Abstract
Neuroblastoma is known as the most prevalent extracranial malignancy in childhood with a neural crest origin. It has been widely accepted that non-coding RNAs (ncRNAs) play important roles in many types of cancer, including glioma and gastrointestinal cancers. They may regulate the cancer gene network. According to recent sequencing and profiling studies, ncRNAs genes are deregulated in human cancers via deletion, amplification, abnormal epigenetic, or transcriptional regulation. Disturbances in the expression of ncRNAs may act either as oncogenes or as anti-tumor suppressor genes, and can lead to the induction of cancer hallmarks. ncRNAs can be secreted from tumor cells inside exosomes, where they can be transferred to other cells to affect their function. However, these topics still need more study to clarify their exact roles, so the present review addresses different roles and functions of ncRNAs in neuroblastoma.
Introduction
Neuroblastoma (NB) is known as the most prevalent extracranial malignancy in childhood, mostly affecting infants and young children [1]. NB is a peripheral sympathetic nervous system cancer arising from immature neuroblasts, and 95% of cases are diagnosed in children under 5 years, and more frequently in boys by 13%. NB involves abnormal proliferation of undifferentiated neural crest cells [2]. In Europe, the annual incidence is six cases per million [3]. NB patients show a wide range of responses to current treatment. Some patients have an ideal outcome with a near-complete cure, while others have shown treatment resistance and a poor prognosis [4,5,6,7]. The NB prognosis is directly related to the age at disease onset. Infants have the best prognosis with a 5-year survival rate of nearly 91%, while in 10–14 year old children the five-year survival rate decreases to 56% [8, 9].
The anatomical sites where NB develops as a solid tumor, include the paravertebral ganglia, adrenal glands, and/or the neck. Although it can potentially spread, NB diagnosis usually occurs in the early stages prior to its spread [3]. There are many different options for treatment of NB, such as surgery, chemotherapy, and radiotherapy. The choice of treatment depends on the tumor presentation, but chemotherapy is the main choice that is used as a standard treatment for NB [2].
The progress in nucleic acid sequencing has enabled us to recognize various types of non-coding RNAs (ncRNAs). Some of them are highly conserved across species, like microRNAs (mi-RNAs) and circular RNAs (circRNAs), while others generally lack conservation across species, such as long-non-coding RNAs (lncRNAs) [2, 3, 10, 11]. ncRNAs account for nearly 60% of the transcriptional output in human cells, and act to regulate cellular pathways and behavior in both pathological and developmental settings [12, 13]. Non-coding RNAs participate in cell regulatory networks by complementary base pairing with specific sequences of DNA or messenger RNA (mRNA). Some ncRNAs, such as miRNAs can target the mRNA sequences of many different genes, while the mRNA of each gene can also be targeted by more than one miRNA [14, 15]. MiRNAs can bind to other types of ncRNAs to increase their stability. LncRNAs and circRNAs can affect the amount and activity of miRNAs by different kinds of pathways and mechanisms, such as sequestration and competition. As key regulators, ncRNA complex structures can affect many essential and important cellular programs. NcRNAs are involved in the activity of many networks, making an understanding of their entire network difficult. Many ncRNA interactions follow distinct patterns, or motifs in large networks from biological to social [16, 17].
In this review, we examine the role of ncRNAs, including miRNAs, lnc RNAs, circRNAs and in NB. We also address the role of exosomal ncRNAs, which are secreted from tumor cells inside exosomes (small extracellular vesicles), where they can be transferred to other cells to alter their function. In recent years the role of RNA-based therapeutic agents has started to be investigated, so it is necessary to understand the activity of complex ncRNA networks in many cancer types, but here we concentrate on NB diagnosis and treatment [18].
MicroRNAs and NB
MiRNAs are small ncRNAs consisting of 19 to 22 nucleotides, and are derived from much larger RNA precursor sequences by the action of RNA cleavage enzymes DICER and DROSHA [19, 20]. These small ncRNAs perform important post-transcriptional regulatory functions by base pairing to complementary sequences present in the 3′ UTR region of specific mRNAs. This binding results in either mRNA destruction or translational prohibition by the RNA-induced silencing complex (RISC). Another part of the gene sequence, which could be targeted by miRNAs is the 5′ UTR or exonic regions, but proteomic studies have revealed that the most important is 3′ UTR sequence targeting [21,22,23]. It was first thought that miRNAs were negative regulators of gene expression at the post-transcriptional level, but further research revealed that some miRNAs could increase mRNA translation in non-proliferating cells, while others could play a regulatory role by targeting complementary sequences in gene promoters [24]. Lines of research have examined the role of miRNAs in cancer, and have found that miRNAs can play either an oncogenic (cancer promoting role) or a tumor suppressor role in various cancers by affecting a range of cell processes such as immune escape, metastasis, apoptosis, proliferation, invasion, migration, and angiogenesis [25,26,27,28]. Along with other cancer types, miRNAs play several key roles in NB pathogenesis [29,30,31]. MiRNA expression profiles in tumor biopsies have been correlated with poor prognosis, more aggressive disease, and poor patient survival [30, 32,33,34]. Some in vitro and in vivo experiments have demonstrated that miRNAs could have positive as well as negative effects on the different Hallmarks of tumors, such as proliferation, invasion, drug resistance, and apoptosis in NB cells [30, 34,35,36,37]. In this section, we review these functions of miRNA in NB, separately (Table 1). Figure 1 also illustrates the role of miRNAs and miRNA inhibitors in NB.
A MicroRNAs are incorporated into the RISC complex to target-specific mRNAs in NB cells, resulting in downregulation or upregulation of target gene expression, and affecting tumor progression. B Anti-miRs inhibit miRNA function by preventing them from binding to their target mRNA, resulting in tumor cell death when miRNA expression is reduced [323].
Invasion, migration, and metastasis
Recent literature has reported the role of miRNAs in metastasis of NB tumors by promoting some processes such as invasion, migration and EMT. For instance, Doublecortin-like kinase 1 (DCLK1) is a protein with two N-terminal doublecortin domains that mediate a wide range of protein-protein interactions [38]. DCLK1 participates in various cell processes like neurogenesis, angiogenesis, DNA damage repair, and retrograde transport [39, 40]. DCLK1 was shown to increase the number of cancer stem cells and lead to regulation of tumor cell pluripotency [41]. Moreover, DCLK1 was overexpressed in colorectal cancer (CRC) where it increased metastasis and prevented cell cycle arrest [42, 43], and it could also promote the epithelial-mesenchymal transition (EMT) in CRC through the PI3K/AKT/NF-B pathway. In pancreatic cancer, DCLK1 could increase cell viability and promote metastasis [1, 44]. The function of miRNAs in NB was evaluated in a study by Wan and colleagues. The authors utilized transwell assays and cell counting kit-8 (CCK-8) to evaluate cell viability and invasion [45]. They evaluated protein expression and EMT markers by Western blotting, and used quantitative real time polymerase chain reaction (qRT-PCR) [45] to measure miRNA and mRNA levels. In NB tissues, they found that miR-424 was down-regulated while DCLK1 was upregulated. Mir-424 influenced DCLK1 expression through targeting the 3’-UTR of DCLK1 mRNA in SK-N-SH and Be2C cells. Mir-424 was able to inhibit cell invasion, viability, and the EMT by inhibiting DCLK1 mRNA. Therefore the mir-424/DCLK1 axis could provide new insights into NB pathogenesis [45].
The matrix metalloproteinase enzymes (MMPs) are members of the zinc-dependent endopeptidase family, which participate in many pathological and normal physiological processes [46]. MMPs play pivotal roles in several cellular processes, including cleaving protein substrates, and producing extracellular matrix degradation to facilitate cell invasion and migration. As well as regulating cell proliferation and apoptosis by controlling protein cleavage, they could also modulate several relevant signaling pathways [47]. In a study by Yuan and colleagues, they evaluated the correlation between MMP-2 (matrix metalloproteinase-2) and micRNA-338-3p in NB cells, and also investigated the regulatory mechanisms and pathways of MMP-2 and mir338-3p [48]. They used miRcode and miRbase bioinformatics tools to predict the target interaction regions of mir-338-3p and MMP-2 mRNA. Correlations between MMP-2 and mir338-3p expression values in NB tissues and SK-N-SH and GI-LI-N NB cells were evaluated by qRT-PCR. Other cell functions were evaluated, including apoptosis by flow cytometry, invasion by Transwell assay, and proliferation by CCK-8 assay. They observed downregulation and overexpression of miR-338-3p and MMP-2, respectively, in metastatic tumor samples. MMP-2 knockdown was associated with reduced EMT and led to lower proliferation and invasion of NB cells. These effects were the same as the effect of mir-338-3p upregulation in malignant cells. MMP-2 overexpression reduced the prohibitory effects of mir-338-3p on NB cells invasion and growth, and increased the metastasis. Thus, their findings revealed that mir-338-3p is able to prohibit cell invasion, growth, and EMT while also promoting apoptosis in NB via targeting MMP-2 and affecting the PI3k/AKT pathway [48].
The non-muscle myosin II (MYH9) is the main protein, which produces intracellular contractile forces and tension during morphogensesis, cytokinesis, spreading, and migration [49,50,51]. MYH9 expression is associate with unfavorable outcomes in those suffering from non-small cell lung cancer, and the miRNA let-7f could target MYH9 mRNA to reduce metastasis and invasion in gastric cancer [52]. Plectin (PLEC) is a member of the plakin family, and acts as a cytoskeletal linker protein to modulate the cytoskeleton stability and dynamics. PLEC can mechanically stabilize the cell by connecting intermediate filaments to desmosomes and hemidesmosomes. PLEC high expression was shown to be associated with unfavorable outcome in those with breast and colorectal malignancy. Because of its ability to stabilize invadopodia, PLEC can promote cancer metastasis by its anchoring to vimentin intermediate filament scaffolds [49, 53, 54]. Nolan and colleagues investigated the anti-oncogenic effects of mir-124-3p in vitro using mesenchymal NB and drug-resistant adrenergic cell lines. They also showed it could reverse cellular transformation [50]. Mir-124-3p low expression was associated with unfavorable outcomes and shorter survival rate in patients. Furthermore, mir-124-3p caused cell cycle arrest and decreased cell viability in vitro. Overexpression of mir-124-3p sensitized cells to chemotherapy drugs, and overcame drug-resistance in a panel of morphologically distinct NB cell lines. Collectively, their results showed that mir-124-3p directly targeted MYH9, PLEC, and ACTN4 to reduce invasion and reverse the resistance-associated EMT [50].
Cell growth and proliferation
The role of miRNAs in cell growth and proliferation of NB cells has been also revealed in multiple studies. For instance, the lysine-specific demethylase 1A (KDM1A) was first enzyme identified as being involved in histone demethylation, an epigenetic regulatory mechanism [55]. It has been unveiled that KDM1A binds to histone substrates via its SWIRM domain, and then demethylates them with the REST corepressor (CoREST), which controls downstream gene expression under both normal as well as pathophysiological circumstances [56, 57]. KDM1A was expressed in different kinds of tumors, including NB, chondrosarcoma, rhabdomyosarcoma, breast, bladder, prostate, lung, gastric, and colorectal cancer [58,59,60]. KDM1A plays various roles in different cancers. For example, it promotes cell proliferation in NB, while it reduces apoptosis in glioma. KDM1A could silence the TIMP metalloproteinase inhibitor 3 (TIMP3), leading to increased invasion in non-small cell lung cancer [6, 61, 62]. A zinc finger protein called ZNF346 (zinc finger 364), a member of the ZNF-protein family, was recently shown to be correlated with cancer, where it was involved in modulating apoptosis and proliferation in NB cells [4, 63, 64]. In the study by Wei and colleagues, they evaluated the functional role of mir-542-3p in the pathogenesis of NB [65]. They reported that ZNF-346 and KDM1A were upregulated and were negatively associated with miRNA-542-3p values. KDM1A suppression led to increased invasion and proliferation in NB cells, as well as to overexpression of mir-542-3p. A high level of mir-542-3p decreased the ZNF345 and KDMA1 levels, while on the other hand, ZNF346 and KDMA1 upregulation reduced mir-542-3p effects on NB cells. The study demonstrated that mir542-3p led to the inhibition of tumor growth in vivo. Their data analysis revealed that mir542-3p targeted KDMA1 and ZNF346, resulting in the downregulation of invasion and proliferation, thus it may provide physicians and scientists with a new approach for NB treatment [65].
The NF-κB transcription factor is upregulated in different kinds of solid tumors including NB [66, 67]. The NF-kB dimer is in an inactive form in the cytoplasm because it is bound to inhibitor of κβ (Iκβ-a) protein. The phosphorylated Iκβ-a is degraded in proteasomes, and the NF-κB dimer can then translocate to the nucleus [68]. The NF-κB is activated in the nucleolus by the catalytic subunit of the IKK complex (IKKβ) [69,70,71]. It has been found that activation of NF-κB signaling promotes tumorigenesis and also resistance to therapy [72,73,74,75,76]. Furthermore, NF-κB can reduce apoptosis in tumor cells by increasing anti-apoptosis gene transcription [77]. Zhou and colleagues evaluated the function and mechanism of mir-429 in NB progression [78]. In their study the target genes for mir-429 were determined by luciferase and Western blotting assays, and also its effects on NB cell migration were evaluated by transwell and scratch wound healing assays. They used a mouse xenograft model with cells showing overexpression of mir-429, and its effects on cell proliferation, apoptosis, and colony formation were assessed. They found that mir-429 induced apoptosis and also reduced proliferation. The reported that miR-429 could bind to the 3’-UTR of IKKβ mRNA. Exogenous overexpression of IKKβ reversed the mir-429 effects in NB cells, and restored proliferation. Overexpression of mir-429 in the xenograft mouse model reduced the tumor growth rate. They suggested that mir-429 could possibly be utilized in NB therapy [78].
Drug resistance
Drug resistance is another process which is important in the progression of tumor cells. Several miRNAs has been found to be involved in this process in NB cells. The MYCN gene encodes the N-myc proto-oncogene, and its expression is associated with unfavorable prognosis and low survival rate in those suffering from NB [51]. The main role of MYCN is to modulate the transcriptional program in a similar manner to MYC [79, 80]. The prognostic significance of MYCN was shown and additionally, it is considered as a novel potential target for NB treatment. BRD4 is an essential chromatin regulator involved in DNA damage and gene regulation. BRD4 stimulate the transcription of several tumor promoter genes, such as MYC, in several malignant cells [81]. Recently it was reported that in MYCN-amplified NB cells, BRD4 binds to the MYCN super-enhancer to promote its transcription [82]. Hence, BET inhibitors (BETis) with the ability to target MYCN was introduced as a novel treatment in MYCN-amplified NB [82, 83]. Moreover, overexpression of MYC also denotes a subset of high-risk patients [84]. Therefore, BRD4 can be taken into account as a potential target in those with high-risk NB with MYC overexpression or amplification. However, two clinical trials conducted among those with solid malignant tumors, have shown that early resistance to BET-is was associated with lower efficacy [85, 86]. Liu et al. evaluated the effects of BET-Is and mir-314-3p on the growth of high-risk NB cells [87]. They found that mir-3140-3p could suppress cell growth in MYCN-amplified NB cells by downregulation of both NMYC and MYC. To assess the response to BET-Is they cultured acquired BET-Is resistant NB cells, then they evaluated the resistance mechanism and functions of BET-Is in NB cells. They found that ERK1/2 acted to increase MYCN stability by blocking proteolysis mediated by ubiquitin through MYCN phosphorylation at Ser62 in NB cells, which were resistant to BET-Is. Additionally, mir-3140-3p was shown to be able to decrease the expression of MYCN via targeting the MAP3K3-ERK1/2 pathway and prohibition of BRD4, and suppress cell growth in NB cells resistant to BET-Is. Therefore mir-3140-3p could function as a target to overcome BET-I resistance in NB [87].
Apoptosis
Apoptosis is a well-known process that can be a good target for treatment of cancer cells. Previous studies has been conducted to evaluate the role of miRNAs in this process in varios cancer cell types such as NB. The CDC42 (Cell division cycle 42) protein has been linked to cell cycle progression, invasion, growth, migration, and angiogenesis in a variety of malignancies [75]. In different kinds of malignancies such as; gastric cancer, nasopharyngeal, glioma and also the NB cancer it has the oncogenic effects [77, 78, 88, 89]. Unlike CDDC42 the BCL2 (B-cell lymphoma2) play an initial roles in the apoptotic mechanism of cancer, which could be used as an important factor in cancer therapies [90, 91]. An experiment revealed that miR-34a can prohibit NB cells progression via suppressing BCL2 [92]. In a study by Mao et al., the effects and mechanisms of mir-149 were evaluated in NB cell apoptosis and proliferation, as well as the chemosensitivity to doxorubicin (Dox). They evaluated apoptosis by flow cytometry, and proliferation by MTT and colony formation assays, along with the sensitivity to doxorubicin. Interactions between mir-149 and BCL2 or CDC42 mRNAs were evaluated by RNA-immunoprecipitation and luciferase analysis. They found that a lower expression of mir-149 was associated with unfavorable outcome in NB patients. The overexpression of mir-149 reduced colony formation and proliferation, activities but increased apoptosis, and sensitized NB cells to Dox treatment. In addition, both BCL2 and CDC42 were found to be targets of mir-149, and the enhancement in their expression was able to reverse the mir-149 effects. They proposed that mir-149 could be used in a new approach to NB treatment [93].
Long-non-coding RNAs and NB
lncRNAs are ncRNAs with several essential roles in biological processes, surpasses 200 nucleotides in length [94,95,96]. Figure 2 shows the classification of lncRNAs based on their location within the genome. A large number of ncRNAs, including lncRNAs, have been identified to be implicated in several important cellular functions and their deregulation has been demonstrated to be an underlying cause of cancer initiation and progression in different malignancies. Lines of research revealed that lots of lncRNAs could act as a tumor suppressor or promoter via affecting cell proliferation, invasion, and cell cycle progression. For instance, the lncRNA XIST (X-inactive-specific transcript) plays a different role (pro-cancer or anti-cancer) in various kinds of cancer, such as cervical, breast, pancreatic and also in NB [97,98,99,100,101]. Many studies have shown that lncRNAs could have various effects on the different properties of tumors, such as proliferation, invasion, cell cycle, and autophagy in NB cells. In this section, we review these functions of lncRNAs in NB, separately. Some of the lncRNAs, which are deregulated and involved NB pathogenesis are listed in Table 2 [102,103,104,105].
An intronic sequence arises from the intron of a gene, while an antisense is generated from the antisense strand of either the intron or exon region. eRNAs (enhancer RNAs) arise from the enhancer zone of transcription and possess 5′ cap methylation and polyadenylation with a limited half-life. Moreover, pseudogene RNAs are transcribed from a pseudogene and may be either long or short. Sense RNAs are lncRNAs generated by transcription of genes located in the sense strand, some of which are protein-coding and result in mRNA synthesis. Intergenic RNAs are transcribed from an intergenic zone located more than 1 kb away from the nearest gene. Finally, bidirectional RNAs are transcribed from a gene locus located on the opposite strand and transcription occurs from a region less than 1000 bp away [324].
Cell growth and proliferation
Controlling of cell growth and proliferation of tumor cells is the key and important aim of cancer treatments. Many examinations has observed the role of lncRNAs in NB cells’ proliferation and growth.
L1CAM (L1 cell adhesion molecule), is a transmembrane glycoprotein belonging to the immunoglobulin superfamily, and participates in nervous system development [106]. L1CAM could be involved in peri-neural invasion by enhancing the expression of metalloproteinase in pancreatic malignancy [107]. Furthermore, L1CAM levels were correlated with prognosis and progression in both endometrial cancer and glioblastoma [108, 109]. Yang et al. investigated how XIST affected the progression of NB [110]. They used MTT assay, colony counting, and flow cytometry to measure cell proliferation, colony formation, and the cell cycle status, respectively. They also measured the xxpression values of XIST, miR-375-5p, and L1CAM mRNA using qRT-PCR. In vitro, the downregulation of XIST was associated with suppressed tumor growth and increased NB cells’ radiosensitivity by modulating the miR-375-5p/L1CAM/XIST axis. Moreover, the investigators observed that the prohibitory effect of XIST downregulation on proliferation of NB cells was overturned when miR-375 was suppressed [110].
Invasion, migration, and metastasis
LncRNAs has been also found to be involved in the process of metastasis and migration. Axl is a member of receptor tyrosine kinases (RTKs), which includes Tyro2, Tyro3 and Tyro4 [111]. Axl has immunoglobulin (Ig)-like domains, two fibronectin domains, and a kinase domain [112,113,114]. It has been validated that MerTK and Axl are involved in several cancer cellular activities, including cell differentiation, survival, proliferation, and adhesion. It was shown that inhibition of Mer or Axl is associated with increased chemosensitivity and cell death in NB [115,116,117]. Bi et al. investigated the expression of Axl in NB cells, and found that its expression is upregulate and has a positive association with MALAT1 (metastasis associated lung adenocarcinoma transcript 1). The authors also found out that the Axl was regulated by MALAT1 and could affect invasion and migration in NB cells. They found that targeting Axl using a selective small molecule inhibitor (R428) significantly suppressed the ability of NB cells to invade and migrate [118].
DKK1 is a secreted glycoprotein, which has received a lot of interest due to its involvement in several cancers. In vitro experiment demonstrated that MYCN is able to decrease the DKK1 expression in the NB cell lines, SHEP-21N and SKNAS-NmycER, and to inhibit NB cell growth. MYCN upregulation was detected in around one fifth of primary NB patient samples, and is was associated with unfavorable outcomes. DKK1 reduced and triggered the motility and apoptosis of NB cells [119,120,121,122]. The histone methylation of the DKK1 gene is a type of epigenetic regulation that maintains a fundamental role in biological and pathological processes. Increasing evidence suggests that NB development can be affected by DNA methylation, but its association with tumorigenesis has not been completely established. Although there may be a substantial effect of DKK1 on cell proliferation, motility, and apoptosis, there is still lack of data concerning the role of DKK1 in cells with or without MYCN upregulation [123,124,125]. In NB, abnormal overexpression of EZH2 suppressed multiple tumor suppressor genes, contributing to an undifferentiated phenotype and a poor prognosis. H3K27me3 is a repressive histone mechanism that participates in cancer process by regulating gene expression and provoking histone methylation [126, 127]. Zhang et al. investigated the role of XIST in NB. QPCR was used to measure the expression values of XIST in NB in vitro and in vivo, and Western blotting was used to measure DKK1 protein expression. The influence of XIST on cell proliferation, migration, and invasion in vitro, as well as carcinogenesis in an NB animal model, was investigated. The binding between XIST and EZH2 was confirmed using RNA pull-down and immunoprecipitation experiments [39]. It was found to be statistically linked to age as well as International NB Staging System (INSS) staging in those suffering from NB, and it was also detected to be substantially increased in NB in vitro and in vivo. XIST inhibited DKK1 via activating H3 histone methylation by EZH2, allowing NB cells to proliferate, migrate, and invade while slowing tumor development [99].
Cell cycle
Regulating cell cycle in tumors such as NB is a potential way for decreasing their progression. In this way lncRNAs are found to take critical roles. For example, a lncRNA found in NIH 3T3 mouse fibroblasts showing increased expression following serum deprivation or rapamycin-stimulated cell cycle arrest, was called GAS5 (growth arrest-specific 5), which is made up of 12 exons, 10 box C/D sno-RNAs (small-nucleolar RNAs), and a 5′-terminal oligo-pyrimidine segment (5′ TOP), and contains more than 28 splice variants. Some experiments revealed apoptotic and anti-growth feature of some GAS5 splice variants in malignant cells; however, further research is demanded to clarify all the function of these variants. GAS5 expression was also found to be lower in a number of advanced cancers, including gastric, bladder, non-small-cell lung, and breast cancer [128,129,130,131,132,133,134,135].
Mazar and colleagues examined the influences of GAS5 on NB progression and growth [136]. They found that GAS5 expression was higher in MYCN-amplified as well as non-amplified cell lines that were used in their study. GAS5 knockdown in both NB cell lines inhibited proliferation, and led to apoptosis and cell cycle arrest. They found new splice variants in sequenced GAS5 clones, two of which were involved in both cell lines. The global transcriptional alteration analysis in cells with GAS5 knockdown declared that p53 stimulation could be the cause of cell cycle arrest. It was also shown that phosphorylation of p53 and BRCA1 can contribute to cell cycle arrest by GADD45A activation. The knockdown of GADD45A and BRCA1 prevented cell cycle arrest by causing p53 loss, so apoptosis was greatly enhanced. Cell cycle arrest following GAS5 knockdown, followed by complementation with the GAS5 FL variant but not the C2 variant, recovered cell cycle arrest via stabilizing HDM2, resulting in p53 loss. Collectively, GAS5 expression is important in NB cell biology processes, and that GAS5 variant splice expression plays an important role by controlling proliferation or apoptosis [137].
Autophagy
Previous studies have reported the role of lncRNAs in autophagy, which is a promising potential therapeutic target in cancer treatment. Autophagy is an intracellular degradative mechanism that happens under various stressful status, such as cancer. The regulation of autophagy plays negative or positive roles in tumor suppression or promotion in various cancers [138].
ATG-5 (autophagy-related gene-5) maintains a mandatory role in controlling apoptosis and autophagy. ATG-5 was found to be a novel target for different kinds of miRNAs to modulate autophagy. For instance Cheng et al. evaluated the role of mir-34 in inhibiting NB progression through downregulation of ATG-5 expression [139,140,141,142,143]. Wen and colleagues evaluated the role of SNHG16 in NB progression. QRT-PCR was recruited to assess the expression levels of SNHG16, ATG-5, and mir-542-3p [144]. The NB migration, proliferation, and invasion were assessed with MTT and transwell assays. A dual-luciferase assay and starBase bioinformatics were used to assess the binding between ATG-5, SNHG16, and mir-542-3p. Western blotting was used to assess the levels of ATG5, p62, and microtubule-associated protein A1/1B-light chain3 (LC3-I/II). SNHG16 knockdown inhibited processes in NB cells, such as proliferation, migration, invasion, and autophagy. Further investigation revealed that ATG-5 was modulated by SNHG16 sponging mir-542-3p, and that downregulation of mir-542-3p overturned the prohibitory impacts of SNHG16 suppression on NB biological processes. Altogether, SNHG16 is able to increase NB migration, proliferation, invasion,, and autophagy by sponging mir-542-3p and overexpressing ATG-5 [144].
Circular RNAs and NB
Circular RNAs (circRNAs) are transcribed from introns or exons and form closed loops by covalent cross-linkage between the two ends (Fig. 3) [145]. CircRNAs can function as miRNA sponges and inhibit their ability to modulate mRNA translation. For instance, circATP82A2 suppressed miR-443 function by directly binding to it [146]. CircRNAs are produced widely in eukaryotic cells and are participated in the pathogenesis of numerous chronic conditions, including cancer, diabetes and cardiovascular disease (CVD) [11, 147, 148]. The miRNA-circRNA interplay has a major role in tumorigenesis. For example, circ0103552 enhanced cellular invasion and proliferation in breast cancer by sponging miR-1236 [149]. Mao and colleagues [150] found that circ0068871 could target miR-181a-5p, modulate FGFR3 expression and promote the activity of STAT3, resulting in enhanced progression of bladder carcinoma. In a study by Huang et al. [151], circ100338 was shown to be overexpressed in HCC (hepatocellular carcinoma), and served as a miR-141-3p inhibitor to enhance proliferation in HCC. In addition, circRNAs has a fundamental function in tumor proliferation as well as metastasis in NB, which we discussed in this section (Table 3).
a ecircRNA (exonic circular RNA) is generated when the splice donor site (the 5’splice site) is spliced back to the splice acceptor site (3’splice site). b The intron 1 is removed, bringing the Exon 2 5′ splice site adjacent to Exon 1 3′ splice site, which results in the formation of an exonic circular RNA containing several exons. In addition, exons may escape splicing and exons 1 and 3 may also be connected to each other. c CiRNA (circular intronic RNAs) are generated by a skipping degradation and debranching process of intron lariats. The reverse complementary sequence of the lariat intron produced upon excision of the pre-mRNA, can then participate to generate a closed-loop structure as a ciRNA. d EIciRNAs (Exon–intron circRNAs) are produced when introns remain between the exons. For instance, intron 3 remains in association with exon 4 and exon 3 to generate an EIciRNA [179].
Cell growth and proliferation
CircRNAs has been found to affect many molecules, proteins and pathways involved in proliferation of tumor cells [152]. For instance, the Hedgehog [140] signaling pathway (HH) has a major role in a number of cancers, such as NB [149, 153,154,155]. For instance, GLI1, which is a terminal HH pathway effector protein, has been shown to function as an oncogene in different cancers, including breast, colorectal, prostate, glioma, pancreatic, gastric adenocarcinoma and cervical cancer [156]. Interestingly, GLI1 was shown to serve as a tumor inhibitor via targeting GLI1 in gastric adenocarcinoma [157]. In a study by Yang et al., circDGKB was shown to be greatly expressed in NB cells relative to to normal cells of the dorsal root ganglia [158]. In addition, circDGKB expression was associated with unfavorable prognosis in those suffering from NB patients. Mechanistically, high expression of circDGKB enhanced proliferation, invasion, and migration in NB, while apoptosis was reduced by its overexpression. Additionally, it was shown that upregulation of circDGKB inhibited miR-873 expression and increased the expression of GLI1. Furthermore, miR-873 carried out the opposite function to circDGKB, and prevented its function in the progression of NB. Additionally, high expression of GLI1 restored the anti-tumor effects of miR-873 in NB tissues. Consequently, circDGKB may enhance tumor progression in NB tissue by regulating the miR-873/GLI1 axis both in vivo and in vitro. CircDGKB may therefore be a promising diagnostic marker and therapeutic target in patients with NB [158].
Invasion, migration, and metastasis
PLK4 (polo-like kinase 4), also known as Sak, has tumor-promoting effects in a wide range of human cancers, including glioblastoma [159], colorectal carcinoma [160] and breast cancer [161]. In this regard, an experiment unveiled that PLK4 was significantly upregulated in NB and may serve as a miR-338-3p target gene and regulate the progression of NB [162]. Tian and colleagues showed that PLK4 was deregulated expressed in NB, and its downregulation suppressed cell metastasis and viability, while enhancing apoptosis [163]. Yang et al. sough to examine the role of circKIF2A in NB pathogenesis was investigated [164]. qRT-PCR was employed to quantify the values of miR-129-5p, KIF2A mRNA, circKIF2A and PLK4 mRNA. RNaseR digestion assay and actinomycin D assays were performed to assess circKIF2A properties. Transwell and MTT assays were used to measure metastasis and proliferation, along with a glycolysis assay. The expression of PLK4, MMP2 and MMP9 were evaluated by Western blotting. Dual-luciferase reporter assay, bioinformatics analysis and RNA pull-down assays were used to evaluate correlations between circKIF2A and miR-129-5p or PLK4. The function of circKIF2A in NB progression was assessed in a murine xenograft model in vivo. NB cell lines and tissues had elevated levels of circKIF2A. CircKIF2A suppression inhibited invasion, proliferation, glycolysis, and migration. They found that circKIF2A may regulate the expression of PLK4 via sponging miR-129-5p. In addition, the anti-tumor effect of circKIF2A knockdown in NB cells was counteracted by suppression of miR-129-5p. Abundant expression of miR-129-5p in NB attenuated the malignant properties through targeting PLK4. Silencing of circKIF2A inhibited NB cells progression. In conclusion, silencing of circKIF2A inhibited proliferation, invasion, glycolysis, and migration by reducing the expression of PLK4 by targeting miR-129-5p [164].
MiR-432 has been shown to have anti-cancer activity in numerous tumors, such as breast cancer [165], HCC [166], and prostate adenocarcinoma [167]. Interestingly, abnormal expression of miR-432 was shown to affect the initiation and progression of NB [168]. Nonetheless, the relationship between miR-432-5p and circ_0132817 in the pathogenesis of NB remains poorly understood. NOL4L (nucleolar protein 4 like) was found to promote tumor progression in NB [169]. Fang and colleagues, designed a study to evaluate the regulatory jigsaw of miR-432-5p/ circ_0132817/ NOL4L, and the effect of this axis on proliferation, glycolysis, invasion and migration in NB [170]. They measured NOL4L and circ_0132817 levels in NB tissue specimens, while the level of miR-432-5p showed an inverse correlation. MiR-432-5p was considered to be a circ_0132817 target, and could specifically target NOL4L. Enhanced expression of circ_0132817 overturned the prohibitory impacts of high expression of miR-432-5p on proliferation, glycolysis, invasion and migration of NB cells. Reduced expression of miR-432-5p also restored the anti-tumor effects caused by silencing of NOL4L. In addition, silencing of circ_0132817 inhibited NB cells growth. Collectively, circ_0132817 enhanced NB initiation and progression via serving as a miR-432-5p sponge and stimulating the expression of NOL4L [170].
DMRT2 belongs to the family of DMRT genes. These genes contains zinc finger DNA-binding domains [157] and play major roles in development of sexual features in vertebrates, C. elegans and Drosophila [171,172,173]. Seo et al. showed that double-knockout mice without PAX3 and DMRT2 genes showed impaired embryonic myogenesis [174]. For instance, homozygote DMRT2 k/o mice had seriously impaired vertebral and rib formation in a study by Bouman et al. [175]. Zhang et al. designed a study to investigate the role of circ-CUX1 in the progression of NB [176]. In their study, the relationship and functional correlations between circ-CUX1, miR-16-5p and DMRT2 were evaluated. They used transwell migration assay, transwell invasion assay, colony formation assay, flow cytometry and MMT assays to assess migration, invasion, colony formation, cell cycle and proliferation; respectively. Measurements of glucose uptake, ATP and lactate synthesis were used to evaluate glycolysis. In addition, RNA pull-down assay, RIP (RNA immunoprecipitation), and dual-luciferase reporter assays were used to verify relationships between circ-CUX1, miR-16-5p and DMRT2. In vivo, Circ-CUX1 enhanced invasion, proliferation, glycolysis, and migration. Circ-CUX1 directly regulated miR-16-5p, and the effects produced by overexpression of miR-16-5p were partially reversed via transfecting a plasmid for circ-CUX1 overexpression. In addition, miR-16-5p directly regulated DMRT2 in NB cells, and thus an anti-miR-16-5p agent may reverse the DMRT2 impacts on invasion, proliferation, glycolysis, and migration in NB cells. Circ-CUX1 suppression inhibited the growth of a xenograft tumor in vivo. They concluded that circ-CUX1 increased malignant properties of NB cells via affecting the miR-16-5p/DMRT2 signaling pathway [176].
Exosomal miRNAs (ExomiRs) and NB
Exosomes are a type of extracellular membrane vesicle that can contain a variety of constituents such as mRNAs, miRNAs, DNA and proteins [177]. These biomolecules can participate in exosomal trafficking in immune cells, cancer cells and fibroblasts, and can also affect various other recipient cells. Exosomes are considered to be important in communication between different cell types [178]. Exosomes are produced when endosomes undergo intraluminal budding, and then generate multi-lobulated structures that are transferred to the plasma membrane, and are finally released into the extracellular space [163]. Exosomes originating from tumor cells can regulate a wide range of biologic processes, such as the sprouting of new blood vessels from existing ones [179,180,181], immune response against cancer [182], and the potential of cancer to metastasize [179, 183]. On the contrary, exosomes derived from healthy cells can suppress tumor growth in some malignant cells [170].
Extracellular vesicles generated from NB cells can enhance metastasis and growth in other cancer cells (Fig. 4). This occurs when the activity of other cell types in the tumor microenvironment such as monocytes or mesenchymal stem cells are altered, or when genes or miRNAs from NB cells are transferred to adjacent cells [184]. Therefore, extracellular vesicles generated by NB cells can enhance tumor growth. In addition, extracellular vesicles synthesized in NB cells may be altered by chemotherapy treatment, and their contents could predict the response to chemotherapeutic regimens. Considering the significant role of extracellular vesicles in the progression of NB and the regulation of host immune responses, it has been proposed that EVs containing drugs could be candidates to be administered in combination with standard therapy to improve the clinical outcome in patients with advanced NB.
Schematic illustration of the underlying mechanisms in the impact of extracellular vesicles on growth of tumor cells and their metastatic dissemination in neuroblastoma (348).
Various pathways involved in the synthesis and release of exosomes may be targeted to suppress the function of EVs [184]. Numerous proteins take part in the process. These include ESCRT (endosomal sorting complex required for transport), Rab27 GTPase family proteins (which along with small molecule DMA, dimethyl amiloride) can inhibit Na+/Ca2+ and Na+/H+ exchangers, and n-SMase (neutral sphingomyelinase) involved in the generation of ceramide. Previous studies have found that inhibition of these factors may help in the treatment of some cancers [171, 185]. Additionally, EVs can be removed from the systemic circulation using antibodies specific for tumor antigens expressed on the EVs derived from cancer cells, or lectins in the process of plasmapheresis [116]. Moreover, EV uptake by target cells is typically mediated an interaction between HSPGs (heparan sulfate proteoglycans) located on the surface of recipient cells and phosphatidylserine present on the surface of EVs, may be inhibited by heparin or Annexin V, respectively. The mentioned drugs have been tested in preclinical models of glioblastoma and squamous carcinoma [171, 183]. Metastasis and immune escape are two hallmark processes of tumors where exomiRs has been found to take role in NB cells (Table 4).
Invasion, migration and metastasis
ExomiRs derived from tumor cells have emerged as key players in cancer promotion via impairment of the metastasis in NB cells.
NEDD4 belongs to the HECT domain of ubiquitin E3 ligase, and is involved in the modulation of cell membrane receptors and the endocytic machinery system [185]. It was proposed that NEDD4 played dual regulatory roles on PTEN activity by accelerating mono-ubiquitination and modifying the nuclear translocation of PTEN [182]. Moreover, NEDD4 can directly ubiquitinate and destroy the Myc protein. This protein was shown to be a marker of a poor prognosis in NB patients. Suppression of NEDD4 protein resulted in enhanced expression of the Aurora A gene, which has a critical role in stabilizing Myc protein in NB [183]. In a study by Ma and colleagues, the activity of exosomal miRNAs derived from tumor cells in the formation and progression of NB cells was evaluated in vitro and in vivo [184]. The levels of expression of numerous exosomal miRNAs were measured in plasma samples of NB patients, and it was found that exosome-derived hsa-miR199a-3p expression was higher and was related to the severity of disease in NB. Moreover, exosomal-derived hsa-miR199a-3p could promote migration and proliferation of NB cells via modulating NEDD4 expression. In conclusion, hsa-miR199a-3p contained in exosomes may increase migration and proliferation of NB cells by reducing the level of NEDD4, indicating that exosomal hsa-miR199a-3p could be a non-invasive and easy-to-apply diagnostic biomarker in NB, and could play a role in new therapies in the near future [184].
TAM (tumor-associated macrophages) positive for CD163, comprise the majority of stromal cells in the microenvironment of NB, and can secrete a variety of immunoinhibitory cytokines and factors, including VEGF, IL-10, TGFβ and IL-4, which encourage the formation of new blood vessels and increase the metastatic potential [186]. A high concentration of TAMs infiltrating the tumor microenvironment is a poor prognostic indicator, and can also induce chemotherapy drug resistance [186,187,188]. However, the prognosis of NB is improved by the presence of numerous infiltrating natural killer cells within the tumor tissue, and the NK cytotoxic activity is supported by a profile of certain cytokines [189]. Increased TGFβ1 levels were found in tissue specimens from advanced NB patients. TGFβ1 inhibits natural killer cell cytotoxicity via reducing the expression of NK receptors, such as NKG2D and DNAM-1, as well as modulating chemokine receptors including CX3CR1, CXCR3 and CXCR4 [190,191,192,193,194,195]. In addition, abundant localized expression of TGFβ1, and the stimulation of non-canonical (MAPK1, ROCK1), as well as canonical (SMADS) TGFβ pathways can induce the EMT and increase the invasion of NB [196, 197]. As a result, the tumor microenvironment has a major role in NB tumorigenesis, and it is essential to explore tumor microenvironment-associated cells among other factors that account for resistance to standard therapies. For instance, NK cell-derived exosomes can promote cytotoxic effects against tumor cells [198,199,200].
Immune escape
The regulation of the immune system is one of the promises of cancer treatment. It is now broadly labeled that tumors are capable to escape the immune response and therefore make immune tolerance. The examination of the processes fundamental this capability of cancer cells has always fascinated the researchers for finding nopvel promising cancer therapies. Recent literature has emphasized the roles of exomiRs in immune escape [201].
Neviani et al., demonstrated that exosomes which were produced by NK cells contained the tumor suppressor miR-186, and exerted cytotoxic effects against NB cells with amplified expression of MYCN [202]. These exosomes exerted their cytotoxic effect primarily via adjusting miR-186 expression. MiR-186 expression was decreased in advanced NB, and this low expression was correlated with an unfavorable outcome in NB patients. Low miR-186 levels correlated with activation markers such as DNAM-1 and NKG2D. MiR-186 directly suppressed the expression of TGFBR2, TGFBR1, AURKA and MYCN. In addition, the introduction of miR-186 into NB cells with high expression of MYCN, or into NK cells suppressed the progression of NB, and reversed the suppression of NK cells induced by TGFβ1. In conclusion, the delivery of miR-186-containing nanoparticles may slow down tumor growth as well as prevent escape from the immune system due to the effects of TGFβ1 in patients with advanced stage NB. Moreover, the administration of ex vivo exosomes isolated from NK cells could be a new treatment approach, especially in conjunction with NK cell-dependent immunotherapy. Exosomes derived from NK cells could display therapeutic activity involving miR-186 to suppress cell growth, invasion and escape from the host immune response by a TGFβ-dependent mechanism in NB [202].
Conclusion
Considering the wide heterogeneity of tumor subtypes and variations in clinical outcome, the establishment of new biological prognostic or diagnostic markers has become increasingly essential in NB. Determination of the expression levels of various ncRNAs has the potential to contribute to the diagnosis of NB. Nonetheless, their clinical application needs to be initially evaluated for diagnostic accuracy and clinical implications. Hence, the functional and clinical value of ncRNAs involved in the pathogenesis of NB, needs to be more assessed in larger scale studies before becoming applicable in clinical trials. Identifying the expression profile of these biomarkers in bodily fluids, including saliva, urine and blood that are often employed in clinical settings for diagnosis, may accelerate this process. As these ncRNAs molecules are relatively stable in the systemic circulation, their correlation with patient risk stratification would support them as possible diagnostic biomarkers in clinical applications. Date derived from RNA-omics and genomic studies within the last decade, in both diseased and normal individuals, has shed light on the biological function of ncRNAs. The clinical importance of these molecules has so far, been underestimated and poorly recognized in NB. In this review, we have presented a discussion of the role of ncRNAs in the biology and pathogenesis of NB. Larger studies are required in the future to explore novel ncRNAs as diagnostic and prognostic biomarkers in NB. Additionally, functional studies in animal and stem cell models may identify the underlying mechanistic pathways of ncRNAs in NB tumorigenesis.
Data availabilty
The primary data for this study is available from the authors on request.
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Anoushirvani, A.A., Jafarian Yazdi, A., Amirabadi, S. et al. Role of non-coding RNAs in neuroblastoma. Cancer Gene Ther 30, 1190–1208 (2023). https://doi.org/10.1038/s41417-023-00623-0
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DOI: https://doi.org/10.1038/s41417-023-00623-0