Expression of lncRNAs in glioma: A lighthouse for patients with glioma

Abstract

Glioma is the most common malignant tumour in the central nervous system, accounting for approximately 30 % of the primary tumours of this system. The World Health Organization grades for glioma include: Grade I (pilocytic astrocytoma), Grade II (astrocytoma, oligodastoma, etc.), Grade III (anaplastic astrocytoma, anaplastic oligodastoma, etc.) and Grade IV (glioblastoma). With grade increases, the proliferation, invasion and other malignant biological properties of the glioma are enhanced, and the treatment results are less satisfactory. The overall survival of patients with glioblastoma is less than 15 months. Recent research has focused on the roles of long non-coding RNAs, previously regarded as "transcriptional noise", in diseases, leading to a new understanding of these roles. Therefore, we conducted this review to explore the progress of research regarding the expression and mechanism of long non-coding RNAs in glioma.

1. Introduction/background

Glioma is the most common form of primary malignant brain tumour with characteristics of heterogeneity on tumour-related genes and tumour susceptibility [1,2]. Therapeutic approaches for glioma include surgery, radiotherapy and chemotherapy; however, the overall prognosis of patients is not optimistic. In particular, the median survival time of patients with glioblastoma (GBM) is 14.6 months [[2], [3], [4]]. We discovered that the treatment options for glioma are less selective than those of other tumour types, and the overall treatment efficacy is poor. For this review, we conducted a literature search using Pubmed. We found that long-coding RNA (lncRNA) has an important role in the development and manifestation of different tumours. Abnormal expression of lncRNA is reported to be associated with the occurrence, development, recurrence, metastasis, and chemotherapy resistance of tumours. Therefore, elucidating the role of lncRNA could assist in diagnosis, prognosis, and targeted treatment. Furthermore, some tumours have entered the clinical validation stage. Postoperative treatment for patients with glioma is mainly based on chemotherapy and radiotherapy; other treatment options are significantly limited. Therefore, studying the molecular mechanisms of proliferation and invasion in glioma is important [5]. Recently, many studies have focused on the mechanisms of lncRNAs in affecting the growth of glioma [6,7]. LncRNAs belong to a large class of noncoding RNAs with a length greater than 200 nucleotides. These RNAs are involved in numerous biological processes, including cancer cell proliferation and invasion [6]. Studies have shown that lncRNAs have an important role in dosage compensation effect, epigenetic regulation, cell cycle control and regulation of cell differentiation [8]. In general, lncRNAs are divided into the following five groups according to their positions within the coding genes: (1) sense lncRNAs overlap with the sense chain of the protein coding sequence; (2) antisense lncRNAs overlap with the antisense chain of the protein coding sequence; (3) bidirectional lncRNAs sequences are located on the antisense chain more than 1000 nucleotides away from the starting point of protein transcription, and transcriptional directions between the sequences are opposite; (4) intronic lncRNAs originate from introns of protein-coding genes which are completely located in the intron of another transcript; and (5) intergenic lncRNAs originate from DNA sequences between two protein-coding genes and are not adjacent to any protein-coding gene. Research has shown that multiple lncRNAs are expressed in glioma and normal brain tissues and these RNAs are significantly different [5,6]. LncRNA expression is related to the clinical classification and prognosis of malignant glioma [9,10]. Hundreds of lncRNAs are differentially expressed in different diseases, and a growing number have been proven to be crucial in glioma pathogenesis. This article aims to outline and summarise the research regarding the expression and mechanism of action of lncRNAs on the tumour characteristics of glioma.

2. The role of lncRNA in tumour development

LncRNA exhibits various biological functions in cancer, including epigenetic regulation, DNA damage and cell cycle regulation, regulation of microRNA (miRNA), involvement in signal transduction pathways, and mediating hormone-induced cancer.

Epigenetics refers to heritable changes in genetic phenotype and gene expression, without involving changes in the DNA sequence. It mainly includes modifications such as DNA methylation, histone modification, and chromatin remodeling. Recently, research has shown that lncRNAs play a crucial role in mediating cancer through epigenetic regulation. LncRNAs can regulate gene expression through epigenetic, transcriptional and post transcriptional regulation, thus participating in various biological processes such as cell proliferation, differentiation and apoptosis in cancer. During cancer development, lncRNAs are involved in regulating various epigenetic complexes, thereby inhibiting or activating gene expression. In addition, lncRNAs can participate in gene transcription processes mediated by DNA methylation, acetylation, and other pathways to regulate tumour development. Further, lncRNAs are widely involved in regulating the occurrence and development of tumours through physiological or pathological processes such as DNA damage repair and cell cycle regulation. DNA damage repair and appropriate cell cycle checkpoint regulation are crucial for maintaining cell integrity. In cancer, lncRNAs act as regulatory molecules to regulate the P53 gene and cell cycle, thereby enhancing the transcription of various downstream genes and causing cell cycle arrest, apoptosis, or aging, maintaining the integrity of the cell genome and clearing damaged cells. Recent research has been conducted on the interaction between lncRNA and miRNA. MiRNA is associated with the occurrence and development of many cancers and can complement and pair with target RNAs, resulting in restricted gene expression and protein synthesis. LncRNAs can directly or indirectly interact with miRNAs, leading to a loss of regulatory function. The competitive endogenous RNA (ceRNA) hypothesis is a novel gene expression regulation model, in which lncRNA transcripts compete with miRNA response elements to bind to the same miRNA to regulate their respective expression levels, thereby affecting cell function. The abnormal activation of lncRNAs in signaling pathways, which in turn promotes the occurrence and development of cancer, has also been extensively studied. Therefore, research on lncRNAs is expected to lead to the development of therapeutic drugs for treating cancer.

3. Expression of lncRNAs in glioma

3.1. High expression of lncRNAs in glioma and different mechanisms of regulation

Some lncRNAs are significantly up-regulated in glioma and act as oncogenes (Table 1). Several studies have shown that lncRNAs, such as lncRNA H19, promote glioma-induced endothelial cell proliferation, migration and tube formation in vitro by down-regulating miR-29a, which may modulate the onset of glioma by affecting the biological behaviours of glioma vascular endothelial cells [11]. Other research on the mechanism of lncRNA H19's influence on glioma shows that H19 may promote glioma cell proliferation and migration by up-regulating CDK6. This influence may predict poor prognosis of patients as a result of ceRNA competing with miRNA-675 [12]. H19 is significantly overexpressed in CD133+ glioblastoma cells and increases neurosphere formation of these cells [13]. Knocking down H19 will suppress glioma cell proliferation and invasion by up-regulating miR-152 [14], providing evidence for the potential application of H19 as a therapy target for glioma. HOTAIR is another important lncRNA overexpressed in glioma, which can promote malignant behaviour through the PI3K/AKT and MEK 1/2 signaling pathways by down-regulating miR-326 [15]. Polycomb repressive complex2 (PRC2) has been found to modulate glioma cell cycle progression by binding HOTAIR's 5'domain to the PRC2 complex [16]. HOTAIR also reduces the permeability of the blood tumour barrier (BTB), resulting in decreased absorption/dose of medications such as those used in chemotherapy [17]. Importantly, HOTAIR is highly expressed in serum exosomes of patients with GBM and can be used as a peripheral tumour marker [18,19]. LINC00152 acts as an oncogene through a 3′-hairpin structure [20] and the miR-103a-3p/FEZF1/CDC25A axis [21]. Regulated by EGFR, NEAT1 is critical for glioma cell growth and invasion by binding to EZH2 and increasing the WNT/β-catenin signaling pathway [22]. It also participates in the action of ceRNA against miR-132 to regulate the expression of SOX2, thereby promoting angiogenic Akt- FGF-2/TGF-β/VEGF signaling through miR-194-5p by the same function [23]. Some researchers have testified that knocking down lncRNA XIST exerts tumour-suppressive functions and anti-angiogenesis ability in human glioma, which increases the BTB permeability by regulating multiple miRNAs [[24], [25], [26]]. Growing evidence [[27], [28], [29], [30]] shows that many lncRNAs, such as CRNDE, ADAMTS9-AS2 [31], AGAP2-AS1 [32], CASC2c [33], ECONEXIN [34], FoxD1-AS1 [35], LINC01116 [36], LINC01140 [37], MANTIS [38], MATN1-AS1 [39], MCM3AP-AS1 [40], and MIAT [41] can contribute to glioma progression. Many other lncRNAs are highly expressed in glioma cells and can promote malignancy.

Table 1.

High expression of lncRNA in glioma and different mechanisms of regulation.

3.2. Low expression of lncRNAs in glioma and different mechanisms of regulation

The down-regulated lncRNAs have anticancer effects and inhibit cell cycle and proliferation (Table 2). Dysregulation of tumour suppressors is common in all types of cancer. LncRNA GAS5 is widely studied in glioma. LncRNA GAS5 suppresses the malignancy of human glioma stem cells via a miR-196a-5p/FOXO1 positive feedback loop [42]. This research provides evidence of a ceRNA regulatory network in which GAS5 and miR-222 [43], miR-18a-5p [44], miR-424 [45] and miR-10b [46] form a reciprocal repression feedback loop to inhibit tumour proliferation. In addition, GAS5 can act directly on target genes or related signaling pathways to play a role in tumour inhibition [[47], [48], [49], [50], [51], [52], [53], [54], [55]]. MEG3, another lncRNA extensively studied in glioma, has anti-tumour mechanisms that are more complex than those of other lncRNAs. MEG3 modulates different targets such as the miR-6088/SMARCB1 [56], miR-330-5p/RUNX3 [57], and miR-96 -5p/MTSS1 axes [58]. In addition, MEG3 regulates the WNT/β-catenin [59,60] and PI3K/AKT/mTOR signaling pathways [61,62], and PTEN [63], VEGF/VEGFR [64] and other target genes [[65], [66], [67], [68], [69], [70], [71], [72]] to inhibit glioma cell proliferation, invasion and migration. LncRNA TUSC7 has an anti-tumour role in modulating miR-23b [73] and improving the sensitivity of glioma cells to temozolomide [74,75]. With deepening research, more tumour suppressor genes have been discovered, such as CASC2 [[76], [77], [78], [79]], ADAMTS9-AS2 [80], ENST00462717 [81], RPL34-AS1 [82], GAS5-AS1 [83], HOTTIP [84], Linc00320 [85], SLC26A4-AS1 [86], and TSLC1-AS1 [87]. Increasing evidence indicates that these lncRNAs may become therapeutic targets for inhibiting the malignant behaviour of glioma.

Table 2.

Low expression of lncRNA in glioma and different mechanisms of regulation.

3.3. Dual expression of lncRNA in glioma and different mechanisms of regulation

Our literature review netted research which revealed the dual expression of two lncRNAs in glioma (Table 3). LncRNA MALAT1 is one of the most conserved lncRNAs in terms of its primary sequence [[88], [89], [90]] and was first recognized as a biomarker to predict metastasis and survival in early-stage non-small cell lung cancer [91]. Research has shown that MALAT1 increases the activity of FBXW7 [92] by inhibiting the expression of miR-155 and the MMP2/ERK/MAPK signaling pathway [93], thereby having antitumour effects. In addition, MALAT1 promotes the proliferation of glioma through various ways [[94], [95], [96], [97]] by reducing the sensitivity of glioma cells to temozolomide [98,99]. Similarly, LncRNA TUG1 has an antitumour role in the upregulation of PTEN by sponging miR-26a [100]. Further, the combination of lncRNA TUG and lncRNA GATA6-AS[[101], [102]] has antitumour effects. Other studies showed that TUG1 promotes tumour vascular endothelial cell proliferation by modulating miR-299 [103], miR-6321 [104], and miR-144 [105] and the Notch pathway [106,107], thus improving the malignant biological behaviour of glioma cells. Further research is required to explore the dual expression of lncRNAs.

Table 3.

Dual expression of lncRNA in glioma and different mechanisms of regulation.

4. Conclusions and perspectives

Glioma is the most common malignant tumour in the central nervous system, accounting for approximately 30 % of primary brain tumours [1]. Glioma is broadly invasive and tends to transition from a low-grade to a high-grade tumour [108]. The 10-year survival rate for low-grade glioma is less than 50 %, and the prognosis for high-grade glioma is worse [109]. At present, the treatment is mainly surgery and adjuvant chemoradiotherapy; however, the curative effects are not optimal [2,3]. To improve the effectiveness of therapies, the pathogenesis of glioma at the genetic and molecular levels must be studied to discover new biomarkers and therapeutic targets. Specifically, breakthrough therapies incorporating lncRNAs could potentially significantly affect prognosis. Historically, due to the lack of related knowledge and research, lncRNAs have been regarded as "transcriptional noise" and transcription by-products of RNA polymerase II on lncRNAs, and therefore have not been considered to have biological effects on glioma [[110], [111], [112]]. Due to the extensive application of lncRNA deep sequencing and gene chip technology, many lncRNAs differentially expressed in glioma have been found. Recently, the research of lncRNA effects on tumours has shown geometric growth; the abnormal expression of lncRNAs found in glioma is now known to have an important role in tumourigenesis, proliferation, angiogenesis, invasion, metastasis, etc. Rynkeviciene et al. showed that lncRNA affects both transcriptional and posttranscriptional factors with complex mechanisms [111], many of which remain unclear. Many studies have found that lncRNAs are associated with glioma tissue types; this association may have an important role in the basic pathological processes of glioma [113,114]. However, further research is needed to discover the specific lncRNAs which are vital in glioma development. Enhanced diagnostic strategies and targeted therapies using lncRNAs may improve prompt diagnosis and offer new treatment options for patients with glioma.

Research on lncRNA has shown that some factors can lead to differences in lncRNA expression or lower expression abundance. One such factor is gene copy number variation (deletion or amplification). This variation occurs at the DNA level. We are aware that lncRNA needs to be transcribed. A missing or amplified corresponding gene of lncRNA on the plasmid can lead to abnormal transcription templates. In addition, transcription factors, histone modifications, and DNA methylation are influencing factors. Further research is needed on these and other factors.

LncRNA can affect various biological processes such as tumour cell apoptosis, drug resistance, and tumour metastasis, playing an important role in revealing the occurrence and development of tumours. However, research on lncRNA is still in its initial stages, and the identified functional lncRNAs are based on biological evidence. To date, the number of lncRNAs speculated by bioinformatics methods represents only a small proportion. The need for in-depth research on the mechanism of lncRNA action and its clinical application remains. Some lncRNAs related to the development of human tumours have little tissue specificity. In addition, the experimental methods for studying lncRNA are limited. Finally, the question of whether known functional lncRNAs can be applied in clinical practice to safely and effectively treat tumours remains unanswered. However, we believe that in the future, a combination of molecular biology, proteomics, and animal experiments can be used to delve into the regulatory roles that specific lncRNAs have in tumour occurrence and development. Furthermore, elucidating the signal transduction pathways that specific lncRNAs participate in during the regulation of promoters and the identification of effective targets may contribute to improving the diagnosis and treatment of tumours.

LncRNA is closely related to the occurrence and development of tumours, and new drug research and development targeting lncRNA has made certain progress. Small molecule inhibitors, nucleic acid drugs, and related regulators of lncRNA have been discovered. With the continuous discovery of lncRNA structural information and functional motifs, designing or discovering small molecule inhibitors with related targets has become a reality. Methylation inhibitor 5-azapurine-2 ′- deoxycytidine (5-aza-dC) can inhibit methylation in the imprinting control region of the H19 gene and downregulate H19 gene expression. The latest research on nucleic acid drug small interfering RNA (siRNA) has also been significant in contributing to the potential development of targeted lncRNA drugs. Research on drugs related to siRNA as a regulator to inhibit lncRNA targets is underway. The indirect regulator of lncRNA is also a new direction for drug research and development. For example, estradiol can induce the increased expression of the antisense transcript lncRNA of HOTAIR by regulating the estrogen receptor, and the overexpression of HOTAIR promotes the development of breast cancer. Therefore, using estrogen receptor inhibitors or estradiol antagonists can indirectly regulate the expression of lncRNA HOTAIR, thereby achieving anticancer effects. These studies indicate that epigenetics-based modulators have the potential to become novel drugs that will exert anti-tumour effects by regulating lncRNA expression and related pathways.

In conclusion, lncRNAs are expected to be tools for targeted treatment combined with traditional or new therapeutic approaches and may compensate for the deficiencies of other treatment methods. We believe that future investigations will lead to affluent clinical translations of glioma-associated lncRNAs and translate into novel therapeutic paradigms, thereby producing improved anti-tumour benefits for patients with glioma.

Data availability statement

No data was used for the research described in the article.

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Ethics approval

Review and/or approval by an ethics committee was not needed for this study because the study did not directly involve patients or patient care.

Informed consent

Informed consent was not required for this study because of the nature of the article.

CRediT authorship contribution statement

Xiaolin Lu: Writing – original draft. Dongzhi Zhang: Writing – review & editing, Resources, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.