsinki Declaration. U87, U251, SHG44 and A172 glioma cell lines and normal human astrocytes (NHA) were purchased from the Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China). All cells were routinely cultured in Dulbeccos modified Eagles medium (DMEM; Gibco, Rockville, MD, USA) containing 10% fetal bovine serum (FBS; Gibco) and 1% penicillin/streptomycin mix (Sigma-Aldrich, St. Louis, MO, USA) in a humidified atmosphere containing 5% CO2 at 37°C.

Real-time quantitative polymerase chain reaction (RT-qPCR)

Total RNA was isolated using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) as per the manufacturers instructions. For the analysis of Bmi1 expression, RNA was reverse-transcribed into cDNA by Moloney murine leukemia virus (M-MLV) reverse transcriptase (Takara Bio, Dalian, China). Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as an internal control for normalization. For the analysis of miR-194 expression, RNA was reverse-transcribed into cDNA by TaqMan MicroRNA reverse transcription kit (Applied Biosystems, Inc., Carlsbad, CA, USA). Small nuclear RNA U6 was used for normalization. The PCR amplification was performed by using the SYBR-Green Master Mix kit (Bio-Rad Laboratories, Hercules, CA, USA) on an Applied Biosystems AB 7500 real-time PCR system (Applied Biosystems). The primers used were as follows: miR-194, forward, 5-atggacctggggccacgaag-3 and reverse, 5-tctggcct gggagcgtcg-3; U6, forward, 5-cgcttcggcagcacatatactaa-3 and reverse, 5-tatggaacgcttcacgaatttgc-3; Bmi1, forward, 5-atgca tcgaacaacgagaatcaagatcact-3 and reverse, 5-tcaaccagaagaa gttgctgatgaccc-3; and GAPDH, forward, 5-ccatgttcgtcatggtg tg-3 and reverse, 5-ggtgctaagcagttggtggtg-3. Gene expression was calculated using the 2−ΔΔCt method, normalized against U6 or GAPDH and then compared with the control group.

Oligonucleotides, plasmids and transfection

miR-194 mimics, miR-194 inhibitor and their negative controls were purchased from Shanghai GenePharma, Co., Ltd. (Shanghai, China). The open reading frame of Bmi1 was inserted into the pcDNA3.0 vector (Invitrogen). All the transfections were performed using Lipofectamine 2000 (Invitrogen) according to the manufacturers instructions.

Migration and invasion assay

For cell migration, 1×105 cells transfected with miR-194 mimics or miR-194 inhibitors were placed in the upper chambers of a Transwell (Costar, Cambridge, MA, USA) with serum-free medium and the lower chambers were filled with medium containing 10% FBS. For cell invasion, the upper chambers were coated with Matrigel (BD Biosciences, San Jose, CA, USA). After being cultured for 24 h at 37°C, the non-migrated or non-invaded cells on the top of the well were gently removed and the cells on the lower surface of the membrane were fixed with 70% ethanol and stained with 0.1% violet (Sigma-Aldrich). The cells were observed and counted under a microscope (Olympus Corp., Tokyo, Japan).

Western blot analysis

Proteins were extracted by cell lysis buffer and the protein concentration was detected by a BCA kit (Beyotime Institute of Biotechnology, Haimen, China). A total of 50 µg protein was separated by SDS-PAGE and electrotransferred to a polyvinylidene fluoride membrane (Bio-Rad Laboratories). The membrane was blocked by 5% non-fat milk and then incubated with primary antibodies at 4°C overnight. The membrane was then incubated with horseradish peroxidase-conjugated secondary antibodies (Bosis, Beijing, China) for 1 h at 37°C. Ultimately, the membrane was detected by an ECL western blotting kit (Pierce, Rockford, IL, USA) according to the manufacturers instructions. The image was analyzed by Image-Pro Plus 6.0 software (Media Cybernetics, Inc., Rockville, MD, USA). The values were normalized against GAPDH and then were compared with the control group. Primary antibodies used in this experiment including anti-E-cadherin, anti-vimentin, anti-Bmi1 and anti-GAPDH were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).

Dual-Luciferase reporter assay

The Bmi1 3-UTR harboring the seed-matched sequences of miR-194 with or without mutation was inserted into pmirGLO Dual-Luciferase vector (Promega Corp., Madison, WI, USA). Glioma cells were seeded into 24-well plates and co-transfected with miR-194 mimics or miR-194 inhibitor and the constructed wild-type or mutant pmirGLO-Bmi1 3-UTR into glioma cells using Lipofectamine 2000. After 48 h, the luciferase activity was analyzed by a Dual-luciferase reporter assay system kit (Promega).

Data analysis

Data are reported as means ± standard deviation (SD). Statistical analyses were performed using SPSS version 11.5 software (SPSS, Inc., Chicago, IL, USA). Differences were calculated by the Students t-test or one-way analysis of variance (ANOVA) followed by Bonferroni post hoc. When the P-value was <0.05, the difference was considered to be statistically significant.

Results

miR-194 is frequently lower in glioma tissues and cell lines

To determine whether miR-194 is involved in glioma development, we first analyzed the expression patterns of miR-194 in glioma specimens by RT-qPCR. The results showed that miR-194 was frequently downregulated in glioma tissues compared with normal brain tissue (Fig. 1A). Moreover, the expression levels of miR-194 were also decreased in the four glioma cell lines examined, particularly in A172 and U87, when compared with normal human astrocytes (Fig. 1B). These results indicate that miR-194 may play an important role in glioma.

miR-194 suppresses glioma cell migration and invasion

To investigate the biological role of miR-194 in glioma, we performed gain- and loss-of-function experiments by transiently transfecting miR-194 mimics or miR-194 inhibitors in A172 and U87 cells. We then detected the functional effect of miR-194 on glioma cell migration and invasion by Transwell assay. The results showed that miR-194 overexpression significantly inhibited glioma cell migration (Fig. 2A and C) and invasion (Fig. 2B and D) in A172 and U87 cells. Conversely, miR-194 suppression markedly increased glioma cell migration (Fig. 2A and C) and invasion (Fig. 2B and D). These data imply a suppressive role of miR-194 on glioma metastasis.

miR-194 suppresses EMT of glioma cells

To further investigate the contribution of miR-194 on glioma metastasis, we examined the biological role of miR-194 in regulating glioma cell EMT. Western blot analysis showed that the expression of epithelial marker E-cadherin was significantly increased, whereas expression of the mesenchymal marker vimentin was markedly decreased by miR-194 overexpression in A172 cells (Fig. 3A-C). In contrast, miR-194 suppression showed the opposite effects (Fig. 3A-C). Similar results were also observed in U87 cells (Fig. 3D-F), suggesting a suppressive role of miR-194 in glioma cell EMT.

miR-194 directly targets Bmi1

To investigate the underlying molecular mechanism by which miR-194 regulates glioma cell EMT, we used bioinformatic analysis to identify the potential target of miR-194. Among these predicted target genes, Bmi1, an important regulator for cancer metastasis (2224), caught our attention. The predicted binding site between miR-194 and Bmi1 3-UTR is illustrated in Fig. 4A. To verify that Bim1 is a direct target gene of miR-194, we performed a Dual-Luciferase reporter assay. The 3-UTR fragments of Bmi1, which contain a wild-type or mutant binding site of miR-194, were cloned into the luciferase reporter vector. Overexpression of miR-194 significantly restrained the luciferase activity in U87 cells transfected with luciferase reporter vector containing wild-type Bmi1 3-UTR, whereas miR-194 suppression promoted the luciferase activity (Fig. 4B). However, neither miR-194 overexpression nor suppression showed an obvious effect on luciferase activity of the luciferase reporter vector containing a mutant 3-UTR (Fig. 4C). Next, we further determined the direct effect of miR-194 on regulating Bmi1 expression. RT-qPCR analysis showed that the mRNA expression of Bmi1 was significantly decreased or increased by miR-194 overexpression or suppression, respectively (Fig. 5A and B). Consistently, western blot analysis identified that Bmi1 protein expression was regulated by miR-194 (Fig. 5C and D). Taken together, these results suggest that miR-194 regulates Bmi1 expression by directly targeting the 3-UTR of Bmi1.

miR-194 inhibits glioma EMT through downregulating Bmi1

To verify whether the tumor suppressor role of miR-194 in glioma is mediated by suppressing the expression of Bmi1, we performed a rescue assay. Glioma cells were co-transfected with miR-194 mimics and Bmi1-overexpressing vector. The decreased protein expression of Bmi1 induced by miR-194 overexpression was significantly restored by transfection with a Bmi1-overexpressing vector (Fig. 6A and E). As expected, the inhibitory role of miR-194 on glioma EMT was rescued by Bmi1 overexpression (Fig. 6A-H). These results suggest that the suppressive role of miR-194 on glioma EMT is mediated by inhibiting Bmi1.

Discussion

It has now been clearly established that miRNAs play an important role in regulating the tumorigenesis and metastasis of glioma (3234). Therefore, the identification of glioma-associated miRNAs as biomarkers for glioma diagnosis, prognosis and treatment is of great importance. In the present study, we found that miR-194 was a novel glioma-associated miRNA that was decreased in glioma specimens and cell lines. The functional experiments indicated that miR-194 inhibited glioma cell migration, invasion and EMT, possibly through targeting and regulating Bmi1. Collectively, our data suggest that miR-194 plays an important role in glioma procession, indicating a novel therapeutic target for glioma.

Growing evidence has demonstrated that miR-194 is a tumor-associated miRNA that is frequently dysregulated in many types of human cancers. miR-194 expression was markedly decreased in hepatocellular carcinoma and miR-194 overexpression inhibited cell proliferation by targeting mitogen-activated protein kinase 4 (30). Other studies reported that miR-194 was frequently downregulated in colorectal cancer (35,36). miR-194 can inhibit colorectal carcinogenesis by targeting mitogen-activated protein kinase 4 (37) or Akt2 (31). Several studies have reported that miR-194 represses the progression and metastasis of non-small lung cancer through targeting bone morphogenetic protein 1 and p27kip1 (38), forkhead box A1 protein (39) and human nuclear distribution protein C (29). miR-194 can suppress gastric cancer cell proliferation and EMT through targeting RING box protein 1 (40) and forkhead box protein M1 (41). The tumor suppressive role of miR-194 is also observed in oral squamous cell carcinoma (42), bladder cancer (43) and clear cell renal cell carcinoma (44). However, the role of miR-194 in glioma remains unknown. In line with these findings, this study demonstrated that miR-194 functioned as a tumor suppressor in glioma. We found that miR-194 was decreased in glioma tissues and cell lines. Overexpression of miR-194 inhibited glioma cell migration, invasion and EMT through inhibiting Bmi1. However, an oncogenic role of miR-194 is observed in pancreatic ductal adenocarcinoma that promotes tumor growth and progression through inhibiting the tumor suppressor DACH1 (45). Therefore, the precise role of miR-194 in cancer progression requires further investigation.

Bmi1 has been suggested as an oncogene that is frequently elevated in various cancer types and is correlated with a worse prognosis (13). Bmi1 has been reported to inhibit tumor suppressor genes including p14ARF, p16INK4a, KIF1Bβ and TSLC1 (46). Bmi1 is a critical regulator for EMT and cancer metastasis (47). Knockdown of Bmi1 abolishes the ionizing irradiation-induced EMT of breast cancer cells (48). Twist1 and Bmi-1 can act cooperatively to inhibit E-cadherin and p16INK4a, leading to EMT induction (49). Bmi1 plays an important role in development of the central nervous system; however, the dysregulation of Bmi1 contributes to the development of brain tumors (50,51). Overexpression of Bmi1 was found in human medulloblastomas, correlated with activation of the sonic hedgehog pathway (50). Bmi1 is highly elevated in glioma tissues and patients with high levels of Bmi1 show a poor survival rate (52). Bmi1 promotes glioma cell migration and invasion via nuclear factor kappa B and p16 (25,28,53). Consistently, our results showed that the inhibition of Bmi1 by miR-194 significantly suppressed the glioma cell migration, invasion and EMT, further implying that Bmi1 can serve as a therapeutic target for preventing glioma metastasis.

In the present study, we demonstrated that miR-194 functions as an EMT regulator in glioma via targeting Bmi1. We showed that miR-194 could directly target the 3-UTR of Bmi1 and inhibit Bmi1 expression. Our findings are consistent with a previous study which revealed that miR-194 suppresses the EMT of endometrial cancer cells by targeting Bmi1 (54). The present study further confirms that Bmi1 is a functional target of miR-194. A recent study (55) suggested that targeting Bmi1 by miRNAs is a promising strategy for cancer prevention. Deng et al (55) reported that miR-376c suppresses cervical cancer cell proliferation and invasion by targeting Bmi1. miR-494-3p enhances the radiosensitivity of oral squamous carcinoma cells through targeting Bmi1 (56). miR-452 and miR-403 can inhibit the metastasis of non-small cell lung cancer through inhibiting Bmi1 (57,58). miR-218, functioning as a negative regulator of Bmi1, is also found in bladder cancer (59) and esophageal squamous cell carcinoma (60). Besides these miRNAs, miR-429, miR-200c, mIR-221 and miR-320a have been demonstrated to directly target Bmi1 in various cancer cells (22,6163). These studies indicate that Bim1 undergoes epigenetic regulation by various miRNAs that may contribute to the development of cancer. A better understanding of Bmi1 by miRNAs will provide a new insight into understanding glioma pathogenesis.

EMT is considered as major modulator of metastasis formation in epithelial solid tumors, and the EMT of glioma has also been widely studied (64). Twist1, ZEB1/ZEB2 and SNAI1/SNAI2 have been suggested as the major regulators for EMT in glioma (6567). Various miRNAs such as miR-200b, miR-590-3p and miR-181c are reported to be involved in regulating EMT of glioma (6870). Our present study showed for the first time that miR-194 was decreased in glioma which could inhibit glioma cell migration, invasion and EMT. Importantly, we found that Bmi1 was a direct target of miR-194 in glioma cells by which miR-194 inhibited glioma cell EMT. miR-194 may serve as a novel biomarker as well as a therapeutic target in glioma. However, further in vivo studies are required to fully elucidate the exact role and molecular mechanism of miR-194 in the regulation of glioma.

Acknowledgements

The present study was supported by the Social Research and Development Program of Shaanxi Province (no. 2016SF-110).

Glossary

Abbreviations

Abbreviations:

Bmi1

B cell-specific moloney murine leukemia virus insertion site

EMT

epithelial-to-mesenchymal transition

FBS

fetal bovine serum

miRNAs

microRNAs

RT-qPCR

real- time quantitative polymerase chain reaction

UTR

3-untranslated region

References

1 

Westphal M and Lamszus K: The neurobiology of gliomas: From cell biology to the development of therapeutic approaches. Nat Rev Neurosci. 12:495–508. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, et al: Malignant astrocytic glioma: Genetics, biology, and paths to treatment. Genes Dev. 21:2683–2710. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Pollack IF: Neuro-oncology: Therapeutic benefits of reirradiation for recurrent brain tumors. Nat Rev Neurol. 6:533–535. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Khasraw M and Lassman AB: Neuro-oncology: Late neurocognitive decline after radiotherapy for low-grade glioma. Nat Rev Neurol. 5:646–647. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Pang JC, Kwok WK, Chen Z and Ng HK: Oncogenic role of microRNAs in brain tumors. Acta Neuropathol. 117:599–611. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Silber J, James CD and Hodgson JG: microRNAs in gliomas: Small regulators of a big problem. Neuromolecular Med. 11:208–222. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Winter J, Jung S, Keller S, Gregory RI and Diederichs S: Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 11:228–234. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Manikandan J, Aarthi JJ, Kumar SD and Pushparaj PN: Oncomirs: The potential role of non-coding microRNAs in understanding cancer. Bioinformation. 2:330–334. 2008. View Article : Google Scholar : PubMed/NCBI

11 

Zhang Y, Dutta A and Abounader R: The role of microRNAs in glioma initiation and progression. Front Biosci (Landmark Ed). 17:700–712. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Besse A, Sana J, Fadrus P and Slaby O: MicroRNAs involved in chemo- and radioresistance of high-grade gliomas. Tumour Biol. 34:1969–1978. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Cao L, Bombard J, Cintron K, Sheedy J, Weetall ML and Davis TW: BMI1 as a novel target for drug discovery in cancer. J Cell Biochem. 112:2729–2741. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Guney I, Wu S and Sedivy JM: Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16INK4a. Proc Natl Acad Sci USA. 103:3645–3650. 2006. View Article : Google Scholar : PubMed/NCBI

15 

Silva J, García JM, Peña C, García V, Domínguez G, Suárez D, Camacho FI, Espinosa R, Provencio M, España P, et al: Implication of polycomb members Bmi-1, Mel-18, and Hpc-2 in the regulation of p16INK4a, p14ARF, h-TERT, and c-Myc expression in primary breast carcinomas. Clin Cancer Res. 12:6929–6936. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Wu J, Hu D, Yang G, Zhou J, Yang C, Gao Y and Zhu Z: Down-regulation of BMI-1 cooperates with artemisinin on growth inhibition of nasopharyngeal carcinoma cells. J Cell Biochem. 112:1938–1948. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Wu Z, Min L, Chen D, Hao D, Duan Y, Qiu G and Wang Y: Overexpression of BMI-1 promotes cell growth and resistance to cisplatin treatment in osteosarcoma. PLoS One. 6:e146482011. View Article : Google Scholar : PubMed/NCBI

18 

Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A and van Lohuizen M: Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13:2678–2690. 1999. View Article : Google Scholar : PubMed/NCBI

19 

Jiang L, Li J and Song L: Bmi-1, stem cells and cancer. Acta Biochim Biophys Sin (Shanghai). 41:527–534. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Itahana K, Zou Y, Itahana Y, Martinez JL, Beausejour C, Jacobs JJ, Van Lohuizen M, Band V, Campisi J and Dimri GP: Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol. 23:389–401. 2003. View Article : Google Scholar : PubMed/NCBI

21 

Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Qiu M, Liang Z, Chen L, Tan G, Wang K, Liu L, Liu J and Chen H: MicroRNA-429 suppresses cell proliferation, epithelial-mesenchymal transition, and metastasis by direct targeting of BMI1 and E2F3 in renal cell carcinoma. Urol Oncol. 33:332.e9–18. 2015. View Article : Google Scholar

23 

Wei XL, Dou XW, Bai JW, Luo XR, Qiu SQ, Xi DD, Huang WH, Du CW, Man K and Zhang GJ: ERα inhibits epithelial-mesenchymal transition by suppressing Bmi1 in breast cancer. Oncotarget. 6:21704–21717. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Paranjape AN, Balaji SA, Mandal T, Krushik EV, Nagaraj P, Mukherjee G and Rangarajan A: Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog. BMC Cancer. 14:7852014. View Article : Google Scholar : PubMed/NCBI

25 

Liang J, Wang P, Xie S, Wang W, Zhou X, Hu J, Shi Q, Zhang X and Yu R: Bmi-1 regulates the migration and invasion of glioma cells through p16. Cell Biol Int. 39:283–290. 2015. View Article : Google Scholar : PubMed/NCBI

26 

Tu Y, Gao X, Li G, Fu H, Cui D, Liu H, Jin W and Zhang Y: MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. Cancer Res. 73:6046–6055. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Jiang L, Song L, Wu J, Yang Y, Zhu X, Hu B, Cheng SY and Li M: Bmi-1 promotes glioma angiogenesis by activating NF-κB signaling. PLoS One. 8:e555272013. View Article : Google Scholar : PubMed/NCBI

28 

Jiang L, Wu J, Yang Y, Liu L, Song L, Li J and Li M: Bmi-1 promotes the aggressiveness of glioma via activating the NF-kappaB/MMP-9 signaling pathway. BMC Cancer. 12:4062012. View Article : Google Scholar : PubMed/NCBI

29 

Zhou L, Di Q, Sun B, Wang X, Li M and Shi J: MicroRNA-194 restrains the cell progression of non-small cell lung cancer by targeting human nuclear distribution protein C. Oncol Rep. 35:3435–3444. 2016.PubMed/NCBI

30 

Zhao Y, Li F, Zhang X, Liu A, Qi J, Cui H and Zhao P: MicroRNA-194 acts as a prognostic marker and inhibits proliferation in hepatocellular carcinoma by targeting MAP4K4. Int J Clin Exp Pathol. 8:12446–12454. 2015.PubMed/NCBI

31 

Zhao HJ, Ren LL, Wang ZH, Sun TT, Yu YN, Wang YC, Yan TT, Zou W, He J, Zhang Y, et al: MiR-194 deregulation contributes to colorectal carcinogenesis via targeting AKT2 pathway. Theranostics. 4:1193–1208. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Kwak PB, Iwasaki S and Tomari Y: The microRNA pathway and cancer. Cancer Sci. 101:2309–2315. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Karsy M, Arslan E and Moy F: Current progress on understanding MicroRNAs in glioblastoma multiforme. Genes Cancer. 3:3–15. 2012. View Article : Google Scholar : PubMed/NCBI

34 

Tivnan A and McDonald KL: Current progress for the use of miRNAs in glioblastoma treatment. Mol Neurobiol. 48:757–768. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Chiang Y, Song Y, Wang Z, Liu Z, Gao P, Liang J, Zhu J, Xing C and Xu H: microRNA-192, −194 and −215 are frequently downregulated in colorectal cancer. Exp Ther Med. 3:560–566. 2012.PubMed/NCBI

36 

Basati G, Razavi AE, Pakzad I and Malayeri FA: Circulating levels of the miRNAs, miR-194, and miR-29b, as clinically useful biomarkers for colorectal cancer. Tumour Biol. 37:1781–1788. 2016. View Article : Google Scholar : PubMed/NCBI

37 

Wang B, Shen ZL, Gao ZD, Zhao G, Wang CY, Yang Y, Zhang JZ, Yan YC, Shen C, Jiang KW, et al: MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway. Cell Cycle. 14:1046–1058. 2015. View Article : Google Scholar : PubMed/NCBI

38 

Wu X, Liu T, Fang O, Leach LJ, Hu X and Luo Z: miR-194 suppresses metastasis of non-small cell lung cancer through regulating expression of BMP1 and p27kip1. Oncogene. 33:1506–1514. 2014. View Article : Google Scholar : PubMed/NCBI

39 

Zhu X, Li D, Yu F, Jia C, Xie J, Ma Y, Fan S, Cai H, Luo Q, Lv Z, et al: miR-194 inhibits the proliferation, invasion, migration, and enhances the chemosensitivity of non-small cell lung cancer cells by targeting forkhead box A1 protein. Oncotarget. 7:13139–13152. 2016.PubMed/NCBI

40 

Chen X, Wang Y, Zang W, Du Y, Li M and Zhao G: miR-194 targets RBX1 gene to modulate proliferation and migration of gastric cancer cells. Tumour Biol. 36:2393–2401. 2015. View Article : Google Scholar : PubMed/NCBI

41 

Li Z, Ying X, Chen H, Ye P, Shen Y, Pan W and Zhang L: MicroRNA-194 inhibits the epithelial-mesenchymal transition in gastric cancer cells by targeting FoxM1. Dig Dis Sci. 59:2145–2152. 2014. View Article : Google Scholar : PubMed/NCBI

42 

Chi H: miR-194 regulated AGK and inhibited cell proliferation of oral squamous cell carcinoma by reducing PI3K-Akt-FoxO3a signaling. Biomed Pharmacother. 71:53–57. 2015. View Article : Google Scholar : PubMed/NCBI

43 

Zhang M, Zhuang Q and Cui L: MiR-194 inhibits cell proliferation and invasion via repression of RAP2B in bladder cancer. Biomed Pharmacother. 80:268–275. 2016. View Article : Google Scholar : PubMed/NCBI

44 

Nofech-Mozes R, Khella HW, Scorilas A, Youssef L, Krylov SN, Lianidou E, Sidiropoulos KG, Gabril M, Evans A and Yousef GM: MicroRNA-194 is a marker for good prognosis in clear cell renal cell carcinoma. Cancer Med. 5:656–664. 2016. View Article : Google Scholar : PubMed/NCBI

45 

Zhang J, Zhao CY, Zhang SH, Yu DH, Chen Y, Liu QH, Shi M, Ni CR and Zhu MH: Upregulation of miR-194 contributes to tumor growth and progression in pancreatic ductal adenocarcinoma. Oncol Rep. 31:1157–1164. 2014.PubMed/NCBI

46 

Kamijo T: Role of stemness-related molecules in neuroblastoma. Pediatr Res. 71:511–515. 2012. View Article : Google Scholar : PubMed/NCBI

47 

Ren H, Du P, Ge Z, Jin Y, Ding D, Liu X and Zou Q: TWIST1 and BMI1 in cancer metastasis and chemoresistance. J Cancer. 7:1074–1080. 2016. View Article : Google Scholar : PubMed/NCBI

48 

Yuan W, Yuan Y, Zhang T and Wu S: Role of Bmi-1 in regulation of ionizing irradiation-induced epithelial-mesenchymal transition and migration of breast cancer cells. PLoS One. 10:e01187992015. View Article : Google Scholar : PubMed/NCBI

49 

Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH, Huang CH, Kao SY, Tzeng CH, Tai SK, et al: Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol. 12:982–992. 2010. View Article : Google Scholar : PubMed/NCBI

50 

Leung C, Lingbeek M, Shakhova O, Liu J, Tanger E, Saremaslani P, Van Lohuizen M and Marino S: Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature. 428:337–341. 2004. View Article : Google Scholar : PubMed/NCBI

51 

Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF and Morrison SJ: Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature. 425:962–967. 2003. View Article : Google Scholar : PubMed/NCBI

52 

Wu Z, Wang Q, Wang L, Li G, Liu H, Fan F, Li Z, Li Y and Tu Y: Combined aberrant expression of Bmi1 and EZH2 is predictive of poor prognosis in glioma patients. J Neurol Sci. 335:191–196. 2013. View Article : Google Scholar : PubMed/NCBI

53 

Sun P, Mu Y and Zhang S: A novel NF-κB/MMP-3 signal pathway involves in the aggressivity of glioma promoted by Bmi-1. Tumour Biol. 35:12721–12727. 2014. View Article : Google Scholar : PubMed/NCBI

54 

Dong P, Kaneuchi M, Watari H, Hamada J, Sudo S, Ju J and Sakuragi N: MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol Cancer. 10:992011. View Article : Google Scholar : PubMed/NCBI

55 

Deng Y, Xiong Y and Liu Y: miR-376c inhibits cervical cancer cell proliferation and invasion by targeting BMI1. Int J Exp Pathol. 97:257–265. 2016. View Article : Google Scholar : PubMed/NCBI

56 

Weng JH, Yu CC, Lee YC, Lin CW, Chang WW and Kuo YL: miR-494-3p induces cellular senescence and enhances radiosensitivity in human oral squamous carcinoma cells. Int J Mol Sci. 17:172016. View Article : Google Scholar

57 

He Z, Xia Y, Pan C, Ma T, Liu B, Wang J, Chen L and Chen Y: Up-regulation of miR-452 inhibits metastasis of non-small cell lung cancer by regulating BMI1. Cell Physiol Biochem. 37:387–398. 2015. View Article : Google Scholar : PubMed/NCBI

58 

Chen T, Xu C, Chen J, Ding C, Xu Z, Li C and Zhao J: MicroRNA-203 inhibits cellular proliferation and invasion by targeting Bmi1 in non-small cell lung cancer. Oncol Lett. 9:2639–2646. 2015.PubMed/NCBI

59 

Cheng Y, Yang X, Deng X, Zhang X, Li P, Tao J and Lu Q: MicroRNA-218 inhibits bladder cancer cell proliferation, migration, and invasion by targeting BMI-1. Tumour Biol. 36:8015–8023. 2015. View Article : Google Scholar : PubMed/NCBI

60 

Wang T, Chen T, Niu H, Li C, Xu C, Li Y, Huang R, Zhao J and Wu S: MicroRNA-218 inhibits the proliferation and metastasis of esophageal squamous cell carcinoma cells by targeting BMI1. Int J Mol Med. 36:93–102. 2015.PubMed/NCBI

61 

Xuan H, Xue W, Pan J, Sha J, Dong B and Huang Y: Downregulation of miR-221, −30d, and −15a contributes to pathogenesis of prostate cancer by targeting Bmi-1. Biochemistry (Mosc). 80:276–283. 2015. View Article : Google Scholar : PubMed/NCBI

62 

Liu L, Qiu M, Tan G, Liang Z, Qin Y, Chen L, Chen H and Liu J: miR-200c inhibits invasion, migration and proliferation of bladder cancer cells through down-regulation of BMI-1 and E2F3. J Transl Med. 12:3052014. View Article : Google Scholar : PubMed/NCBI

63 

Qi X, Li J, Zhou C, Lv C and Tian M: MicroRNA-320a inhibits cell proliferation, migration and invasion by targeting BMI-1 in nasopharyngeal carcinoma. FEBS Lett. 588:3732–3738. 2014. View Article : Google Scholar : PubMed/NCBI

64 

Kahlert UD, Nikkhah G and Maciaczyk J: Epithelial-to-mesenchymal(−like) transition as a relevant molecular event in malignant gliomas. Cancer Lett. 331:131–138. 2013. View Article : Google Scholar : PubMed/NCBI

65 

Elias MC, Tozer KR, Silber JR, Mikheeva S, Deng M, Morrison RS, Manning TC, Silbergeld DL, Glackin CA, Reh TA, et al: TWIST is expressed in human gliomas and promotes invasion. Neoplasia. 7:824–837. 2005. View Article : Google Scholar : PubMed/NCBI

66 

Han SP, Kim JH, Han ME, Sim HE, Kim KS, Yoon S, Baek SY, Kim BS and Oh SO: SNAI1 is involved in the proliferation and migration of glioblastoma cells. Cell Mol Neurobiol. 31:489–496. 2011. View Article : Google Scholar : PubMed/NCBI

67 

Mikheeva SA, Mikheev AM, Petit A, Beyer R, Oxford RG, Khorasani L, Maxwell JP, Glackin CA, Wakimoto H, González-Herrero I, et al: TWIST1 promotes invasion through mesenchymal change in human glioblastoma. Mol Cancer. 9:1942010. View Article : Google Scholar : PubMed/NCBI

68 

Pang H, Zheng Y, Zhao Y, Xiu X and Wang J: miR-590-3p suppresses cancer cell migration, invasion and epithelial-mesenchymal transition in glioblastoma multiforme by targeting ZEB1 and ZEB2. Biochem Biophys Res Commun. 468:739–745. 2015. View Article : Google Scholar : PubMed/NCBI

69 

Li J, Yuan J, Yuan X, Zhao J, Zhang Z, Weng L and Liu J: MicroRNA-200b inhibits the growth and metastasis of glioma cells via targeting ZEB2. Int J Oncol. 48:541–550. 2016.PubMed/NCBI

70 

He X, Liu Z, Peng Y and Yu C: MicroRNA-181c inhibits glioblastoma cell invasion, migration and mesenchymal transition by targeting TGF-β pathway. Biochem Biophys Res Commun. 469:1041–1048. 2016. View Article : Google Scholar : PubMed/NCBI

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March-2017
Volume 37 Issue 3

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Online ISSN:1791-2431

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Spandidos Publications style
Zhang X, Wei C, Li J, Liu J and Qu J: MicroRNA-194 represses glioma cell epithelial‑to‑mesenchymal transition by targeting Bmi1. Oncol Rep 37: 1593-1600, 2017
APA
Zhang, X., Wei, C., Li, J., Liu, J., & Qu, J. (2017). MicroRNA-194 represses glioma cell epithelial‑to‑mesenchymal transition by targeting Bmi1. Oncology Reports, 37, 1593-1600. https://doi.org/10.3892/or.2017.5376
MLA
Zhang, X., Wei, C., Li, J., Liu, J., Qu, J."MicroRNA-194 represses glioma cell epithelial‑to‑mesenchymal transition by targeting Bmi1". Oncology Reports 37.3 (2017): 1593-1600.
Chicago
Zhang, X., Wei, C., Li, J., Liu, J., Qu, J."MicroRNA-194 represses glioma cell epithelial‑to‑mesenchymal transition by targeting Bmi1". Oncology Reports 37, no. 3 (2017): 1593-1600. https://doi.org/10.3892/or.2017.5376