Astrocytoma classification according to the World Health Organization (2016).
Abstract
Noncoding RNAs represent a high proportion of the human genome and regulate gene expression by means of innumerable and unimaginable modes of action. Particularly, long noncoding RNAs have emerged as central regulators of gene expression and alterations on their function have been associated with many types of cancer, such as astrocytomas. Astrocytomas are the most common type of gliomas in the central nervous system, and glioblastoma multiforme is their most aggressive form. Although adult and pediatric astrocytomas exhibit certain molecular similarities, they are considered as distinct molecular entities. Since to date there is no effective treatments for these tumors, different efforts are being made to find molecular tools useful for this purpose. Studies have shown that both tumor and circulating expression of lncRNAs were altered in astrocytoma, which was useful to distinguish the patients with this neoplasia from those without cancer, as well as to determine different prognostic factors related to the disease. According to these studies, different “molecular signatures” of specific lncRNAs were established, and they have a potential use in the medical practice. From a system biological perspective, complex interaction networks, conformed by lncRNAs, microRNAs, mRNAs, and proteins, were elucidated and predicted to control many oncogenic processes.
Keywords
- astrocytoma
- biomarker
- interacting network
- lncRNA
- microRNA
1. Introduction
Noncoding RNAs (ncRNAs) represent a significant fraction of the human genome [1], and the great diversity and forms of action of these RNA species has put them at the center of biomedical research of diseases, such as cancer [2, 3, 4]. LncRNAs are not the exception, and many of them have been proposed as possible diagnostic and prognostic biomarkers for Ast [5]. LncRNAs are RNAs of more than >200 nucleotides in length, which have to meet certain additional criteria to be classified within this category [6]. The evolutionary conservation of lncRNAs among species is poor [7], and they are transcribed by a variety of transcriptional mechanisms [6]. Many cellular processes are regulated by lncRNAs and this could be at both cytoplasmic and nuclear levels, as well as distance by moving them to their target tissues through different bodily fluids, such as blood [8]. LncRNAs exert their functions by establishing interactions with other lncRNA and RNA species, as well as with proteins [9], and changes on their functioning have been associated with cancer and particularly with astrocytomas (Ast) [5].
Gliomas represent 81% of the Central Nervous System (CNS) tumors of which the most common subtypes in adults are glioblastoma multiforme (GBM), anaplastic Ast (AAst), and oligodendrogliomas [10, 11]. In the pediatric counterpart, pilocytic Ast (PAst) is the most common type in pediatric age [11]. According to the new classification of the World Health Organization (WHO), Ast are now classified according to the presence or absence of
2. Astrocytoma
Although the new WHO classification of tumors of the CNS takes into account phenotypic traits, it also takes into account other criteria, such as the genotype and integral diagnoses of the disease [12]. According to this classification, Ast are now classified mainly by the presence or absence of
2.1 Astrocytomas that lack IDH1 and IDH2 mutations
These tumors have a well circumscribed growth pattern, lack IDH alterations, and they frequently have
PAst are the most common type of Ast in pediatric age and are characterized by their biphasic pattern: compact bipolar cells with Rosenthal fibers, microquistes, and granular bodies (Figure 1A). As a general rule, PAst are well-defined tumors (Figure 2A); so they can be surgically resected without causing damage to the adjacent tissue and they do not progress to more aggressive stages; therefore, PAst are considered as neoplasms of good prognosis.
PAst are developed along the neuroaxis, and they are preferably located in the cerebellum [22, 23, 24]. It is important to mention that there are genetic diseases such as neurofibromatosis 1 (
2.2 Diffuse gliomas (tumors with IDH1 and IDH2 mutations)
In the previous WHO classification, diffuse Ast (DAst) were classified as an independent group, but now they are classified along with anaplastic Ast (Aast; Grade III) and glioblastoma (GBM; Grade IV) (Figures 1B–D and 2B–D), as well as with diffuse oligodendrogliomas (Grade I and II) [12]. Although factors such as growth and tumor behavior are still taken into account, the feature that distinguishes them as diffuse gliomas are the
2.2.1 Glioblastoma
According to the new WHO classification, the GBM was also classified into the group of diffuse gliomas and subclassified into the
2.3 Pediatric diffuse gliomas
Pediatric diffuse gliomas have the K27 mutation in the gene
3. LncRNAs in astrocytoma
LncRNAs have emerged as important molecular elements in different types of cancer, and Ast are not the exception [5, 30, 31, 32]. To date, diverse studies have shown the high complexity of the lncRNA study in Ast, due to the wide variety of mechanisms by which lncRNAs exerts their biological actions and because of the high tumor heterogeneity [33, 34, 35]. Changes in the nucleotide sequence of lncRNAs, their transcription rate, the expression of specific variants, in their expression levels, among others, could lead to an aberrant amplification of cell signals [36, 37, 38]. Given that GBM is the most aggressive type of cancer that begins within the brain [39, 40], most studies have been focused on this tumor subtype and to a lesser extent in the other WHO grades of adult Ast or in all WHO grades of p-Ast. Despite the significant effort that has been made in recent years to learn more about Ast, to the best of our knowledge, to date, there are very few molecular tools really applicable to diagnose, prognose, or treatment of these tumors [41, 42, 43]. Therefore, there is great interest to establish these molecular tools for GBM and evidence indicates that lncRNAs seem to be good candidates to serve such purpose.
3.1 LncRNAs as potential astrocytoma biomarkers
Expression changes of a biomolecule are a powerful tool to establish molecular “signatures” or “fingerprints” useful to distinguish and identify subgroups of a disease with a particular clinical behavior [44, 45, 46, 47]. In this sense, expression changes of lncRNAs have been useful to differentiate both adult and pediatric Ast from nonneoplastic tissues, and some of them have the potential to be used in the medical practice as biomarkers. The meta-analysis performed by Zhang et al. [48] demonstrated for the first time the usefulness of the lncRNAs aberrantly expressed for Ast diagnosis and prognosis. This study showed that the expression profile of lncRNAs allowed to differentiate Ast or oligodendrogliomas from nonneoplastic tissues and to associate it with Ast malignancy or with lineage distinction in gliomas (Table 2). Subsequently, the same group established the first “molecular signature” of lncRNAs for Ast diagnosis and prognosis, which distinguished this neoplasia from nonneoplastic tissues, as well as Ast malignancy or patient’s survival (Table 2) [49]. Additionally, a second group of precise lncRNAs was specific for Ast, and it was functional to differentiate them from the control tissues; from this signature, two lncRNAs were also associated with Ast malignancy, since their expression distinguished Ast WHO grades (Table 2) [50]. However, none of the lncRNAs that were part of the first molecular signature was established in the second, which could be related to the samples included in each study—referring to age, sex, with or without treatment, radiotherapy, among others—, as well as to the bioinformatic approach used in each study. This evidence emphasizes the importance that has the homogenization of patient’s samples included in a study has and how crucial it is to specify the clinic features of the included patients.
In addition to changes in the lncRNA expression, their promoter methylation status seems to be useful for Ast diagnosis and prognosis. Specifically, it was shown that expression and the promoter methylation pattern of
3.2 LncRNAs as potential GBM biomarkers
Specifically for GBM, different lncRNAs have also been found as potential biomarkers for its diagnosis and prognosis (Table 3). In this sense, Xu et al. [51] identified lncRNAs, which were associated with patient’s survival; particularly, high expression of
3.3 Circulating lncRNAs
It is a fact that the establishment of novel biomarkers for Ast is essential and their identification and clinical application by means of less invasive methods would be ideal. To date, many studies have demonstrated the usefulness of circulating lncRNAs for diagnosis and prognosis of many diseases, including GBM [46, 54, 55]. The profile expression of lncRNAs was determined in blood serum of GBM patients and high levels of
3.4 Search for GBM biomarkers from a system biological perspective
Since a biomolecule does not act alone and depends on the cellular context to carry out its biological functions, different groups of study have focused on the identification of the lncRNA interactome in GBM. Evidence indicates that lncRNAs could interact with themselves, as well as with other biomolecules, such as mRNAs, miRNAs, and proteins; changes on the lncRNA activity at distinct molecular levels could affect their interaction networks and the correct cellular functioning [5, 75, 76, 77].
Yan et al. [78] established interaction networks between lncRNAs and mRNAs aberrantly expressed in GBM, and based on this, they postulated “hub genes” which were involved in GBM pathogenesis. Similarly, under this perspective, it was found that complexes conformed by lncRNA•mRNA (
3.5 Radio and chemoresistance
A major clinical problem is the resistance to chemotherapy and radiotherapy; therefore, identification of “molecular tools” that can predict and in the best-case scenario, improve the cellular response to these treatments would be ideal. Wang et al. [80] established a prediction model for radiosensitivity by detecting differential expressed lncRNAs and mRNAs after irradiation. Interestingly, the algorithm differentiated those patients that were radiosensitive and with a greater survival, from the patients with radioresistance; unfortunately, as far as we know, this is the only study focused on GBM radioresistance.
In addition, the involvement of lncRNAs in chemoresistance has been widely studied. LncRNAs
3.6 LncRNAs in stem cells
Many lines of evidence have shown the involvement of lncRNAs in the control of many cellular processes in cancer stem cells (CSCs) [85, 86, 87], but their participation in Ast has been very poorly studied. These cells are able to self-renew and differentiate into diverse cancer cell lineages to form tumors, so CSCs have been proposed as potential targets for cancer treatment. To further understand this, Balci et al. [88] determined the profile expression of lncRNAs in GBM stem cells (GSCs) relative to control stem cells. From these differentially expressed lncRNAs,
Although many studies have focused on studying the changes on the expression of lncRNAs, very few have attempted to determine the mechanisms underlying this deregulation. In this sense, Zhang et al. [89] showed a feedback loop which controlled the expression of the lncRNA
4. Action mechanisms of lncRNAs in GBM
In addition to expression changes, it is necessary for the elucidation of the action mechanisms by which lncRNAs are acting. Evidence showed that lncRNAs act at both cytoplasmic and nuclear levels and that this is done directly and/or by their interaction with protein complexes and/or with other lncRNAs or different RNA species, such as mRNAs and miRNAs [5, 75, 76, 77]. Also, lncRNAs can regulate many signaling pathways by controlling the cytoplasmic disposal of mRNAs and miRNAs and even by producing small RNA species, such as miRNAs [89].
4.1 Sponge lncRNAs
This class of lncRNAs regulates miRNA disposal in the cell cytoplasm by capturing them and blocking their action [90, 91]. To date, all lncRNAs identified as “sponges” in the GBM acting as suppressors and involved in lncRNA upregulation and miRNA attenuation were associated with GBM Table 4). LncRNAs
“Sponges” LncRNAs | microRNA | mRNA target | Cellular process altered | Signaling pathway |
---|---|---|---|---|
H19 NEAT1 | Let-7e | NRAS (NRAS Proto-Oncogene, GTPase) | H19: stem cells phenotype NEAT1: | |
XIST | miR-152 | Proliferation, migration, invasion, apoptosis evasion, tumor growth and poor mice survival | ||
TUG1 | miR-299 | VEGFA (Vascular Endothelial Growth Factor A) | Angiogenesis induction | |
RP11-838N2.4 | miR-10 | EphA8 (EPH Receptor A8) | Apoptosis evasion | Apoptosis |
SNHG7 | miR-5095 | CTNNB1 (Catenin Beta 1) | Proliferation, migration, invasion, apoptosis evasion | Wnt/β catenin |
MALAT1 | miR-203 | TYMS (Thymidylate Synthetase) | Low chemotherapy response Shorter survival time of patients | |
CRNDE | miR-136-5p | Wnt2 (Wnt Family Member A2) BCL2 (BCL2 Apoptosis Regulator) | Apoptosis evasion | Wnt Apoptosis |
CASC2 | miR-101 | CPEB1 (Cytoplasmic Polyadenylation Element Binding Protein 1) | Cell proliferation Tumorigenesis |
Similarly, GBM malignancy was mediated by the overexpression of
A very interesting case was that of the lncRNA
4.2 By interacting with mRNAs
Besides the lncRNA interaction with miRNAs, there is evidence indicating that lncRNAs can carry out their biological functions when they interact with mRNAs and/or proteins [5, 75, 76, 77]. As mentioned above,
5. Pediatric Ast
Adult and p-Ast are distinct molecular entities and are classified into different groups; therefore, studies in pediatric Ast are imperative. The first study performed in p-Ast was the one where the overexpression
We identified in the laboratory the expression profile of lncRNAs in p-Ast of WHO grades I–IV, given that the function of lncRNAs in p-Ast has been poorly studied. Similar to that observed for adult Ast, p-Ast showed many lncRNAs with expression changes relative to the control tissues, among histological grades or even in the same histological grade [5]. In addition, it was identified that the interaction of many differentially expressed lncRNAs with mRNAs and/or miRNAs aberrantly expressed was identified. As explained above, these interactions could lead to the amplification of the aberrant signals and to the modification of many signaling pathways. According to this, there were several hub lncRNAs in p-Ast that in relation to their interactions with mRNAs could be altering pathways such as FOXO, chemokine, hedgehog, MAPK, and others (Figure 4). Additionally, hub lncRNAs potentially useful to distinguish GBM from the other histopathological WHO grades were predicted to control diverse metabolic pathways and signaling pathways such as Ras, hippo, apellin, etc. (Figure 4).
The interaction of differentially expressed lncRNAs and miRNAs was shown to be a complex network that could be involved in modifications on proteoglycans in cancer, fatty acid metabolism, cell cycle, and spliceosome. Notably, data analysis revealed the presence of circular lncRNAs (circRNAs) with expression changes in p-Ast (Figure 5). According to the interactions of circRNAs with miRNAs, this type of lncRNAs was predicted to be involved in regulating cellular growth, survival, migration, invasion, adhesion, among others [5] (Table 5).
KEGG pathway | p-value | Number of genes | Number of miRNAs | Potential cellular processes altered |
---|---|---|---|---|
Proteoglycans in cancer | 8.91e−11 | 120 | 14 | Cellular growth and survival Cell migration and invasion Cell adhesion Apoptosis Angiogenesis Vascular permeability |
Fatty acid metabolism | 9.64e−09 | 28 | 12 | Fatty acid metabolism |
Adherens junction | 3.85e−08 | 49 | 12 | Actin polymerization Cell growth and differentiation Gene expression |
Cell cycle | 3.85e−08 | 85 | 14 | Ubiquitin mediated proteolysis DNA biosynthesis Origin recognition complex Mini-Chromosome maintenance |
Protein processing in the endoplasmic reticulum | 2.59e−07 | 101 | 14 | Proteasome Apoptosis |
Fatty acid elongation | 1.78e-06 | 13 | 7 | Fatty acid degradation Fatty acid biosynthesis |
p53 signaling pathway | 2.12e−06 | 50 | 14 | Cell cycle arrest Apoptosis Inhibition of angiogenesis and metastasis DNA repair and damage prevention Inhibition of IGF-1/mTOR pathway Exosome mediated secretion p53 negative feedback Cellular senescence |
Hippo signaling pathway | 2.29e-06 | 77 | 14 | Pro-apoptotic genes Anti-apoptotic genes Pro-proliferation genes Cell contact inhibition Organ size control Adherens junctions |
TGF-beta signaling pathway | 2.32e−06 | 48 | 12 | Differentiation, neurogenesis, ventral mesoderm specification Angiogenesis, extracellular matrix neogenesis, immunosuppression, apoptosis induction. G1 arrest Gonadal growth, embryo differentiation, placenta formation Left-right axis determination |
Prion diseases | 9.44e−06 | 15 | 9 | Neuronal apoptosis Autophagy Oxidative stress Proliferation of astrocytes |
The integration of proteome and mirnome, as well as transcriptome data showed a convergence of all these biomolecules in the control of common signaling pathways, which gave an overview of the action of complex networks in cancer, particularly p-Ast [5, 47]. For example, although it is widely known that the MAPK pathway is altered in ~88% of gliomas, these data showed novel molecular components involved in this signaling pathway in p-Ast, which also allow to differentiate GBM from the other histological grades. The lncRNA
6. Conclusions
The lncRNA study in Ast has demonstrated an aberrant expression of this type of RNAs in both tumors and blood, which was useful to distinguish Ast from its nonneoplastic counterpart. The elucidation of molecular signatures from circulating lncRNAs is very promising due to their potential use as noninvasive tools for the diagnosis and prognosis of Ast. From another approach, it could be relevant the identification of complete interaction networks in which lncRNAs, other RNA species, and proteins were involved, since this would give a “panoramic vision” of how the aberrant system functions in astrocytic tumors. This could be crucial for the creation of molecular tools for their treatment.
Acknowledgments
This work was partially supported by the grant FIS/IMSS/PROT/G17 from The Mexican Institute of Social Security (IMSS). The English edition was carried out by Areli Ruiz Esparza, translator in-chief at SINTAGMA TRANSLATIONS.
References
- 1.
ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012; 489 :57-74. DOI: 10.1038/nature11247 - 2.
Zhang C, Zhao LM, Wu H, Tian G, Dai SL, Zhao RY, et al. C/D-Box Snord105b promotes tumorigenesis in gastric cancer via ALDOA/C-Myc pathway. Cellular Physiology and Biochemistry. 2018; 45 :2471-2482. DOI: 10.1159/000488265 - 3.
López-Aguilar JE, Velázquez-Flores MA, Simón-Martínez LA, Ávila-Miranda R, Rodríguez-Florido MA, Ruiz-Esparza Garrido R. Circulating microRNAs as biomarkers for pediatric astrocytomas. Archives of Medical Research. 2017; 48 :323-332. DOI: 10.1016/j.arcmed.2017.07.002 - 4.
Marshall EA, Sage AP, Ng KW, Martinez VD, Firmino NS, Bennewith KL, et al. Small non-coding RNA transcriptome of the NCI-60 cell line panel. Scientific Data. 2017; 4 :170157. DOI: 10.1038/sdata.2017.157 - 5.
Ruiz Esparza-Garrido R, Rodríguez-Corona JM, López-Aguilar JE, Rodríguez-Florido MA, Velázquez-Wong AC, Viedma-Rodríguez R, et al. Differentially expressed long non-coding RNAs were predicted to be involved in the control of signaling pathways in pediatric astrocytoma. Molecular Neurobiology. 2017; 54 :6598-6608. DOI: 10.1007/s12035-016-0123-9 - 6.
Jarroux J, Morillon A, Pinskaya M. History, discovery, and classification of lncRNAs. Advances in Experimental Medicine and Biology. 2017; 1008 :1-46. DOI: 10.1007/978-981-10-5203-3_1 - 7.
Necsulea A, Soumillon M, Warnefors M, Liechti A, Daish T, Zeller U, et al. The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature. 2014; 505 :635-640. DOI: 10.1038/nature12943 - 8.
Botti G, Marra L, Malzone MG, Anniciello A, Botti C, Franco R, et al. LncRNA HOTAIR as prognostic circulating marker and potential therapeutic target in patients with tumor diseases. Current Drug Targets. 2017; 18 :27-34 - 9.
Noh JH, Kim KM, McClusky WG, Abdelmohsen K, Gorospe M. Cytoplasmic functions of long noncoding RNAs. Wiley Interdisciplinary Reviews: RNA. 2018; 9 :e1471. DOI: 10.1002/wrna.1471 - 10.
Ostrom QT, Gittleman H, Stetson L, Virk S, Barnholtz-Sloan JS. Epidemiology of intracranial gliomas. Progress in Neurological Surgery. 2018; 30 :1-11. DOI: 10.1159/000464374 - 11.
Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro-Oncology. 2014; 16 (Suppl 4):iv1-iv63 - 12.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathologica. 2016; 131 :803-820. DOI: 10.1007/s00401-016-1545-1 - 13.
Kim W, Liau LM. IDH mutations in human glioma. Neurosurgery Clinics of North America. 2012; 23 :471-480. DOI: 10.1016/j.nec.2012.04.009 - 14.
Pathak P, Jha P, Purkait S, Sharma V, Suri V, Sharma MC, et al. Altered global histone-trimethylation code and H3F3A-ATRX mutation in pediatric GBM. Journal of Neuro-Oncology. 2015; 121 :489-497. DOI: 10.1007/s11060-014-1675-z6 - 15.
Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nature Genetics. 2014; 46 :444-450. DOI: 10.1038/ng.2938 - 16.
Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012; 482 :226-231. DOI: 10.1038/nature10833 - 17.
Faury D, Nantel A, Dunn SE, Guiot M, Haque T, Hauser P, et al. Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors. Journal of Clinical Oncology. 2007; 25 :1196-1208. DOI: 10.1200/JCO.2006.07.8626 - 18.
Zeng H, Xu N, Liu Y, Liu B, Yang Z, Fu Z, et al. Genomic profiling of long non-coding RNA and mRNA expression associated with acquired temozolomide resistance in glioblastoma cells. International Journal of Oncology. 2017; 51 :445-455. DOI: 10.3892/ijo.2017.4033 - 19.
Chen W, Xu XK, Li JL, Kong KK, Li H, Chen C, et al. MALAT1 is a prognostic factor in glioblastoma multiforme and induces chemoresistance to temozolomide through suppressing miR-203 and promoting thymidylate synthase expression. Oncotarget. 2017; 8 :22783-22799. DOI: 10.18632/oncotarget.15199 - 20.
Mineo M, Ricklefs F, Rooj AK, Lyons SM, Ivanov P, Ansari KI, et al. The long non-coding RNA HIF1A-AS2 facilitates the maintenance of mesenchymal glioblastoma stem-like cells in hypoxic niches. Cell Reports. 2016; 15 :2500-2509. DOI: 10.1016/j.celrep.2016.05.018 - 21.
Liu Y, Xu N, Liu B, Huang Y, Zeng H, Yang Z, et al. Long noncoding RNA RP11-838N2.4 enhances the cytotoxic effects of temozolomide by inhibiting the functions of miR-10a in glioblastoma cell lines. Oncotarget. 2016; 7 :43835-43851. DOI: 10.18632/oncotarget.9699 - 22.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathologica. 2007; 114 :97-109. DOI: 10.1007/s00401-007-0243-4 - 23.
Bristol RE. Low-grade glia tumors: Are they all the same? Seminars in Pediatric Neurology. 2000; 16 :23-26 - 24.
Broniscer A, Baker JS, West NA, Fraser MM, Proko E, Kocak M, et al. Clinical and molecular characteristics of malignant transformation of low-grade glioma in children. Journal of Clinical Oncology. 2007; 25 :682-689 - 25.
Pascual-Castroviejo I, Pascual-Pascual SI, Viaño J, Velázquez-Fragua R, Carceller-Benito F, Gutiérrez-Molina M, et al. Cerebral hemisphere tumours in neurofibromatosis type 1 during childhood. Revista de Neurologia. 2010; 50 :453-457 - 26.
Pong WW, Gutmann DH. The ecology of brain tumors: Lessons learned from neurofibromatosis-1. Oncogene. 2011; 30 :1135-1146. DOI: 10.1038/onc.2010.519 - 27.
Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. The New England Journal of Medicine. 2005; 372 :2481-2498. DOI: 10.1056/NEJMoa1402121 - 28.
Reuss DE, Kratz A, Sahm F, Capper D, Schrimpf D, Koelsche C, et al. Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neuropathologica. 2015; 130 (3):407-417. DOI: 10.1007/s00401-015-1454-8 - 29.
Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clinical Cancer Research. 2013; 19 :764-772. DOI: 10.1158/1078-0432.CCR-12-3002 - 30.
Huang SK, Luo Q , Peng H, Li J, Zhao M, Wang J, et al. A panel of serum noncoding RNAs for the diagnosis and monitoring of response to therapy in patients with breast cancer. Medical Science Monitor. 2018; 24 :2476-2488 - 31.
Ma Y, Luo T, Dong D, Wu X, Wang Y. Characterization of long non-coding RNAs to reveal potential prognostic biomarkers in hepatocellular carcinoma. Gene. 2018; 663 :148-153. pii:S0378-1119(18)30427-X. DOI: 10.1016/j.gene.2018.04.053 - 32.
Matjasic A, Popovic M, Matos B, Glavac D. Expression of LOC285758, a potential long non-coding biomarker, is methylation-dependent and correlates with glioma malignancy grade. Radiology and Oncology. 2017; 51 :331-341. DOI: 10.1515/raon-2017-0004 - 33.
Nakajima N, Nobusawa S, Nakata S, Nakada M, Yamazaki T, Matsumura N, et al. BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: A histological and molecular analysis focusing on intratumoral heterogeneity. Brain Pathology. 2017. DOI: 10.1111/bpa.12572 - 34.
Smith SJ, Diksin M, Chhaya S, Sairam S, Estevez-Cebrero MA, Rahman R. The invasive region of glioblastoma defined by 5ALA guided surgery has an altered cancer stem cell marker profile compared to central tumour. International Journal of Molecular Sciences. 2017; 18 :E2452. DOI: 10.3390/ijms18112452 - 35.
Hu W, Wang T, Yang Y, Zheng S. Tumor heterogeneity uncovered by dynamic expression of long noncoding RNA at single-cell resolution. Cancer Genetics. 2015; 208 :581-586. DOI: 10.1016/j.cancergen.2015.09.005 - 36.
Jiang Y, Du F, Chen F, Qin N, Jiang Z, Zhou J, et al. Potentially functional variants in lncRNAs are associated with breast cancer risk in a Chinese population. Molecular Carcinogenesis. 2017; 56 :2048-2057. DOI: 10.1002/mc.22659 - 37.
Sen R, Doose G, Stadler PF. Rare splice variants in long non-coding RNAs. Noncoding RNA. 2017; 3 :E23. DOI: 10.3390/ncrna3030023 - 38.
Wang Y, Li Z, Zheng S, Zhou Y, Zhao L, Ye H, et al. Expression profile of long non-coding RNAs in pancreatic cancer and their clinical significance as biomarkers. Oncotarget. 2015; 6 :35684-35698. DOI: 10.18632/oncotarget.5533 - 39.
Bleeker FE, Molenaar RJ, Leenstra S. Recent advances in the molecular understanding of glioblastoma. Journal of Neuro-Oncology. 2012; 108 :11-27. DOI: 10.1007/s11060-011-0793-0 - 40.
McNeill KA. Epidemiology of brain tumors. Neurologic Clinics. 2016; 34 :981-998. DOI: 10.1016/j.ncl.2016.06.014 - 41.
Omuro A, Beal K, McNeill K, Young RJ, Thomas A, Lin X, et al. Multicenter phase IB trial of carboxyamidotriazole orotate and temozolomide for recurrent and newly diagnosed glioblastoma and other anaplastic gliomas. Journal of Clinical Oncology. 2018. DOI: JCO2017769992. DOI: 10.1200/JCO.2017.76.9992 - 42.
Roberto GM, Paiva HH, Botelho de Souza LE, Pezuk JA, Vieira GM, Francisco de Oliveira H, et al. DTCM-glutarimide delays growth and radiosensitizes glioblastoma. Anti-Cancer Agents in Medicinal Chemistry. 2018; 18 :1. DOI: 10.2174/1871520618666180423105740 - 43.
Sousa F, Moura RP, Moreira E, Martins C, Sarmento B. Therapeutic monoclonal antibodies delivery for the glioblastoma treatment. Advances in Protein Chemistry and Structural Biology. 2018; 112 :61-80. DOI: 10.1016/bs.apcsb.2018.03.001 - 44.
Álvarez-Chaver P, De Chiara L, Martínez-Zorzano VS. Proteomic profiling for colorectal cancer biomarker discovery. Methods in Molecular Biology. 2018; 1765 :241-269. DOI: 10.1007/978-1-4939-7765-9_16 - 45.
Assmann TS, Recamonde-Mendoza M, Puñales M, Tschiedel B, Canani LH, Crispim D. MicroRNA expression profile in plasma from Type 1 diabetic patients: Case-control study and bioinformatic analysis. Diabetes Research and Clinical Practice. 2018; 141 :35-46. pii:S0168-8227(17)32036-3. DOI: 10.1016/j.diabres.2018.03.044 - 46.
Umu SU, Langseth H, Bucher-Johannessen C, Fromm B, Keller A, Meese E, et al. A comprehensive profile of circulating RNAs in human serum. RNA Biology. 2018; 15 :242-250. DOI: 10.1080/15476286.2017.1403003 - 47.
Ruiz Esparza-Garrido R, Velázquez-Flores MÁ, Diegopérez-Ramírez J, López-Aguilar E, Siordia-Reyes G, Hernández-Ortiz M, et al. A proteomic approach of pediatric astrocytomas: MiRNAs and network insight. Journal of Proteomics. 2013; 94 :162-175. DOI: 10.1016/j.jprot.2013.09.009 - 48.
Zhang X, Sun S, Pu JK, Tsang AC, Lee D, Man VO, et al. Long non-coding RNA expression profiles predict clinical phenotypes in glioma. Neurobiology of Disease. 2012; 48 :1-8. DOI: 10.1016/j.nbd.2012.06.004 - 49.
Zhang XQ , Sun S, Lam KF, Kiang KM, Pu JK, Ho AS, et al. A long non-coding RNA signature in glioblastoma multiforme predicts survival. Neurobiology of Disease. 2013; 58 :123-131. DOI: 10.1016/j.nbd.2013.05.011 - 50.
Zhi F, Wang Q , Xue L, Shao N, Wang R, Deng D, et al. The use of three long non-coding RNAs as potential prognostic indicators of astrocytoma. PLoS One. 2015; 10 :e0135242. DOI: 10.1371/journal.pone.0135242 - 51.
Xu C, Qi R, Ping Y, Li J, Zhao H, Wang L, et al. Systemically identifying and prioritizing risk lncRNAs through integration of pan-cancer phenotype associations. Oncotarget. 2017; 8 (7):12041-12051. DOI: 10.18632/oncotarget.14510 - 52.
Reon BJ, Anaya J, Zhang Y, Mandell J, Purow B, Abounader R, et al. Expression of lncRNAs in low-grade gliomas and glioblastoma multiforme: An in silico analysis. PLoS Medicine. 2016; 13 :e1002192. DOI: 10.1371/journal.pmed.1002192 - 53.
Wang Y, Wang Y, Li J, Zhang Y, Yin H, Han B. CRNDE, a long-noncoding RNA, promotes glioma cell growth and invasion through mTOR signaling. Cancer Letters. 2015; 367 :122-128. DOI: 10.1016/j.canlet.2015.03.027 - 54.
Wang YH, Ji J, Wang BC, Chen H, Yang ZH, Wang K, et al. Tumor-derived exosomal long noncoding RNAs as promising diagnostic biomarkers for prostate cancer. Cellular Physiology and Biochemistry. 2018; 46 :532-545. DOI: 10.1159/000488620 - 55.
Li H, Yuan X, Yan D, Li D, Guan F, Dong Y, et al. Long non-coding RNA MALAT1 decreases the sensitivity of resistant glioblastoma cell lines to temozolomide. Cellular Physiology and Biochemistry. 2017; 42 :1192-1201. DOI: 10.1159/000478917 - 56.
Shen J, Hodges TR, Song R, Gong Y, Calin GA, Heimberger AB, et al. Serum HOTAIR and GAS5 levels as predictors of survival in patients with glioblastoma. Molecular Carcinogenesis. 2018; 57 :137-141. DOI: 10.1002/mc.22739 - 57.
Lv R, Zhang J, Zhang W, Huang Y, Wang N, Zhang Q , et al. Circulating HOTAIR expression predicts the clinical response to neoadjuvant chemotherapy in patients with breast cancer. Cancer Biomarkers. 2018; 22 :249-256. DOI: 10.3233/CBM-170874 - 58.
Cantile M, Scognamiglio G, Marra L, Aquino G, Botti C, Falcone MR, et al. HOTAIR role in melanoma progression and its identification in the blood of patients with advanced disease. Journal of Cellular Physiology. 2017; 232 :3422-3432. DOI: 10.1002/jcp.25789 - 59.
Li N, Wang Y, Liu X, Luo P, Jing W, Zhu M, et al. Identification of circulating long noncoding RNA HOTAIR as a novel biomarker for diagnosis and monitoring of non-small cell lung cancer. Technology in Cancer Research & Treatment. 2017; 16 :1060-1066. DOI: 10.1177/1533034617723754 - 60.
Zhang L, Song X, Wang X, Xie Y, Wang Z, Xu Y, et al. Circulating DNA of HOTAIR in serum is a novel biomarker for breast cancer. Breast Cancer Research and Treatment. 2015; 152 :199-208. DOI: 10.1007/s10549-015-3431-2 - 61.
Li J, Wang Y, Yu J, Dong R, Qiu H. A high level of circulating HOTAIR is associated with progression and poor prognosis of cervical cancer. Tumour Biology. 2015; 36 :1661-1665. DOI: 10.1007/s13277-014-2765-4 - 62.
Gao L, Liu Y, Guo S, Yao R, Wu L, Xiao L, et al. Circulating long noncoding RNA HOTAIR is an essential mediator of acute myocardial infarction. Cellular Physiology and Biochemistry. 2017; 44 :1497-1508. DOI: 10.1159/000485588 - 63.
Permuth JB, Chen DT, Yoder SJ, Li J, Smith AT, Choi JW, et al. Linking circulating long non-coding RNAs to the diagnosis and malignant prediction of intraductal papillary mucinous neoplasms of the pancreas. Scientific Reports. 2017; 7 :10484. DOI: 10.1038/s41598-017-09754-5 - 64.
Tan Q , Zuo J, Qiu S, Yu Y, Zhou H, Li N, et al. Identification of circulating long non-coding RNA GAS5 as a potential biomarker for non-small cell lung cancer diagnosisnon-small cell lung cancer, long non-coding RNA, plasma, GAS5, biomarker. International Journal of Oncology. 2017; 50 :1729-1738. DOI: 10.3892/ijo.2017.3925 - 65.
Liang W, Lv T, Shi X, Liu H, Zhu Q , Zeng J, et al. Circulating long noncoding RNA GAS5 is a novel biomarker for the diagnosis of nonsmall cell lung cancer. Medicine (Baltimore). 2016; 95 :e4608. DOI: 10.1097/MD.0000000000004608 - 66.
Han L, Ma P, Liu SM, Zhou X. Circulating long noncoding RNA GAS5 as a potential biomarker in breast cancer for assessing the surgical effects. Tumour Biology. 2016; 37 :6847-6854. DOI: 10.1007/s13277-015-4568-7 - 67.
Fayda M, Isin M, Tambas M, Guveli M, Meral R, Altun M, et al. Do circulating long non-coding RNAs (lncRNAs) (LincRNA-p21, GAS 5, HOTAIR) predict the treatment response in patients with head and neck cancer treated with chemoradiotherapy? Tumour Biology. 2016; 37 :3969-3978. DOI: 10.1007/s13277-015-4189-1 - 68.
Zidan HE, Karam RA, El-Seifi OS, Abd Elrahman TM. Circulating long non-coding RNA MALAT1 expression as molecular biomarker in Egyptian patients with breast cancer. Cancer Genetics. 2018; 220 :32-37. DOI: 10.1016/j.cancergen.2017.11.005 - 69.
Zhang R, Xia Y, Wang Z, Zheng J, Chen Y, Li X, et al. Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer. Biochemical and Biophysical Research Communications. 2017; 490 (2):406-414. DOI: 10.1016/j.bbrc.2017.06.055 - 70.
He B, Zeng J, Chao W, Chen X, Huang Y, Deng K, et al. Serum long non-coding RNAs MALAT1, AFAP1-AS1 and AL359062 as diagnostic and prognostic biomarkers for nasopharyngeal carcinoma. Oncotarget. 2017; 8 :41166-41177. DOI: 10.18632/oncotarget.17083 - 71.
Duan W, Du L, Jiang X, Wang R, Yan S, Xie Y, et al. Identification of a serum circulating lncRNA panel for the diagnosis and recurrence prediction of bladder cancer. Oncotarget. 2016; 7 :78850-78858. DOI: 10.18632/oncotarget.12880 - 72.
Pang EJ, Yang R, Fu XB, Liu YF. Overexpression of long non-coding RNA MALAT1 is correlated with clinical progression and unfavorable prognosis in pancreatic cancer. Tumour Biology. 2015; 36 :2403-2407. DOI: 10.1007/s13277-014-2850-8 - 73.
Ren S, Liu Y, Xu W, Sun Y, Lu J, Wang F, et al. Long noncoding RNA MALAT-1 is a new potential therapeutic target for castration resistant prostate cancer. The Journal of Urology. 2013; 190 :2278-2287. DOI: 10.1016/j.juro.2013.07.001 - 74.
Peng H, Wang J, Li J, Zhao M, Huang SK, Gu YY, et al. A circulating non-coding RNA panel as an early detection predictor of non-small cell lung cancer. Life Sciences. 2016; 151 :235-242. DOI: 10.1016/j.lfs.2016.03.002 - 75.
Jalali S, Gandhi S, Scaria V. Distinct and modular organization of protein interacting sites in long non-coding RNAs. Frontiers in Molecular Biosciences. 2018; 5 :27. DOI: 10.3389/fmolb.2018.00027 - 76.
Li G, Liu K, Du X. Long non-coding RNA TUG1 promotes proliferation and inhibits apoptosis of osteosarcoma cells by sponging miR-132-3p and upregulating SOX4 expression. Yonsei Medical Journal. 2018; 59 :226-235. DOI: 10.3349/ymj.2018.59.2.226 - 77.
Sun XJ, Wang Q , Guo B, Liu XY, Wang B. Identification of skin-related lncRNAs as potential biomarkers that involved in Wnt pathways in keloids. Oncotarget. 2017; 8 :34236-34244. DOI: 10.18632/oncotarget.15880 - 78.
Yan Y, Zhang L, Jiang Y, Xu T, Mei Q , Wang H, et al. LncRNA and mRNA interaction study based on transcriptome profiles reveals potential core genes in the pathogenesis of human glioblastoma multiforme. Journal of Cancer Research and Clinical Oncology. 2015; 141 :827-838. DOI: 10.1007/s00432-014-1861-6 - 79.
Wang JB, Liu FH, Chen JH, Ge HT, Mu LY, Bao HB, et al. Identifying survival-associated modules from the dysregulated triplet network in glioblastoma multiforme. Journal of Cancer Research and Clinical Oncology. 2017; 143 :661-671. DOI: 10.1007/s00432-016-2332-z - 80.
Cao Y, Wang P, Ning S, Xiao W, Xiao B, Li X. Identification of prognostic biomarkers in glioblastoma using a long non-coding RNA-mediated, competitive endogenous RNA network. Oncotarget. 2016; 7 :41737-41747. DOI: 10.18632/oncotarget.9569 - 81.
Li Q , Jia H, Li H, Dong C, Wang Y, Zou Z. LncRNA and mRNA expression profiles of glioblastoma multiforme (GBM) reveal the potential roles of lncRNAs in GBM pathogenesis. Tumour Biology. 2016; 37 :14537-14552 - 82.
Zhang K, Li Q , Kang X, Wang Y, Wang S. Identification and functional characterization of lncRNAs acting as ceRNA involved in the malignant progression of glioblastoma multiforme. Oncology Reports. 2016; 36 :2911-2925. DOI: 10.3892/or.2016.5070 - 83.
Wang WA, Lai LC, Tsai MH, Lu TP, Chuang EY. Development of a prediction model for radiosensitivity using the expression values of genes and long non-coding RNAs. Oncotarget. 2016; 7 :26739-26750. DOI: 10.18632/oncotarget.8496 - 84.
Izuogu OG, Alhasan AA, Mellough C, Collin J, Gallon R, Hyslop J, et al. Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular. BMC Genomics. 2018; 19 :276. DOI: 10.1186/s12864-018-4660-7 - 85.
Ruan ZB, Chen GC, Ren Y, Zhu L. Expression profile of long non-coding RNAs during the differentiation of human umbilical cord derived mesenchymal stem cells into cardiomyocyte-like cells. Cytotechnology. 2018; 70 :1247-1260. DOI: 10.1007/s10616-018-0217-5 - 86.
Balci T, Yilmaz Susluer S, Kayabasi C, Ozmen Yelken B, Biray Avci C, Gunduz C. Analysis of dysregulated long non-coding RNA expressions in glioblastoma cells. Gene. 2016; 590 :120-122. DOI: 10.1016/j.gene.2016.06.024 - 87.
Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, et al. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017; 31 :591-606.e6. DOI: 10.1016/j.ccell.2017.02.013 - 88.
Ma X, Shao C, Jin Y, Wang H, Meng Y. Long non-coding RNAs: A novel endogenous source for the generation of Dicer-like 1-dependent small RNAs in Arabidopsis thaliana. RNA Biology. 2014; 11 :373-390. DOI: 10.4161/rna.28725 - 89.
Gaiti F, Hatleberg WL, Tanurdžić M, Degnan BM. Sponge long non-coding RNAs are expressed in specific cell types and conserved networks. Noncoding RNA. 2018; 4 :E6. DOI: 10.3390/ncrna4010006 - 90.
Zhou Y, Meng X, Chen S, Li W, Li D, Singer R, et al. IMP1 regulates UCA1-mediated cell invasion through facilitating UCA1 decay and decreasing the sponge effect of UCA1 for miR-122-5p. Breast Cancer Research. 2018; 20 :32. DOI: 10.1186/s13058-018-0959-1 - 91.
Gong W, Zheng J, Liu X, Ma J, Liu Y, Xue Y. Knockdown of NEAT1 restrained the malignant progression of glioma stem cells by activating microRNA let-7e. Oncotarget. 2016; 7 :62208-62223. DOI: 10.18632/oncotarget.11403 - 92.
Li W, Jiang P, Sun X, Xu S, Ma X, Zhan R. Suppressing H19 modulates tumorigenicity and stemness in U251 and U87MG glioma cells. Cellular and Molecular Neurobiology. 2016; 36 (8):1219-1227 - 93.
Yao Y, Ma J, Xue Y, Wang P, Li Z, Liu J, et al. Knockdown of long non-coding RNA XIST exerts tumor-suppressive functions in human glioblastoma stem cells by up-regulating miR-152. Cancer Letters. 2015; 359 :75-86. DOI: 10.1016/j.canlet.2014.12.051 - 94.
Cai H, Liu X, Zheng J, Xue Y, Ma J, Li Z, et al. Long non-coding RNA taurine upregulated 1 enhances tumor-induced angiogenesis through inhibiting microRNA-299 in human glioblastoma. Oncogene. 2017; 36 :318-331. DOI: 10.1038/onc.2016.212 - 95.
Ren J, Yang Y, Xue J, Xi Z, Hu L, Pan SJ, et al. Long noncoding RNA SNHG7 promotes the progression and growth of glioblastoma via inhibition of miR-5095. Biochemical and Biophysical Research Communications. 2018; 496 :712-718. DOI: 10.1016/j.bbrc.2018.01.109 - 96.
Li DX, Fei XR, Dong YF, Cheng CD, Yang Y, Deng XF, et al. The long non-coding RNA CRNDE acts as a ceRNA and promotes glioma malignancy by preventing miR-136-5p-mediated downregulation of Bcl-2 and Wnt2. Oncotarget. 2017; 8 :88163-88178. DOI: 10.18632/oncotarget.21513 - 97.
Liu C, Sun Y, She X, Tu C, Cheng X, Wang L, et al. CASC2c as an unfavorable prognosis factor interacts with miR-101 to mediate astrocytoma tumorigenesis. Cell Death & Disease. 2017; 8 :e2639. DOI: 10.1038/cddis.2017.11 - 98.
Chakravadhanula M, Ozols VV, Hampton CN, Zhou L, Catchpoole D, Bhardwaj RD. Expression of the HOX genes and HOTAIR in a typical teratoid rhabdoid tumors and other pediatric brain tumors. Cancer Genetics. 2014; 207 :425-428. DOI: 10.1016/j.cancergen.2014.05.014 - 99.
Yan ZY, Sun XC. LincRNA-ROR functions as a ceRNA to regulate Oct4, Sox2, and Nanog expression by sponging miR-145 and its effect on biologic characteristics of colonic cancer stem cells. Zhonghua Bing Li Xue Za Zhi. 2018; 47 :284-290. DOI: 10.3760/cma.j.issn.0529-5807.2018.04.011 - 100.
Li C, Lu L, Feng B, Zhang K, Han S, Hou D, et al. The lincRNA-ROR/miR-145 axis promotes invasion and metastasis in hepatocellular carcinoma via induction of epithelial-mesenchymal transition by targeting ZEB2. Scientific Reports. 2017; 7 :4637. DOI: 10.1038/s41598-017-04113-w - 101.
Feng S, Yao J, Chen Y, Geng P, Zhang H, Ma X, et al. Expression and functional role of reprogramming-related long noncoding RNA (lincRNA-ROR) in glioma. Journal of Molecular Neuroscience. 2015; 56 :623-630. DOI: 10.1007/s12031-014-0488-z