MicroRNA-based chemoresistance in glioblastoma

Zhenghui Ma; Huandi Zhou; Qing Chang; Xiaoying Xue

doi:10.4103/glioma.glioma_4_19

REVIEW

Year : 2019 | Volume : 2 | Issue : 2 | Page : 83-87

MicroRNA-based chemoresistance in glioblastoma

Zhenghui Ma¹, Huandi Zhou¹, Qing Chang², Xiaoying Xue¹
¹ Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
² Department of Pathology, Peking University Health Science Center, Peking University School of Basic Medical Science, Peking University Third Hospital, Beijing, China

Date of Web Publication

27-Jun-2019

Correspondence Address:
Xiaoying Xue
Department of Radiotherapy, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, Hebei Province
China

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_4_19

Abstract

Glioblastoma (GBM) is the most common malignant tumor of the central nervous system in adults. GBM is characterized by violent invasion and poor prognosis. Commonly, there are three main conventional methods to treat GBM, surgery, radiotherapy, and chemotherapy. GBM patients have a median survival ranging from 12 to 15 months, with all tumors developing, at some point, resistance to chemotherapy. There is recently growing interest in the relationship between microRNAs (miRNAs) and chemotherapy resistance in GBM. This paper aims to explore the molecular mechanism, by which miRNAs participate in the formation of chemotherapy resistance in GBM. Here, we summarize the published data relating miRNA to chemotherapy resistance in GBM. We discuss the relationship between mechanisms that miRNA impact upon and provide insight into potential future studies and clinical therapeutics.

Keywords: Apoptosis, chemoresistance, chemotherapy, DNA damage repair, epithelial–mesenchymal transformation, glioblastoma, microRNA, multidrug resistance

How to cite this article:
Ma Z, Zhou H, Chang Q, Xue X. MicroRNA-based chemoresistance in glioblastoma. Glioma 2019;2:83-7

How to cite this URL:
Ma Z, Zhou H, Chang Q, Xue X. MicroRNA-based chemoresistance in glioblastoma. Glioma [serial online] 2019 [cited 2023 Oct 2];2:83-7. Available from: http://www.jglioma.com/text.asp?2019/2/2/83/261675

Introduction

MicroRNAs (miRNAs), are short (21–22 nucleotides) noncoding single-stranded RNA molecules, encoded by endogenous genes.^[1] They regulate gene expression in eukaryotic organisms by incomplete binding with the 3'-untranslated region (3'-UTR) of messenger RNAs.^[2] MiRNAs play an important role in tumor growth and progression by regulating tumor suppressor genes.^[3] They participate in a series of biological processes in vivo including cell proliferation, apoptosis, development, metabolism, and DNA repair. They are also closely related to the occurrence and development of various diseases, especially a variety of tumors.^[4] MiRNAs regulate the expression of target genes by inhibiting their translation or directly inducing the degradation of target messenger RNA.^[5] Generally speaking, miRNAs play pivotal roles in multiple areas of tumor dynamics including proliferation, invasion, metastasis, and chemotherapy resistance.^[6]

Glioblastoma (GBM) is a type of glioma that appears mostly in adults, rapidly develops, and has a strong invasiveness mostly in the white matter of frontal and temporal lobes. GBM has a poor prognosis, with most patients dying within 2 years of diagnosis.^[7] The standard treatment of GBM is surgery plus postoperative radiotherapy and chemotherapy.^[8],[9],[10] Temozolomide (TMZ), an alkylating agent, is the preferred chemotherapeutic drug for GBM and can be administered orally with few adverse reactions and is used usually in conjunction with or after radiotherapy. However, the development of tumor resistance to chemotherapy is the main reason that GBM treatments are noncurative.

In recent years, it has been found that the abnormal expression of miRNAs in tumor is closely related to chemotherapy resistance in GBM. In this paper, the latest progress in the association between miRNAs and the formation of chemotherapy resistance in GBM is summarized and the targeted molecular mechanisms are discussed.

The Role of Micrornas in the Development of Chemotherapy Resistance in Glioma

Chemotherapy resistance is the main cause of failure in GBM chemotherapy and results from the abnormal expression of miRNAs. There is an intricate relationship between miRNAs and GBM chemotherapy resistance. MiRNAs perform different functions in tumors, which can not only lead to the formation of chemotherapy resistance but also enhance the lethal effect of chemotherapy drugs. MiRNAs are involved in GBM chemotherapy resistance mainly by inhibiting cell apoptosis,^[11] mediating epithelial interstitial transformation,^[12] regulating self-repair after cell injury,^[13] regulating cell signal transduction pathways,^[14] increasing drug inactivation,^[15] mediating multidrug resistance (MDR),^[16] and mediating ion channels.^[17]

MicroRNAs enhance chemotherapy resistance to glioblastoma

MicroRNAs promote the formation of glioblastoma chemoresistance by inhibiting apoptosis

Based on the findings that most chemotherapeutic drugs could induce apoptosis in cancer cells, abnormal apoptosis is a major mechanism leading to drug resistance. In a study by Shi et al.,^[18] they showed that aberrant miRNA expression could affect the chemotherapy sensitivity in GBM. They found that multiple miRNAs such as miR-21, miR-195, miR-455-3p, and miR-10a had a correlation with TMZ resistance. The apoptosis-promoting factor, Bax, and apoptosis inhibitor, Bcl-2, coregulate apoptosis in glioma cells. Thus, an increased Bax/Bcl-2 ratio indicates increased apoptosis.^[19] In the study of Shi et al.,^[18] compared with untreated U87MG cells, the Bax/Bcl-2 ratio was increased in TMZ-treated U87MG cells. However, when miR-21 was overexpressed in U87MG cells, it downregulated Bax and upregulated Bcl-2, and protected the cell from apoptosis. This suggests that miR-21 can suppress apoptosis induced by TMZ in U87MG cells and promote chemotherapy resistance in glioma cells. The nuclear factor-κB (NF-κB) signaling pathway is involved in the physiological and pathological processes of inflammation, trauma, immune response, tumor proliferation, differentiation, and cell apoptosis.^[20] Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1) is a negative regulator of the NF-κB signaling pathway. Li et al.^[21] found that miR-21 in U373MG cells could inhibit LRRFIP1 and enhance NF-κB signaling, thus, leading to inhibition of apoptosis induced by the chemotherapy VM-26. The signal transducers and activators of transcription 3 (STAT3) factor, can inhibit apoptosis in GBM by acting on the kinase pathway, pathway phosphatidylinositol 3'-kinase (PI3K)/protein kinase B (AKT). However, downregulation of miR-21 inhibits STAT3 activity. In a study by Ren et al.,^[22] when U251 glioma cells were treated with a combination of paclitaxel and miR-21 inhibitors, paclitaxel was lethal at a much lower concentration than treatment with paclitaxel alone. This indicates that miR-21 inhibitors could block PI3K/AKT signal pathway by inhibiting the expression and phosphorylation of STAT3 and thus suppressing apoptosis in GBM. Ujifuku et al.^[11] established a chemoresistant cell line U251R from a TMZ-sensitive GBM cell line U251MG and found that three miRNAs (miR-195, miR-455-3p and miR-10a) were highly expressed in U251R cells. They showed that by inhibiting miR-455-3p or miR-10a, U251R cells became TMZ sensitive. Thus, miRNAs can increase TMZ resistance in glioma cells by inhibiting TMZ-induced apoptosis.

MicroRNAs may increase glioblastoma resistance by inducing drug inactivation

Chemotherapy drugs act as cytotoxic agents after entering cells, but many miRNAs help degrade chemotherapy drugs by regulating the expression and activity of intracellular enzymes such as cytochrome P450 isoenzyme (CYP3A4) and increase the chemotherapy resistance in GBM. Most drugs are metabolized by CYP3A4, and the expression of CYP3A4 is negatively regulated by the nuclear receptors, 1,25-dihydroxy Vitamin D₃, and progesterone X receptor (PXR).^[23] These receptors are inhibited posttranslationally by multiple miRNAs. MiR-27b and miR-125b can inhibit the 1,25-dihydroxy Vitamin D₃ receptor,^[24] and the PXR receptor is inhibited by miR-148a,^[25] which resulted in increased CYP3A4-induced chemotherapy metabolism and resistance.

MicroRNAs induce the formation of chemoresistance in a way of multidrug resistance in glioblastoma

MDR is a main reason for cancer chemotherapy failure, and the mechanism of MDR is complex. It contains a p-glycoprotein, MDR related protein family, human breast cancer resistant protein adenosine triphosphate (ATP)-binding cassette superfamily G member 2 (ABCG2) and 45 other related proteins.^[26] Again, miRNAs can regulate MDR components at the posttranslational level. P-glycoprotein, a transmembrane glycoprotein, can transport drugs from intracellular to extracellular, and thus reduce the intracellular concentration of drugs and lead to chemoresistance.^[16] In GBM chemoresistance cells, miR-451 and miR-27a were observed to be highly expressed. Moreover, inhibiting miR-451 and miR-27a lead to decreased p-glycoprotein. Consequently, this leads to a reduction in the intracellular drug efflux, suggesting the positive regulatory significance of these two miRNAs on mediating the drug efflux pump. Human breast cancer drug resistance protein ABCG2, an important drug efflux protein in cells, could aid in the development of MDR by excluding drugs from cells depending.^[27] Li et al.^[28] found that miR-328 could degrade ABCG2 and decreased expression of miR-328 in GBM cells promoted ABCG2 and chemotherapy resistance. Therefore, miRNAs can participate in GBM chemotherapy resistance through MDR.

MicroRNAs reduce the chemotherapeutic resistance of glioblastoma

MicroRNAs reduce glioblastoma resistance through ion channels

Ether-a-go-go potassium channel 1 (EAG1) is a member of EAG potassium channel family. EAG1 inhibitor can block cell cycle in premitosis.^[29] Bai et al.^[14] found that high expression of miR-296-3p functioned to suppress EAG1 protein and then lower the resistance to chemotherapy drugs. In comparison with parental U251 cell lines, miR-296-3p is downregulated in U251AR cells with chemotherapy resistance. With increased EAG1 protein expression, there was cell cycle arrest and resistance to chemotherapy. Other data showed that overexpression of miR-296-3p made cells sensitive to imatinib, while downregulation of miR-296-3p increased chemotherapy resistance in GBM.^[14] Hence, miR-296-3p may hinder the formation of imatinib resistance in GBM by regulating EAG1.

MicroRNAs reinforce glioblastoma's sensitivity to chemotherapy by retarding DNA damage repair

The enzyme, O-6-methylguanine-DNA methyltransferase (MGMT), helps repair DNA damage caused by alkylating agents.^[30] It was observed that miR-198 acted directly on MGMT, and there is a negative correlation between the protein level of MGMT and miR-198 levels. In TMZ resistant GBM cells, overexpression of miR-198 re-established TMZ sensitivity.^[31] Quintavalle et al.^[32] discovered that miR-221/222 can also depress the expression of MGMT through direct interaction with MGMTs 3′-UTR, leading to decreased DNA damage repair and increased TMZ sensitivity. MiR-603 transcript was also shown to have a negative correlation with MGMT.^[13] As expected, overexpression of miR-603 in the GBM cell line, A1207, resulted in downregulation of MGMT and increased TMZ sensitivity.^[13]

MicroRNAs decrease glioblastoma resistance by mediating epithelial–mesenchymal transformation

Epithelial–mesenchymal transformation (EMT) has been considered a key factor in the formation of chemotherapeutic resistance in GBM.^[33] A study has shown that human embryonic protein Snail family transcriptional repressor 2 (SNAI2), a zinc finger transcriptional suppressor, can induce tightly bound epithelial cells to rupture into a loose mesenchymal phenotype, namely EMT.^[34] MiR-203 has a disruptive effect on SNAI2 by binding to its 3′-UTR.^[34] Liao et al.^[12] found that miR-203 expression was significantly downregulated in resistant GBM cells U251AR and U87AR, with increased expression of SNAI2 and formation of a EMT-like phenotype. After miR-203 transfection, SNAI2 decreased, and EMT was reversed, along with sensitivity to imatinib. Therefore, miRNA may increase the chemotherapeutic sensitivity of GBM by mediating EMT.

The Probable Mechanism of Micrornas

There seems to be a balance within the cell between miRNAs that promote and inhibit chemotherapy resistance [Figure 1] and [Table 1]. However, when the expression of one of these miRNAs is either increased or decreased, this balance is disturbed and chemosensitivity is affected. The downstream effect of this imbalance can lead to several possible mechanisms: (1) Apoptosis: miR-195, miR-455-3P, miR-10a can inhibit apoptosis by inhibiting cell damage, and miR-21 has powerful and complicated functions that inhibit apoptosis by reducing the Bax/Bcl-2 ratio, promote the NF-κB and PI3K/AKT pathways. (2) Drug inactivation: miR-27b and miR-125b promote drug inactivation by inhibiting Vitamin D₃ receptor, and miR-148a promotes CYP3A4 expression by inhibiting PXR receptor. (3) MDR: miR-451 and miR-27a mediate MDR by promoting the expression of p-glycoprotein and miR-328 promotes drug outflow by inhibiting the expression of ABCG2. (4) EMT: miR-203 inhibits the formation of EMT-like phenotypes by inhibiting SNAI2. (5) Ion channel: miR-296-3p blocks the cell cycle by inhibiting the expression of ion channel EAG1. (6) DNA damage repair: miR-198 inhibits DNA damage repair by inhibiting MGMT.

Figure 1: The mechanism of miRNA in the formation of chemotherapy resistance in GBM. MiRNA-21 could inhibit apoptosis to increase chemotherapy resistance in U87MG cells. MiR-195, miR-455-3P, and miR-10a can inhibit apoptosis by inhibiting cell damage to increase chemotherapy resistance in U251R cells. MiR-27b and miR-125b promote drug inactivation by inhibiting VitD3 receptor to increase chemotherapy resistance in vitro. MiR-148a promotes CYP3A4 expression by inhibiting PXR receptor to increase chemotherapy resistance in vitro. MiR-451 and miR-27a mediate the mechanism of multi-drug resistance by promoting the expression of p-glycoprotein to increase chemotherapy resistance in HEK293 cells. MiR-328 promotes drug outflow by inhibiting the expression of ABCG2 to increase chemotherapy resistance in vivo. MiR-203 inhibits the formation of EMT-like phenotypes by inhibiting SNAI2 to decrease chemotherapy resistance in U251AR and U87AR cells. MiR-296-3p blocks the cell cycle by inhibiting the expression of ion channel EAG1 to decrease chemotherapy resistance in U251AR cells. MiR-198 inhibits DNA damage repair by inhibiting MGMT to decrease chemotherapy resistance in human samples. miRNA: MicroRNA, GBM: Glioblastoma, EMT: Epithelial–mesenchymal transformation, ABCG2: Adenosine triphosphate-binding cassette superfamily G member 2, PXR: Progesterone X receptor, VitD3: Vitamin D₃, STAT3: Signal transducers and activators of transcription 3, LRRFIP1: Leucine-rich repeat flightless-interacting protein 1, EAG1: Ether-a-go-go potassium channel 1, MGMT: O-6-methylguanine-DNA methyltransferase, NF-κB: Nuclear factor-κB, PI3K: Phosphatidylinositol 3′-kinase, AKT: Protein kinase B, CYP3A4: Cytochrome P450 isoenzyme, MDR: Mediating multidrug resistance, SNAI2: Snail family transcriptional repressor 2

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Table 1: The mechanism of microRNAs in the formation of chemotherapy resistance of glioblastoma

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Conclusion

Understanding the relationship between miRNAs and chemotherapy resistance could impact therapy in GBM. For that reason, in this paper, we review the effects of several related miRNAs on GBM resistance and their possible mechanisms, providing a basis for the treatment of chemotherapy resistance in GBM patients. The advantage of miRNA-based targeted therapy is that it exists naturally in cells and has high specificity for binding to targets. However, our understandings of these interactions are still basic at present. Therefore, before using miRNAs for chemotherapy resistance in GBM patients, further work is needed to fully understand their complex interactions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Yang JS, Lai EC. Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Mol Cell 2011;43:892-903.
2.	Van Peer G, Mets E, Claeys S, De Punt I, Lefever S, Ongenaert M, et al. Ahigh-throughput 3′ UTR reporter screening identifies microRNA interactomes of cancer genes. PLoS One 2018;13:e0194017.
3.	Iorio MV, Croce CM. MicroRNA dysregulation in cancer: Diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 2012;4:143-59.
4.	Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM, Zhang GZ, et al. Biological functions of microRNAs: A review. J Physiol Biochem 2011;67:129-39.
5.	Cai Y, Yu X, Hu S, Yu J. A brief review on the mechanisms of miRNA regulation. Genomics Proteomics Bioinformatics 2009;7:147-54.
6.	Qiu SC. Mir-233-3p Regulates the Growth of Glioma Cells and the Sensitivity of Temozolomide to Chemotherapy by Targeting STMN1. Guangzhou, China: Southern Medical University; 2015.
7.	Xiong XP, Kong L, Hu CC. Resection of parietal lobe gliomas: Incidence and evolution of neurological deficits in 28 consecutive patients correlated to the location and morphological characteristics of the tumor. Zhongguo Shenjing Zhongliu Zazhi 2005;3:290-5.
8.	Bi LP, Xu GZ. The advances in the multidiscipline modality treatment of glioblastoma multiforme. Yi Xue Zongshu 2014;20:649-52.
9.	Ma L, Sheng HS, Fan J, Liu WG. Efficacy of temozolomide combined with interferon in the treatment of glioblastoma after surgical sadiotherapy. Zhejiang Yi Xue 2008;30:401-2.
10.	Gao JF, Yao QH, Li XH, Long YB, Chen ZB. Expressions of miR-9 and PPARγ in human brain gliomas and their clinical meanings. Zhongguo Linchuang Shenjing Waike Zazhi 2018;23:17-9.
11.	Ujifuku K, Mitsutake N, Takakura S, Matsuse M, Saenko V, Suzuki K, et al. MiR-195, miR-455-3p and miR-10a(*) are implicated in acquired temozolomide resistance in glioblastoma multiforme cells. Cancer Lett 2010;296:241-8.
12.	Liao H, Bai Y, Qiu S, Zheng L, Huang L, Liu T, et al. MiR-203 downregulation is responsible for chemoresistance in human glioblastoma by promoting epithelial-mesenchymal transition via SNAI2. Oncotarget 2015;6:8914-28.
13.	Kushwaha D, Ramakrishnan V, Ng K, Steed T, Nguyen T, Futalan D, et al. Agenome-wide miRNA screen revealed miR-603 as a MGMT-regulating miRNA in glioblastomas. Oncotarget 2014;5:4026-39.
14.	Bai Y, Liao H, Liu T, Zeng X, Xiao F, Luo L, et al. MiR-296-3p regulates cell growth and multi-drug resistance of human glioblastoma by targeting ether-a-go-go (EAG1). Eur J Cancer 2013;49:710-24.
15.	Ji GH, Yang P, Zhang CY. Advances in the mechanism of chemotherapy resistance in tumors. Zhongyi Lin Chuang Yanjiu 2014;6:125-31.
16.	Chistiakov DA, Chekhonin VP. Contribution of microRNAs to radio-and chemoresistance of brain tumors and their therapeutic potential. Eur J Pharmacol 2012;684:8-18.
17.	Zhou JH, Wu DZ. Research progress on ion channels and multidrug resistance of tumors. Shijie Zhongliu Zazhi 2003;2:239-41.
18.	Shi L, Chen J, Yang J, Pan T, Zhang S, Wang Z, et al. MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing bax/Bcl-2 ratio and caspase-3 activity. Brain Res 2010;1352:255-64.
19.	Salakou S, Kardamakis D, Tsamandas AC, Zolota V, Apostolakis E, Tzelepi V, et al. Increased bax/Bcl-2 ratio up-regulates caspase-3 and increases apoptosis in the thymus of patients with myasthenia gravis.In Vivo 2007;21:123-32.
20.	Hu ZY, Zhang SY, Li F, Wu XB, Yang Z, Zhang E. Advances in research on drug resistance related signal transduction pathways in tumors. She Zhi 2014;26:412-4.
21.	Li Y, Li W, Yang Y, Lu Y, He C, Hu G, et al. MicroRNA-21 targets LRRFIP1 and contributes to VM-26 resistance in glioblastoma multiforme. Brain Res 2009;1286:13-8.
22.	Ren Y, Zhou X, Mei M, Yuan XB, Han L, Wang GX, et al. MicroRNA-21 inhibitor sensitizes human glioblastoma cells U251 (PTEN-mutant) and LN229 (PTEN-wild type) to taxol. BMC Cancer 2010;10:27.
23.	Urquhart BL, Tirona RG, Kim RB. Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: Implications for interindividual variability in response to drugs. J Clin Pharmacol 2007;47:566-78.
24.	Mohri T, Nakajima M, Takagi S, Komagata S, Yokoi T. MicroRNA regulates human vitamin D receptor. Int J Cancer 2009;125:1328-33.
25.	Takagi S, Nakajima M, Mohri T, Yokoi T. Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4. J Biol Chem 2008;283:9674-80.
26.	Zhang H, Fu LW. Multidrug resistance-associated proteins and their roles in multidrug resistance. Yao Xue Xue Bao 2011;46:479-86.
27.	Li X, Pan YZ, Seigel GM, Hu ZH, Huang M, Yu AM. Breast cancer resistance protein BCRP/ABCG2 regulatory microRNAs (hsa-miR-328, -519c and -520h) and their differential expression in stem-like ABCG2+ cancer cells. Biochem Pharmacol 2011;81:783-92.
28.	Li WQ, Li YM, Tao BB, Lu YC, Hu GH, Liu HM, et al. Downregulation of ABCG2 expression in glioblastoma cancer stem cells with miRNA-328 may decrease their chemoresistance. Med Sci Monit 2010;16:HY27-30.
29.	Chen H, Zhang L, Guo YH, Lin YL, Hong LL. Expression and significance of ether à go-go 1 channels in human ovarian cancer. Dongnan Guofang Yiyao 2016;18:17-20.
30.	Suri V, Jha P, Sharma MC, Sarkar C. O6-methylguanine DNA methyltransferase gene promoter methylation in high-grade gliomas: A review of current status. Neurol India 2011;59:229-35. [PUBMED] [Full text]
31.	Nie E, Jin X, Wu W, Yu T, Zhou X, Shi Z, et al. MiR-198 enhances temozolomide sensitivity in glioblastoma by targeting MGMT. J Neurooncol 2017;133:59-68.
32.	Quintavalle C, Mangani D, Roscigno G, Romano G, Diaz-Lagares A, Iaboni M, et al. MiR-221/222 target the DNA methyltransferase MGMT in glioma cells. PLoS One 2013;8:e74466.
33.	Iwadate Y. Epithelial-mesenchymal transition in glioblastoma progression. Oncol Lett 2016;11:1615-20.
34.	Cobaleda C, Pérez-Caro M, Vicente-Dueñas C, Sánchez-García I. Function of the zinc-finger transcription factor SNAI2 in cancer and development. Annu Rev Genet 2007;41:41-61.