MiRNAs as a potential diagnostic and prognostic biomarker in glioma.
Abstract
Glioma is the most aggressive tumor of glial cells in the brain and spinal cord. It comprises 30% of all brain tumors. Even in the presence of current multimodal therapeutic regimens, the life expectancy of more than 2 years is very rare. MicroRNAs (miRNAs) are short, non-coding RNAs produced naturally in the body and control gene expression. Many evidence-based hypotheses show that miRNA expression is aberrantly influenced in glioma due to amplification or deletion of miRNA genes, inappropriate transcriptional regulation of miRNAs, dysregulated epigenetic alterations, or faults in the miRNA biogenesis machinery. In some circumstances, miRNAs promote tumorigenesis, whereas under other circumstances, they can act as tumor suppressors in glioma. In gliomas, miRNA is involved in cell proliferation signaling, evasion of growth suppressors, resistance to cell death, tumor cell infiltration, metastasis, and angiogenesis. More and more research is pointing to miRNAs as prospective biomarkers for glioma diagnosis, prognosis, and treatment targets or tools; however, these claims have yet to be validated. Here, we discuss the role of microRNAs (miRNAs) as tumor suppressors and oncogenes in the growth of glioma.
Keywords
- MiRNA
- glioma
- carcinogenesis
- diagnostic biomarkers
- therapeutics
1. Introduction
Gliomas are the primary brain neoplasm of the central nervous system (CNS) hypothesized to develop from neuroglial stem or progenitor cells. They have histologically been categorized as astrocytic, oligodendroglial, or ependymal tumors based on their histological appearance and accordingly given WHO categories I–IV, which indicate varying degrees of aggressiveness [1]. Due to the advent of new prognostic markers of glioma, WHO updated their classification based on new molecular markers in 2016 [2, 3]. Glioblastoma multiforme (GBM) has a high degree of lethality and low median survival of ~15 months after the initial diagnosis and the five-year survival is less than 10% [4]. The centerpiece of GBM treatment is surgery, followed by radiation and adjuvant chemotherapy. The blood-brain barrier (BBB) severely restricts therapeutic agent delivery to the CNS. Therefore, the accessibility of the drug to the tumor sites is the main obstacle for the development of new therapeutics for GBM [5]. Temozolomide (TMZ) is a first-choice alkylating agent inducted as a standard therapy for glioblastoma multiforme (GBM) and astrocytoma. TMZ has limited efficacy due to the development of intrinsic and extrinsic drug resistance in glioma [6].
Growing shreds of evidence suggest that microRNA (miRNA) has a role in the onset and progression of gliomas [7]. miRNAs were first identified in the nematode
Continued research on miRNA is critical to understand its functional role in early diagnosis and treatment of GBM. This book chapter provides an overview of the pivotal role of miRNAs in glioma development, with special emphasis on their function as a diagnostic biomarker and their therapeutic potential.
2. MicroRNA biogenesis
The biogenesis of miRNA is classified into canonical and non-canonical pathways [13]. Most of the miRNAs are processed using the well-established canonical biogenesis mechanism. The microprocessor complex, comprised of the RNA-binding protein DiGeorge Syndrome Critical Region 8 (DGCR8) and the ribonuclease III enzyme Drosha, converts pri-miRNAs generated from their genes into pre-miRNAs [14]. DGCR8 recognizes N [6] methyl adenosine mark, a type of post-transcriptional modification that promotes the initiation of miRNA biogenesis [15]. RNase III enzyme DROSHA recognizes and cleaves miRNA hairpins, resulting in the release of pre-miRNAs,
Non-canonical pathways begin with shRNA being cleaved by the microprocessor complex and then exported to the cytoplasm through the Exportin5/RanGTP complex. They undergo further processing that requires Argonaute 2 (AGO2) but does not need Dicer [20]. AGO2 is an RNA-binding protein that plays a crucial role in RNA-silencing processes. It regulates chromatin structure, transcriptional gene control, and RNA splicing, and plays a critical role in the development and function of microRNAs [21]. Two different types of miRNAs are processed through the non-canonical pathway. One of them, called mirtrons, is generated from an mRNA intron during the splicing process and the other is pre-miRNA that is capped with 7-methylguanosine (m7G) [20, 22]. A functioning miRISC complex is the endpoint of all possible routes that bind to mRNA and leads to translational inhibition (Figure 1) [23].
3. MicroRNA in the pathogenesis of glioma
Over the last several decades, researchers have worked hard to catalog miRNAs with aberrant expression patterns in glioma and choose the most promising ones for further evaluation as potential therapeutic targets. Multiple studies have shown a wide variety of miRNAs that play important roles in gliomas [24]. Ten signature miRNAs were described through TCGA analysis of mRNA expression data that may be crucial to distinguish between low- and high-risk GBM patients. Three of which were tumor-suppressing (miRNA-20a, miRNA-106a, and miRNA-17-5p), and seven of which were oncogenic (miRNA-31, miRNA-222, miRNA-148a, miRNA-221, miRNA-146b, miRNA-200b, and miRNA-193a) [25]. A significant proportion of miRNAs were observed to be overexpressed in glioma compared to normal brain tissue, 95 have relatively lower expression, and inconsistent findings were detected for 17 miRNAs [26].
3.1 MicroRNAs in glioma cell proliferation, migration, and invasion
Tumor-suppressing miRNAs are progressively linked to the advancement of antitumor treatment,
Other classes of miRNAs are also reported whose upregulation suppresses tumor cell proliferation such as miRNA-1825. This miRNA was found to be decreased in GBM patients, whereas its upregulation suppresses tumor progression by targeting CDK-14 through the Wnt/β-catenin signaling pathway [32]. According to another study, miRNA-10a regulates Wnt/β-catenin signaling and induces tumor generation via targeting myotubularin-related protein 3 [33]. In glioma tissues, decreased levels of miRNA-382-5p significantly increased the proliferation, invasion, and migration of tumor cells. Conversely, the transfer of mimics of miRNA-382-5p significantly decreases neoplasm formation as well as epithelial-to-mesenchymal transition (EMT) [34]. It has been established that the EMT plays a crucial role in the spread of tumors. The miRNA-16 suppresses EMT mainly through the downregulation of p-FAK and p-Akt expression and NF-kB and slug transcriptional activity [35].
During tumorigenesis, many proteolytic enzymes, including matrix metalloproteinases (MMPs), are overexpressed. Their job is to dissolve and degrade the matrix proteins of the surrounding normal brain tissue, which act as a barrier to migration and invasion of tumor cells [36]. Compared to healthy controls, glioma patients express more MMP-9. Further studies revealed that the expression status of MMP-9 and miRNA-34a was inversely correlated. Overexpression of miRNA-34a suppressed cell proliferation and migration in human glioma cells by MMP-9 [37]. Moreover, in GBM, miRNA-25 is elevated, and its expression levels correlate strongly with disease progression. miRNA-25 silencing significantly reduces tumor cell movement and invasiveness, by increasing the expression of cell adhesion molecule 2 (CADM2). This establishes CADM2 as a suitable target for miRNA-25 since CADM2 is dramatically downregulated in glioma [38]. On the other hand, miR-146b-5p, a tumor-suppressing miRNA, has been shown to have a negative correlation with its target gene MMP16. Glioma cells exhibit considerably lower amounts of miR-146b-5p, while simultaneously displaying higher levels of MMP16. The excessive production of miR-146b-5p also facilitates the disintegration of mRNA associated with MMP16 as well as restored miRNA action against glioma cell migration and invasion [39].
Cancer patients also have abnormal TGF-β signaling, and this abnormal signaling likely plays a role in the development and progression of several malignancies, including glioma [40]. A correlation study showed a positive relationship between TGF-β concentration and miRNA-132 mRNA levels. Additionally, it is reported that miRNA-132 specifically targets SMAD7 3’-UTR, resulting in downregulation of SMAD7 expression and modification of the TGF-β signaling pathway. Patients with glioma have an inverse relationship between miRNA-132 and SMAD7 [41]. Degradation or lower level of SMAD7 promotes autophagy-induced EMT and chemoresistance in glioma [42]. Evidence from these investigations shows that aberrant miRNA expression has a major role in tumor cell growth, migration, and invasion. All these findings strengthen the case for miRNAs as a potential therapeutic target in glioma.
3.2 MicroRNAs and angiogenesis network in glioma
The development of GBM is reliant on the establishment of new blood vessels since gliomas are highly vascularized tumors [43]. In response to various stimuli, vascular endothelial cells (ECs) proliferate, migrate, and differentiate to form new blood vessels, a process known as angiogenesis [44]. More intriguing is the discovery of miRNAs regulating angiogenesis
Primary tumor endothelial cells of glioma have higher miR-296 levels than normal brain cells. Growth factor-induced miR-296 directly targets the hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) mRNA, decreasing HGS levels and reducing HGS-mediated degradation of the growth factor receptors VEGFR2 and PDGFR-β. This activates angiogenesis in glioma cells [45]. Also, dysregulation of miRNA-24 in glioma cells promotes microvascular proliferation of endothelial cells as well as enhances the expression of molecules related to angiogenesis like MMP-2, 9, VEGF, and TGF-β [46]. Additionally, miRNA-101 is downregulated in GBM as a result of that Enhancer of zeste homolog 2 (EZH2)-induced proliferation, migration, and angiogenesis. Inhibition of EZH2 in glioma reduced angiogenesis and tumor growth [47].
Several miRNAs have been identified to play a crucial role in angiogenesis, and the transfer of RNAs from GBM cells to brain endothelial cells through extracellular vesicles induces angiogenesis. miRNA-148a and miRNA-9-5p both are linked with glioma angiogenesis and poor patient survival. When miRNA-9 is supplied to human umbilical ECs (HUVEC) through GBM-derived EVs, the number and length of tubules that develop as a consequence are inextricably linked with miRNA-9 expression in HUVECs [48, 49]. Transcriptional study identified RGS5, SOX7, and ABCB1 as a miRNA-9 target. Out of these, RGS5 and SOX7 are crucial for angiogenesis and cellular proliferation [48, 50, 51]. In experimental models of GBM, suppressing miRNA-148a normalizes the abnormal tumor angiogenesis [52].
Similarly, GSCs-derived miRNA-26a promotes proliferation, migration, and angiogenesis through inhibition of PTEN [53]. Vascular endothelial growth factor (VEGF) and VEGF receptor transcriptional activity may be controlled by the transcription factor Myc-associated zinc finger protein (MAZ). MAZ expression is regulated through miRNA-125; consequently, miR-125b overexpression prevents tumor angiogenesis [54, 55]. Several other miRNAs are also identified such as miRNA-124-3p, miRNA-15b, and miRNA-152 that play important roles in glioma cell invasion and angiogenesis. Neuropilin-1 (NRP-1) promotes GBM cell development and growth that suppress miRNA-124-3p expression [56], while miRNA-15b and miRNA-152 inhibit glioma cell migration and angiogenesis through NRP-2 and MMP-3, respectively [57].
3.3 MicroRNAs in the generation of glioma stem cells
When compared to normal brain samples, GBM contains dysregulated levels of many miRNAs that play a crucial role in the generation of stem cell-like properties [26]. Loss of function assay of miRNA-663a induces proliferation, migration, invasion as well as stem cell-like properties in glioma. Gain of function assay shows overexpression of miRNA-663a represses cancer stem cell-like properties
A microarray-based screening of 455 high-grade glioma patients identified differences in the level of miRNA-10a, miRNA-10b, and miRNA-139 that are crucial for the growth and differentiation of GSCs [61]. Enhanced differentiation of neurons was seen in murine astrocytic neural stem cells, murine oligodendroglioma-derived S100-v-erbB+ stem cells, human GBM CD133+ CSCs, and GBM cell lines after transfection with miRNA-124a or miRNA-137. In addition, G0/G1 cell cycle arrest and reduced expression of cell cycle components CDK6 and phosphorylated Rb were seen after co-transfection of miRNA-124a and miRNA-137 in GBM [62]. The miRNA-302-367 inhibits clonal development and SHH/GLI1/NANONG network regulation in GBM cells by targeting CXC chemokine receptor type 4 (CXCR4) and its ligand, stromal-derived factor 1 (SDF1). These findings suggest that miRNA-302-367 regulated a key pathway essential for the regeneration of neuron and stem cell phenotype [62]. Downregulation of miRNA-29b and miRNA-125a in CD133+ GSCs was also documented [63]. Similarly, like miRNA-125a, miRNA-125b plays a critical function in controlling the expansion of GBM cells and the activity of CSCs. A reduction in miRNA-125b in GBM cells was seen after all-trans-retinoic acid treatment [64].
Several other studies also identified miRNA dysregulation in GSCs compared to GBMs. Recent studies found miRNA-128a-3p, 34-5p, and 181a-3p to be downregulated, whereas miRNA-17-5p and miRNA-221-3p were increased in stem-like cells [65]. Also, miRNA-145 was typically under-expressed in GCSs, and its upregulation enhances chemosensitivity and cellular apoptosis [66]. MiRNA-27a-3p, miRNA-22-3p, and miRNA-221-3p were delivered to GSCs by EVs from monocyte-derived macrophages, and by concurrently targeting CHD7. These miRNAs induced proneural-to-mesenchymal transition in GSCs [67]. The miRNA expression profile reveals MiR-9, miR-9(*), miR-17, and miR-106b to be significantly abundant in CD133(+) cells, which also include populations of GSCs [68].
3.4 MicroRNAs in drug resistance in glioma
Several mechanisms of drug resistance include dysfunctional DNA repair, overexpression of drug efflux transporters, apoptosis inhibition, and increased epithelial-to-mesenchymal transition. The expression levels of MDR transporters are significantly impacted by miRNAs, which play a crucial role in controlling glioblastoma MDR [69]. Among the ABC transporter family, ABCG2 is particularly prominent in glioblastoma [70]. Downregulation of miRNA-328 reduces ABCG2 expression and chemoresistance in glioblastoma, suggesting that miRNA-328 plays a critical role in ABCG2 expression [71]. Therefore, miR-328 therapy combined with radiation or chemotherapy may be a useful approach for treating GBM [72]. Likewise, miRNA-1268a is downregulated after the TMZ treatment as a result of its target membrane transporter ABCC1/MRP1 being upregulated. Contrarily, overexpression of miRNA-1238a inhibits protein translation of ABCC1 and restores sensitivity to Temozolomide (TMZ) [73]. Moreover, by repressing miR-128-3p’s effects on MRP1, RUNX1 makes GBM resistant to TMZ. Overcoming TMZ resistance in GBM may be possible
Reversal of MDR in glioblastoma cells is also described after overexpression of miR-9 levels, which is associated with the suppression of ABC transporters such as MDR1, ABCC3, and ABCC6 [75]. In GBM, miRNA-381 was shown to be overexpressed; blocking miRNA-381 or driving neurofilament light polypeptide (NEFL) expression and greatly sensitizing GBM cells to the chemotherapeutic drug TMZ. Multiple multidrug resistance proteins (ABCG2, ABCC3, and ABCC5) and stemness factors (ALDH1, CD44, CKIT, KLF4, Nanog, Nestin, and SOX2) are the possible target of miRNA-381 by which these cells are sensitized to TMZ [76]. The ABCB1 is another drug efflux transporter that is overexpressed in resistant GBM cells and the study identified that expression of the transporter is controlled through miRNA-4539 and miRNA-4261 [77]. The aforementioned research emphasizes the importance of miRNA in ABC transporter-mediated drug efflux and suggests it as a viable therapeutic target for reestablishing chemosensitivity in gliomas.
Temozolomide is a first-choice alkylating agent inducted as a standard therapy for GBM and astrocytoma [78]. TMZ has limited efficacy due to the development of intrinsic and extrinsic drug resistance [79]. TMZ is an alkylating agent that generates methyldiazonium cation transfers their methyl group on N7 and O6 sites of guanine and the N3 on adenine [80]. The TMZ adduct imparts mutation in DNA fixed
DNA mismatch repair (MMR) is a mechanism that detects and repairs DNA replication and recombination errors, including insertions, deletions, and misincorporations of nucleotides [81]. Compared to other cell types, radioresistant glioma cells had considerably high levels of DNA2 and low levels of miR-3059-3p. It has been identified that miR-3059-3p regulates radioresistance by targeting DNA2 and controlling homologous recombination pathways through Rad51 & 52. MiR-3059-3p-mediated downregulation of DNA2 inhibited the HR pathway, making GBM cells more radiosensitive [82]. Glioma cell proliferation is inhibited and senescence-related genes p53, Cdkn1a, and Cdkn2c are upregulated after delivery of miR-34a. Increased levels of miR-34a also reduce telomerase activity, shorten telomeres, and cause DNA damage. Forced overexpression of SIRT1 can counteract these pro-senescent effects [83].
Patients with GBM exhibited downregulation of miRNA-198 [84]. Reduced levels of these miRNAs are associated with a worse outcome for patients. Increased chemosensitivity to TMZ is also associated with elevated expression of miRNA-198, as shown by
Additionally, multiple studies have shown the role of miRNAs in GBM tumorigenesis and onset of chemoresistance via activation of base excision repair proteins such as PARP, XRCC, Rad51, and others [87]. miRNA-151a depletion led to the development of TMZ resistance. And according to another study, enhanced miRNA-151a production sensitizes TMZ-resistant GBM cells by decreasing XRCC4-mediated DNA repair [88].
4. MicroRNA as glioma diagnostic biomarker
As we discussed earlier, miRNAs act as either oncogenes or tumor suppressors in glioma. Changes in the expression of these molecules have been linked to several cancer types, making them a promising molecular tool for non-invasive cancer detection and prognosis [89]. Hereby, we list some of the miRNAs that could be of diagnostic and prognostic significance (Table 1).
S.No. | Name of miRNAs | Sample Type | Marker Type | Reference |
---|---|---|---|---|
1. | miRNA-21. | Tissue, Plasma, EVs, CSF, plasma, and serum. | Diagnostic and Prognostic. | [90, 91, 92, 93] |
2. | miRNA-128, miRNA-342-3p. | Plasma | Diagnostic and Prognostic. | [93] |
3. | miRNA-221 | Tissue, CSF, Plasma, and serum. | Diagnostic | [90, 94, 95] |
4. | miRNA-451 | EVs | Diagnostic | [96] |
5. | miRNA-182 | Tissue and Plasma. | Diagnostic | [97, 98] |
6. | miRNA-27a | Tissue, EVs, and CSF. | Prognostic | [99, 100] |
7. | miRNA-21-5p, miRNA-218-5p, miRNA-193b-3p, miRNA-331-3p, miRNA-374a-5p, miRNA-548c-3p, miRNA-520f-3p, miRNA-27b-3p, miRNA-30b-3p. | CSF | Diagnostic, Prognostic. | [101] |
8. | miRNA-125, miRNA-222. | CSF, Blood. | Diagnostic | [102] |
9. | miRNA-10b | Tissue, CSF, Serum. | Diagnostic, Prognostic. | [92, 103] |
10. | miRNA-183 | Tissue | Prognostic | [104] |
5. Therapeutic potential of miRNAs in glioma
Overall, the findings described in this chapter show that miRNAs are implicated in many pathways that worsen glioma patients’ prognoses by promoting tumor growth, invasion, and resistance to therapy. What needs to be examined are the translational implications of these results and strategies to utilize this information in clinical practice. As we are aware, cancer is a complex disease that develops and spreads
Scientists are actively investigating how to alter synthetic miRNAs to facilitate better translocation to host cells
Recent studies also employ polymer nanoparticles as delivery vehicles for microRNAs (miRNAs) in GBM. Commonly used polymers include Poly (lactic-co-glycolic acid) or PLGA and Polyethyleneimine (PEI). Increased TMZ chemosensitivity was seen in both
6. Conclusion
Genome-wide profiling shows that miRNA expression is linked to tumor subtype, tumor grade, and patient outcomes in different cancers including glioma. Hence, miRNAs can be used as diagnostic, prognostic, and therapeutic biomarkers. Since it has been shown that miRNA deletion or overexpression is associated with glioma, researchers all over the globe have been trying to determine what functions miRNA play in cancer and what causes their expression to be dysregulated. MicroRNAs are hypothesized to behave as oncogenes or tumor suppressors in glioma by modifying particular targets. Numerous therapeutically promising miRNA antagonists and miRNA analogs are now in clinical trials, but further work is required to verify them as diagnostic and prognostic biomarkers in a large cohort of patient samples.
Acknowledgments
Manendra Singh Tomar is the recipient of a Junior research fellowship from the University Grants Commission, Government of India.
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