Biomedical Research

Abstract

Glioma is the most common and aggressive primary adult brain tumor. The median survival time of the glioma patients is less than 15 months under conventional treatments. The etiology of the glioma is still unknown. The emerging evidence suggested that many factors contributed to human glioma formation, metastasis, relapse, and resistant to radiation, and chemotherapy/therapies resistance. Recent reports showed that the long non-coding RNAs (lncRNAs) had multifunctional roles in regulating human glioma tumorogenesis processes through both transcriptional and post-transcriptional regulation of gene expression. In this review, the related lncRNAs which have been reported were summarized, the functions of the lncRNAs which acted as oncogenes or tumor suppressor genes during human glioma development was discussed, and the current mechanisms of lncRNAs was elaborated in a variety of biological properties of human glioma.

Keywords

Glioma, Tumorigenesis, LncRNAs.

Introduction

Glioma is the most common and aggressive primary brain tumor in adult. Gliomas make up about 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. The exact causes of gliomas are still not known. Different oncogenes work in the development of gliomas. Different cancer genes have synergistic in the development of glioma. Treatment for brain gliomas depends on the location, cell type, and grade of malignancy. So far, there is no way to cure gliomas. Surgery, radiation therapy, and chemotherapy are combined together to treat the human gliomas. The median survival time of the glioma patients is less than 15 months under conventional treatments. The etiology of the glioma is unknown till now [1-4]. According to aggressiveness, the World Health Organization (WHO) classified them into Grades 1 and 2 or Low-Grade Gliomas (LGG), and Grades 3 and 4 or High-Grade Gliomas (HGG). Human glioma is characterized by a wide clinical and histological heterogeneity, because 35-40% of them have epigenetic modifications as the underlying mechanism driving malignancy [5]. Clinicians and scientists all over the world can’t predict the clinical evolution of each patient who is diagnosed with this human glioma till now.

The global human genome project which is started at 1990’s is expected to understand the human Genetic information especially genes information which encodes functional proteins. Finally, only 20000 protein coding genes were discovered [6-8]. More than 98% of eukaryotic transcriptomes compose of non-coding RNAs with no functional protein-coding capacity [9-11]. Investigators categorized the non-coding RNAs (ncRNAs) as short ncRNAs, mid-size ncRNAs, and long non-coding RNAs (lncRNAs) by their lengths. LncRNA is a large class of ncRNA which have a length of more than 200 nucleotides (nt) and plays important roles in lots of physiological and pathological processes [12]. LncRNAs have many roles in regulating embryonic pluripotency, differentiation, development and various diseases, especially in cancers [13-16]. Recently, many evidences demonstrated that lncRNAs take part in many signalling pathways related to human glioma progression, invasion, metastasis, and drugresistance [17-19]. In most reviews, the relationship of the lncRNAs and glioma has been analysed. It is known that expression of different types of lncRNAs in different pathological grade of gliomas, or even in the same pathological grade of gliomas expression is not the same. The recurrence rate and survival time of the patients with the same pathological grade were also different. Whether this difference is related to the expression of different lncRNAs is still unclear. In this review, the updated research data will be focused and the current knowledge of lncRNAs contributing to these processes in human glioma occurrence and development will be summarized.

The Function of the IncRNAs

In human genome, no more than 2% of human genome sequence can be transcribed into protein. Most of the human genome sequence can’t be transcribed into functional protein. They are transcribed into non-coding RNA (ncRNAs), which include short ncRNA, mid-size ncRNA, and lncRNA. LncRNAs may be classified according to their mode of action and functions in cells such as, 1) mediators on signalling pathway, 2) serving as molecular decoys, 3) work as molecular guides for the ribonucleoprotein complexes to certain specific chromatin site, and also have 4) scaffold function for the proper complex formation [8,15]. According to GENCODE gene annotation V22, there are 15,900 human lncRNA genes that can produce 27,670 long non-coding RNA transcripts. However, there are only 9,894 small non-coding RNAs genes in the human genome [20]. The expression of lncRNAs has tissue specificity. It has been suggested through multiple studies that the brain and central nervous system express the greatest amount of lncRNAs of any tissue type. They have important roles in regulating transcriptional and non-transcriptional processes [21].

X-inactive specific transcript (Xist) which is the first lncRNA was discovered in 1990 by Brown et al. first. They found Xist as a novel protein non-coding RNA only expressed by inactive X-chromosomes only in female mammals in their study. It was revealed that Xist can silence one of X-chromosome activation by coating one X-chromosome leading to its epigenetic function [22]. Later, many lncRNAs were described successively as a sort of important regulators.

The nucleus is a highly structured cellular compartment. The chromatin-associated processes such as DNA replication, transcription, RNA processing and RNA export were organized and regulated in nucleus. Recent studies showed that lncRNAs had the complex secondary structures and played roles in these processes including mRNA splicing, nuclear localization, cell survival, cell cycle, and migration [19,21,23-26]. Many studies have indicated that lncRNAs have roles in various cancers as prognostic markers. For example, HOTAIR has a role in colorectal cancer and MALAT1 has a role in non-small cell lung cancer [27-29]. Many reports showed they also had roles in breast cancer. In high-grade glioma HOTAIR is overexpressed whose upregulation is predictive of poor prognosis. In addition, HOTAIR has an important role in cell cycle progression, but the mechanism is not clear till now [29,30].

In different human glioma subtypes (Astrocytoma, less dendritic cell tumor, tumor of the ventricular canal, and glioblastoma) lncRNAs are differentially expressed and some lncRNAs are associated with biological characteristics of human glioma in the same subtype. In human glioma several lncRNAs may possibly play a vital role in cancer occurrence, metastasis, drug resistance and recurrence [8,13,16]. Many studies have shown that inhibiting or overexpression of specific lncRNAs can have an effect on the process of human glioma progression, showing a potential therapeutic application of lncRNAs in human glioma. Some specially lncRNA may not only affect the biologic processes of human glioma, but also modulate the function of the vascular endothelial cells which is associated with the Blood-Tumor Barrier (BTB) that contributes to the failure of conventional chemotherapy by restricting sufficient drug molecules delivery to tumor tissues [18]. If we know the mechanism how the lncRNA influence the BTB, we can find a new method to improve the prognosis of glioma. The purpose of this review was to summarize the involvement of different lncRNAs in the human glioma aggression, metastasis, and chemoradiotherapy resistance processes.

lncRNAs in Human Glioma Bioprocesses

Many studies have shown lncRNAs involving in occurrence and development of human glioma as tumorigenic factors or tumor suppressor. These lncRNAs have the aberrant expression level in malignant glioma compared to normal tissues. LncRNAs can work as molecular signalling mediators which modulate a certain set of gene expression [12]. LncRNAs that serve as molecular decoys can take proteins or RNAs away from a specific location [31]. LncRNAs can take part in the assembly of protein complexes. LncRNAs work as the molecular guides through locating certain ribonucleoprotein complexes to a specific target site on the chromatin [17].

H19, a 2.3 kb carcinogenic lncRNA which locates on human chromosome 11p15.5, doesn’t contain any known open reading frames [32,33]. H19 is located on the downstream of Insulin-like Growth Factor 2 (IGF-2). They share the same imprinting mechanism. H19 has been well studied in many different cancers, including bladder, breast, colon, glioma, pancreatic, liver, and ovarian cancers [34-39]. Recent study shows that C-Myc regulates these two genes (H19 and IGF-2) independently and does not affect H19 imprinting. C-Myc binds to evolutionarily conserved E-boxes near the imprinting control region to facilitate histone acetylation and transcriptional initiation of the H19 promoter. C-Myc significantly induces the expression of the H19 noncoding RNA in diverse cell types, including glioblastoma. C-Myc up-regulates H19, down-regulates IGF2 transcripts and does not affect imprinting of the H19/IGF2 locus [40]. In vivo assays overexpression of H19 promotes tumor development after subcutaneous injection of H19-recombined cells into SCID mice [34].

Similar to H19, non-coding RNA Hox transcript antisense intergenic RNA (HOTAIR) has been characterized as a negative prognostic factor in breast and colon cancer patients. In Zhang’s study, it was found that HOTAIR expression was closely associated with glioma grade and poor prognosis [41]. A study showed that low expression of HOTAIR can inhibit cell invasion, decrease cell proliferation and alter cell cycle progression. Down-regulation of HOTAIR can induce cell cycle G₀/G₁ arrest [42]. This suggested that HOTAIR played an important role in glioma molecular classification and may serve as a novel therapeutic target for classical and mesenchymal glioma subtypes. Xue et al. found that HOTAIR was the target of miR-326 which mediated the tumor-suppressive effects of HOTAIR knockdown on glioma cell lines [43]. Overexpressing of miR-326 reduced the FGF1 expression which played an oncogenic role in glioma by activating PI3K/AKT and MEK 1/2 pathways. They got the same findings in vivo [44-46]. These results provided a new potential therapeutic strategy for glioma treatment. The HOTAIR-miR-326-FGF1 axis might represent a promising therapeutic strategy for the treatment of human glioma. A research by Zhang et al. demonstrated that in GBM cells, HOTAIR regulated cell cycle progression predominantly via the HOTAIR 5’ domain-PRC2 axis, which was EZH2-dependent. HOTAIR 5’domain-PRC2 is a new regulatory axis that modulates cell cycle progression in GBM cells. Previous studies have indicated that EZH2 was overexpressed in glioma stem-like cells and adult glioblastoma patient samples [28,47,48].

In order to know whether other lncRNAs influence the profiling of human glioma, Kraus finished a research this is to find lncRNAs that have roles in human glioma [49]. They found that not only H19 and but also HOXA6as, Zfhx2as and BC200 are suitable as normalisers in glioma and normal brain. These lncRNAs are applicable for the accurate normalisation of lncRNA expression profiling in various glioma alone and in combination with brain tissue. This enables to perform valid longitudinal studies, e.g. of glioma before and after malignisation to identify changes of lncRNA expressions probably driving malignant transformation [21,50,51]. We only know that these lncRNAs have important roles in profiling of human glioma, but the true mechanism is not clear.

So many studies show that there is a kind of cell which have self-renewal capacity and differentiation potential in cancer tissue [52,53]. The first solid CSCs were identified in human breast carcinoma by Hajj et al. [54]. They isolated a small cellular subpopulation which has self-renewal capacity from breast tumors patients. Marco used custom microarrays to examine Ultra-Conserved Regions’ (UCR) expression across samples from different tissues and different types of cancer. The expression in embryonic stem cells of selected UCRs was validated by real time PCR. In their study, they found the uc. 283-plus lncRNA was highly expressed in some solid cancers and associated with pluripotency. It is showed in their research that uc.283-plus was over-expressed in glioma samples. The high expression of uc.283-plus in glioma is correlated with a 'cancer stem cell phenotype', a well-studied event occurring in glioma [55,56]. Lujambio et al. identified RNA in the uc.283 genomic region but transcribed from the opposite strand in various types of cancer cell lines [57]. They also showed that uc.283-minus could be regulated by epigenetic alteration. Recently, Hudson et al. produced a list of the possible ucRNA-mRNA interactions based on sequence complementarity according to the thermodynamics of the loop-loop RNA interactions [58-60]. The mechanism of the lncRNA uc.283 working in the human glioma is not clear till now. These studies may be a starting point for the further characterization of lncRNA uc.283 in human glioma tissues and the role mechanism of the lncRNA uc.283.

As everyone knows, there is Blood-Brain Barrier (BBB) in the body. The BBB is a highly selective permeability barrier that separates the circulating blood from the brain Extracellular Fluid (BECF) in the central nerve system. The BBB acts very effectively to protect the brain from many common bacterial infections [61]. It can also affect the absorption and effects of drugs. One of the reasons listed for the failure of brain chemotherapy is the presence of BBB [62]. The BBB is frequently impaired in brain tumor, creating the BTB [63]. BBB and BTB are different. The existence of BTB contributes to the failure of conventional chemotherapy by restricting sufficient drug molecules delivery to tumor tissues [18,64,65]. There are two methods for drugs cross the BTB: paracellular or transcellular. The first method is the main route of absorption for chemotherapy drug molecules [65-68]. If we can know the regulatory roles of lncRNAs on BTB permeability, we may investigate novel methods to safely open the BTB. For BTB, when BTB permeability is increased, the expressions of tight junction proteins including ZO-1, occludin, and claudin-5 will be significantly down regulated [69]. Taurine upregulated gene 1 (TUG1) is a lncRNA located at chromosome 22q12 which was originally identified that plays crucial roles in vision system [18,70]. Beside, TUG1 is required for regulating carcinogenesis in several of tumors [71,72]. Heng et al. have finished a research whose purpose was to know the lncRNA TUG1’s role in BTB. Their research indicated that knockdown of TUG1 increased BTB permeability via binding to miR-144 and then reducing endothelial cells tight junction protein expression by targeting HSF2 [18]. In their recently study [73], they found that TUG1’s up expression was associational with the tumor-induced endothelial cell proliferation, migration and tube formation. Their study indicated that knockdown of the TUG1 reduced the expression of vascular endothelial growth factor A (VEGFA). MiR-299 worked as a bridge in this progress. The mechanism of this progress maybe TUG1 make the VEGFA up-expression through the miR-299 was down-expression. In future, TUG1 may provide a novel therapeutic target for glioma treatment.

As we know, human glioma is the most common and most aggressive malignant primary brain tumor in adult. The prognosis of disease is poor and the reason for this disease is not clear. In recent years, many researches indicated that lncRNAs not only have important roles in many normal bio-progresses but also in many diseases especially in many cancers such as human glioma and breast cancer. In this review, we summary the lncRNAs which have roles in the human glioma. H19, HOTAIR, HOXA6as, Zfhx2as and BC200, uc.283-plus and TUG1 have roles in the human glioma, but they work in different progresses of the disease (Table 1). In this review, we summarized the roles of different lncRNAs in the glioma. The regulation mechanisms of lncRNA in the glioma biological processes are not clear. We think the lncRNAs not only have roles in the biological processes of the glioma but also related to the recurrence rate and survival time of the patients. The epigenomic reprogramming by lncRNAs can be the real reason for the human glioma. Till now, the human glioma is mainly classified according to the pathological type. Recent studies show that the prognosis of the human glioma is related to the expression of lncRNAs type and the expression quantity of the lncRNAs. LncRNAs may be useful future therapeutic targets for human glioma and can be used to classify the human glioma types. LncRNAs could serve as a new target for targeted therapy. Therefore, clarifying the mechanisms of lncRNAs in the various biological processes of the human glioma will be a critical step in exploring new strategies in future cancer therapy. LncRNAs may be related to the pathological grading of glioma. Different patients with the same pathological grade have the different disease progress. LncRNAs may be better able to respond to the disease process and to the extent of the glioma's nausea. LncRNAs may be a better target for clinical treatment of gliomas.

Table 1. The characterized lncRNAs with potential roles in glioma.

Acknowledgements

The study was supported by Shanghai Municipal Commission of Health and Family Planning (No. 201440319).

References

1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114: 97-109.
2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987-996.
3. Goodenberger ML, Jenkins RB. Genetics of adult glioma. Cancer Genet 2012; 205: 613-621.
4. Radner H, El-Shabrawi Y, Eibl RH, Brustle O, Kenner L, Kleihues P, Wiestler OD. Tumor induction by ras and myc oncogenes in fetal and neonatal brain: modulating effects of developmental stage and retroviral dose. Acta Neuropathol 1993; 86: 456-465.
5. Kondo Y, Katsushima K, Ohka F, Natsume A, Shinjo K. Epigenetic dysregulation in glioma. Cancer Sci 2014; 105: 363-369.
6. Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, Chalk AM, Chiu KP, Choudhary V, Christoffels A, Clutterbuck DR, Crowe ML, Dalla E, Dalrymple BP, de Bono B, Della Gatta G, di Bernardo D, Down T, Engstrom P, Fagiolini M, Faulkner G, Fletcher CF, Fukushima T, Furuno M, Futaki S, Gariboldi M, Georgii-Hemming P, Gingeras TR, Gojobori T, Green RE, Gustincich S, Harbers M, Hayashi Y, Hensch TK, Hirokawa N, Hill D, Huminiecki L, Iacono M, Ikeo K, Iwama A, Ishikawa T, Jakt M, Kanapin A, Katoh M, Kawasawa Y, Kelso J, Kitamura H, Kitano H, Kollias G, Krishnan SP, Kruger A, Kummerfeld SK, Kurochkin IV, Lareau LF, Lazarevic D, Lipovich L, Liu J, Liuni S, McWilliam S, Madan Babu M, Madera M, Marchionni L, Matsuda H, Matsuzawa S, Miki H, Mignone F, Miyake S, Morris K, Mottagui-Tabar S, Mulder N, Nakano N, Nakauchi H, Ng P, Nilsson R, Nishiguchi S, Nishikawa S, Nori F, Ohara O, Okazaki Y, Orlando V, Pang KC, Pavan WJ, Pavesi G, Pesole G, Petrovsky N, Piazza S, Reed J, Reid JF, Ring BZ, Ringwald M, Rost B, Ruan Y, Salzberg SL, Sandelin A, Schneider C, Schonbach C, Sekiguchi K, Semple CA, Seno S, Sessa L, Sheng Y, Shibata Y, Shimada H, Shimada K, Silva D, Sinclair B, Sperling S, Stupka E, Sugiura K, Sultana R, Takenaka Y, Taki K, Tammoja K, Tan SL, Tang S, Taylor MS, Tegner J, Teichmann SA, Ueda HR, van Nimwegen E, Verardo R, Wei CL, Yagi K, Yamanishi H, Zabarovsky E, Zhu S, Zimmer A, Hide W, Bult C, Grimmond SM, Teasdale RD, Liu ET, Brusic V, Quackenbush J, Wahlestedt C, Mattick JS, Hume DA, Kai C, Sasaki D, Tomaru Y, Fukuda S, Kanamori-Katayama M, Suzuki M, Aoki J, Arakawa T, Iida J, Imamura K, Itoh M, Kato T, Kawaji H, Kawagashira N, Kawashima T, Kojima M, Kondo S, Konno H, Nakano K, Ninomiya N, Nishio T, Okada M, Plessy C, Shibata K, Shiraki T, Suzuki S, Tagami M, Waki K, Watahiki A, Okamura-Oho Y, Suzuki H, Kawai J, Hayashizaki Y. The transcriptional landscape of the mammalian genome. Science 2005; 309: 1559-1563.
7. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 2004; 431: 931-945.
8. Park JY, Lee JE, Park JB, Yoo H, Lee SH. Roles of long non-coding RNAs on tumorigenesis and glioma development. Brain Tumor Res Treat 2014; 2: 1-6.
9. Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermuller J, Hofacker IL, Bell I, Cheung E, Drenkow J, Dumais E, Patel S, Helt G, Ganesh M, Ghosh S, Piccolboni A, Sementchenko V, Tammana H, Gingeras TR. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 2007; 316: 1484-1488.
10. Kapranov P, Willingham AT, Gingeras TR. Genome-wide transcription and the implications for genomic organization. Nat Rev Genet 2007; 8: 413-423.
11. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011; 12: 861-874.
12. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell 2011; 43: 904-914.
13. Qiu MT, Hu JW, Yin R, Xu L. Long noncoding RNA: an emerging paradigm of cancer research. Tumour Biol 2013; 34: 613-620.
14. Bartolomei MS, Zemel S, Tilghman SM. Parental imprinting of the mouse H19 gene. Nature 1991; 351: 153-155.
15. Shi X, Sun M, Liu H, Yao Y, Song Y. Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett 2013; 339: 159-166.
16. Hung T, Chang HY. Long noncoding RNA in genome regulation: prospects and mechanisms. RNA Biol 2010; 7: 582-585.
17. Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, Merkurjev D, Ohgi KA, Meng D, Zhang J, Evans CP, Rosenfeld MG. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 2013; 500: 598-602.
18. Cai H, Xue Y, Wang P. The long noncoding RNA TUG1 regulates blood-tumor barrier permeability by targeting miR-144. Oncotarget 2015; 6: 19759-19779.
19. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 2010; 464: 1071-1076.
20. Engstrom PG, Steijger T, Sipos B, Grant GR, Kahles A, Ratsch G, Goldman N, Hubbard TJ, Harrow J, Guigo R, Bertone P. Systematic evaluation of spliced alignment programs for RNA-seq data. Nat Methods 2013; 10: 1185-1191.
21. Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 2009; 23: 1494-1504.
22. Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R,Willard HF. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 1991; 349: 38-44.
23. Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, Horlings HM, Shah N, Umbricht C, Wang P, Wang Y, Kong B, Langerod A, Borresen-Dale AL, Kim SK, van de Vijver M, Sukumar S, Whitfield ML, Kellis M, Xiong Y, Wong DJ, Chang HY. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet 2011; 43: 621-629.
24. Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 2005; 309: 1570-1573.
25. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA, Blencowe BJ, Prasanth SG, Prasanth KV. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 2010; 39: 925-938.
26. Meola N, Pizzo M, Alfano G, Surace EM, Banfi S. The long noncoding RNA Vax2os1 controls the cell cycle progression of photoreceptor progenitors in the mouse retina. RNA 2012; 18: 111-123.
27. Schmidt LH, Spieker T, Koschmieder S, Schaffers S, Humberg J, Jungen D, Bulk E, Hascher A, Wittmer D, Marra A, Hillejan L, Wiebe K, Berdel WE, Wiewrodt R, Muller-Tidow C. The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol 2011; 6: 1984-1992.
28. Zhang K, Sun X, Zhou X, Han L, Chen L, Shi Z, Zhang A, Ye M, Wang Q, Liu C, Wei J, Ren Y, Yang J, Zhang J, Pu P, Li M, Kang C. Long non-coding RNA HOTAIR promotes glioblastoma cell cycle progression in an EZH2 dependent manner. Oncotarget 2015; 6: 537-546.
29. Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, Tanaka F, Shibata K, Suzuki A, Komune S, Miyano S, Mori M. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res 2011; 71: 6320-6326.
30. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY. Long noncoding RNA as modular scaffold of histone modification complexes. Science 2010; 329: 689-693.
31. Kallen AN, Zhou XB, Xu J, Qiao C, Ma J. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell 2013; 52: 101-112.
32. Brannan CI, Dees EC, Ingram RS, Tilghman SM. The product of the H19 gene may function as an RNA. Mol Cell Biol 1990; 10: 28-36.
33. Keniry A, Oxley D, Monnier P, Kyba M, Dandolo L. The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat Cell Biol 2012; 14: 659-665.
34. Lottin S, Adriaenssens E, Dupressoir T, Berteaux N, Montpellier C, Coll J, Dugimont T, Curgy JJ. Overexpression of an ectopic H19 gene enhances the tumorigenic properties of breast cancer cells. Carcinogenesis 2002; 23: 1885-1895.
35. Luo M, Li Z, Wang W, Zeng Y, Liu Z, Qiu J. Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett 2013; 333: 213-221.
36. Scaiewicz V, Sorin V, Fellig Y, Birman T, Mizrahi A, Galula J, Abu-Lail R, Shneider T, Ohana P, Buscail L, Hochberg A, Czerniak A. Use of H19 gene regulatory sequences in DNA-based therapy for pancreatic cancer. J Oncol 2010; 2010: 178174.
37. Sorin V, Ohana P, Mizrahi A, Matouk I, Birman T, Hochberg A, Czerniak A. Regional therapy with DTA-H19 vector suppresses growth of colon adenocarcinoma metastases in the rat liver. Int J Oncol 2011; 39: 1407-1412.
38. Fellig Y, Ariel I, Ohana P, Schachter P, Sinelnikov I, Birman T, Ayesh S, Schneider T, de Groot N, Czerniak A, Hochberg A. H19 expression in hepatic metastases from a range of human carcinomas. J Clin Pathol 2005; 58: 1064-1068.
39. Medrzycki M, Zhang Y, Zhang W, Cao K, Pan C. Histone h1.3 suppresses h19 noncoding RNA expression and cell growth of ovarian cancer cells. Cancer Res 2014; 74: 6463-6473.
40. Barsyte-Lovejoy D, Lau SK, Boutros PC, Khosravi F, Jurisica I, Andrulis IL, Tsao MS, Penn LZ. The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res 2006; 66: 5330-5337.
41. Zhang JX, Han L, Bao ZS, Wang YY, Chen LY, Yan W, Yu SZ, Pu PY, Liu N, You YP, Jiang T, Kang CS. HOTAIR, a cell cycle-associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma. Neuro Oncol 2013; 15: 1595-1603.
42. Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, Kim S, Safe S. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene 2013; 32: 1616-1625.
43. Ke J, Yao YL, Zheng J, Wang P, Liu YH, Ma J, Li Z, Liu XB, Li ZQ, Wang ZH, Xue YX. Knockdown of long non-coding RNA HOTAIR inhibits malignant biological behaviors of human glioma cells via modulation of miR-326. Oncotarget 2015; 6: 21934-21949.
44. Kefas B, Comeau L, Erdle N, Montgomery E, Amos S, Purow B. Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. Neuro Oncol 2010; 12: 1102-1112.
45. Qiu S, Lin S, Hu D, Feng Y, Tan Y, Peng Y. Interactions of miR-323/miR-326/miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients. J Transl Med 2013; 11: 10.
46. King ML, Lindberg ME, Stodden GR, Okuda H, Ebers SD, Johnson A, Montag A, Lengyel E, MacLean Ii JA, Hayashi K. WNT7A/beta-catenin signalling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer. Oncogene 2015; 34: 3452-3462.
47. Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC, Baumer K, Le Bitoux MA, Marino D, Cironi L, Marquez VE, Clement V, Stamenkovic I. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res 2009; 69: 9211-9218.
48. Orzan F, Pellegatta S, Poliani PL, Pisati F, Caldera V. Enhancer of Zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol Appl Neurobiol 2011; 37: 381-394.
49. Kraus TF, Greiner A, Guibourt V, Lisec K, Kretzschmar HA. Identification of stably expressed lncrnas as valid endogenous controls for profiling of human glioma. J Cancer 2015; 6: 111-119.
50. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet 2009; 10: 155-159.
51. Durrenberger PF, Fernando FS, Magliozzi R, Kashefi SN, Bonnert TP, Ferrer I, Seilhean D, Nait-Oumesmar B, Schmitt A, Gebicke-Haerter PJ, Falkai P, Grunblatt E, Palkovits M, Parchi P, Capellari S, Arzberger T, Kretzschmar H, Roncaroli F, Dexter DT, Reynolds R. Selection of novel reference genes for use in the human central nervous system: a BrainNet Europe Study. Acta Neuropathol 2012; 124: 893-903.
52. Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 2012; 21: 283-296.
53. Watkins S, Sontheimer H. Unique biology of gliomas: challenges and opportunities. Trends Neurosci 2012; 35: 546-556.
54. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983-3988.
55. Gronych J, Pfister SM, Jones DT. Connect four with glioblastoma stem cell factors. Cell 2014; 157: 525-527.
56. Zhang X, Sun S, Pu JK, Tsang AC, Lee D, Man VO, Lui WM, Wong ST, Leung GK. Long non-coding RNA expression profiles predict clinical phenotypes in glioma. Neurobiol Dis 2012; 48: 1-8.
57. Lujambio A, Portela A, Liz J, Melo SA, Rossi S, Spizzo R, Croce CM, Calin GA, Esteller M. CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer. Oncogene 2010; 29: 6390-6401.
58. Mückstein U, Tafer H, Hackermuller J, Bernhart SH, Stadler PF. Thermodynamics of RNA-RNA binding. Bioinformatics 2006; 22: 1177-1182.
59. Lorenz R, Bernhart SH, Honer Zu Siederdissen C, Tafer H, Flamm C. ViennaRNA Package 2.0. Algorithms Mol Biol 2011; 6: 26.
60. Galasso M, Dama P, Previati M, Sandhu S, Palatini J, Coppola V, Warner S, Sana ME, Zanella R, Abujarour R, Desponts C, Teitell MA, Garzon R, Calin G, Croce CM, Volinia S. A large scale expression study associates uc.283-plus lncRNA with pluripotent stem cells and human glioma. Genome Med 2014; 6: 76.
61. Chen Y, Imai H, Ito A, Saito N. Novel modified method for injection into the cerebrospinal fluid via the cerebellomedullary cistern in mice. Acta Neurobiol Exp (Wars) 2013; 73: 304-311.
62. Deeken JF, Loscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 2007; 13: 1663-1674.
63. Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol 2007; 25: 2306-2312.
64. Kemper EM, Boogerd W, Thuis I, Beijnen JH, van Tellingen O. Modulation of the blood-brain barrier in oncology: therapeutic opportunities for the treatment of brain tumours? Cancer Treat Rev 2004; 30: 415-423.
65. Neuwelt E, Abbott NJ, Abrey L, Banks WA, Blakley B, Davis T, Engelhardt B, Grammas P, Nedergaard M, Nutt J, Pardridge W, Rosenberg GA, Smith Q, Drewes LR. Strategies to advance translational research into brain barriers. Lancet Neurol 2008; 7: 84-96.
66. Abbott NJ. Blood-brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis 2013; 36: 437-449.
67. Tajes M, Ramos-Fernandez E, Weng-Jiang X, Bosch-Morato M, Guivernau B, Eraso-Pichot A, Salvador B, Fernandez-Busquets X, Roquer J, Munoz FJ. The blood-brain barrier: structure, function and therapeutic approaches to cross it. Mol Membr Biol 2014; 31: 152-167.
68. Gu YT, Qin LJ, Qin X, Xu F. The molecular mechanism of dexamethasone-mediated effect on the blood-brain tumor barrier permeability in a rat brain tumor model. Neurosci Lett 2009; 452: 114-118.
69. Liu LB, Xue YX, Liu YH, Wang YB. Bradykinin increases blood-tumor barrier permeability by down-regulating the expression levels of ZO-1, occludin, and claudin-5 and rearranging actin cytoskeleton. J Neurosci Res 2008; 86: 1153-1168.
70. Young TL, Matsuda T, Cepko CL. The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina. Curr Biol 2005; 15: 501-512.
71. Zhang Q, Geng PL, Yin P, Wang XL, Jia JP. Down-regulation of long non-coding RNA TUG1 inhibits osteosarcoma cell proliferation and promotes apoptosis. Asian Pac J Cancer Prev 2013; 14: 2311-2315.
72. Liu Y, Yang S, Zhang X. Down-regulation of long non-coding RNA TUG1 suppresses melanoma cell proliferation and induces apoptosis via up-regulating microRNA-9. Biochem Biophys Res Commun 2013.
73. Cai H, Liu X, Zheng J, Xue Y, Ma J, Li Z, Xi Z, Li Z, Bao M, Liu Y. Long non-coding RNA taurine upregulated 1 enhances tumor-induced angiogenesis through inhibiting microRNA-299 in human glioblastoma. Oncogene 2016.