Functions and Roles of Long-Non-Coding RNAs in Human Nasopharyngeal Carcinoma Open Access

Head and neck cancer are carcinomas arising from the mucosal epithelia of the head and neck region as well as various cell types of salivary glands, and thyroid [1]. Among these, nasopharyngeal carcinoma (NPC) is a unique malignant head and neck cancer with clinical, demographic, and geographic features distinct from other head and neck epithelial malignancies with different etiopathogenesis and a broad range of histopathological appearances. NPC is one of common aggressive squamous cell carcinomas, which is frequently occurring in males and are usually younger than patients with squamous cell head and neck cancers. There are geographic regions in the world where NPC is endemic, such as in Southeast Asia, especially in Southern China, Northern Africa, and parts of the Mediterranean basin [2, 3]. The incidence accounted for about 40% of the worlds new cases according to the World Health Organization’s global burden of disease cancer collaboration (GBDCC) and GLOBOCAN reported data of 2012 [4]. In contrast to patients with early-stage NPC, who have 5-year overall survival (OS) rate for up to 95% [5-7], the 5-year OS rate declines to 41%–63% in patients with advanced-stage disease [8, 9]. Genetic predisposition, and epigenetic variations, ethnic background, environmental factors including exposure to chemical carcinogens, and latent Epstein-Barr virus (EBV) infection, among others play important roles in the development of this malignancy [10-13]. According to global cancer statistics reported by the International Agency for Research on Cancer, over 85, 000 new NPC cases occur annually, among which 80 % are located in Asia and 5 % in Europe [14]. NPC is mainly characterized by poorly or undifferentiated carcinoma. Recent epidemiological studies suggested that incidence and mortality of NPC are gradually declining, even in endemic regions, which is probably a result of a combination of improvement of lifestyle modification, quantitative assessment of circulating EBV DNA population screening, prognostication, disease surveillance, advances in radiotherapy, comprehensive chemotherapy and effective systemic strategies. The development of vascular endothelial growth factor (VEGF) inhibition and immunotherapy targeting EBV-specific tumor antigens may offer promising alternatives to patients with NPC especially in advanced stages [15]. Nevertheless, management of NPC still remains one of the biggest clinical challenges. Although local radiation, surgery, and other combining treatments, and advantage to concurrent chemoradiation in the treatment of advanced disease provide good control of the most NPC, the prognosis of certain patients with NPC still remains poor due to the fact of advanced stage at the time of diagnosis, regional relapse, and distant metastasis. In addition, the high radiotherapy resistance is a severe obstacle for the treatment of NPC [16, 17]. Moreover, adverse effects, including upper gastrointestinal impairment and bone marrow suppression, depressed the toleration, and limited outcome of concurrent chemo-radiotherapies may affect the quality of life and survival in NPC patients. The recent development in the understanding of tumor biology, host cell-virus interaction and genetics have provided potential new ways for targeted therapies and become the focus of research in this field. In addition, in-depth understanding the molecular mechanisms and the disease characteristics are also greatly desired, which led us to explore new strategies to improve the therapeutics of patients with NPC.

It is well known that RNA plays a crucial role in the organization and regulation of genome by the activity of a large amount of protein-coding genes and non-protein coding RNAs (ncRNAs). According to the Encyclopedia of DNA Elements (ENCODE) project, the transcripts cover 62-75% of our genome, among which are mostly noncoding RNAs [18]. They appear to comprise a hidden layer of internal signals that control various levels of gene expression in physiology and development, including chromatin architecture, epigenetic memory, transcription, RNA splicing, editing, translation and turnover [19]. Based on sizes, ncRNAs are divided into two highly diverse groups: small ncRNAs (sncRNAs) and long ncRNAs (lncRNAs), sncRNAs particularly microRNAs (miRNAs) are extensively studied because of their function as gene regulators during development and disease [20]. MiRNAs are endogenous non-coding small RNAs about 19–25 nucleotide long, which contribute to the regulation of their target gene mRNA by usually base-pairing to the 3′-untranslated region (3′-UTR), and results in either mRNA degradation or translation inhibition by RNA silencing and post-transcriptional regulation of gene expression [21, 22]. It has been reported that miRNAs can control a variety of biological processes including cellular differentiation, proliferation, cell mobility and cell death [23]. Moreover, evidence indicated that miRNAs can function either as tumor suppressors or oncogenes in tumor progression by suppressing both oncogenic or tumor suppressive mRNAs, respectively [24, 25]. LncRNAs are transcripts of more than 200 nucleotides without functional protein-coding ability in a conventional way and are mostly transcribed by RNA polymerase II from different regions across the genome [26, 27]. They are often expressed in a disease-, tissue- or developmental stage-specific manners, and represent a new research frontier in molecular biology. To date, more than 10, 000 intergenic lncRNAs have been identified in mammals, and a rapidly growing number of lncRNAs have been implicated in a variety of biological processes and functions [28]. LncRNAs play important roles in regulating gene expression at epigenetic, transcriptional and post-transcriptional levels. More and more lncRNAs have been found to be involved in normal cell physiological activities, and also demonstrated to be participated in the pathological process of tumors and other diseases. There are various genomic origins of lncRNAs, which can be classified into five categories based on their relationship with protein-coding genes: sense, antisense, intergenic, intronic and bidirectional lncRNAs. Sense or antisense lncRNAs may overlap with one or more exons of other transcripts from the same or opposite strand. Intergenic lncRNAs are within a genomic interval between two coding genes that are more then 1000 base pairs away from the nearest coding gene. Intronic lncRNAs initiate inside an intron in either direction and terminate without overlapping exons. Finally, the bidirectional lncRNAs are less than 1000 base pairs downstream from the transcription initiation site and are on the complementary strand of protein-coding genes [29-31]. LncRNAs are predominately located in the nucleus, and the functional mechanisms of lncRNAs have not yet well elucidated. Recent studies have found a diverse population of lncRNAs with different sizes and functions in different species. These populations are expressed dynamically and act as important regulators in a variety of biological functions, especially in gene expression [32]. Accumulating evidence indicate that lncRNAs, by interacting with DNA, RNA, protein molecules and/or their combinations, play a critical role in regulation of cellular processes including genetic imprinting, chromatin remodeling, splicing regulation, mRNA decay, transcription, and translational regulation [33-36]. Expression and activity of lncRNAs are deregulated in several types of human cancer, therefore, aberrant expressions of lncRNAs can cause various human diseases, including cancers [34, 37] and contribute to tumor occurrence and development through numerous mechanisms, ranging from epigenetic, transcriptional and posttranscriptional regulation of relevant genes to the control of cell cycle distribution, cell differentiation, and epigenetic modifications [38-41]. Nevertheless, the functions and mechanisms of the vast majority of lncRNAs still remain unknown. Thus, deepening understanding these areas are critical not only from a mechanistic standpoint, but also for the development of novel biomarkers and effective therapeutic targets for cancer.

Many lncRNAs are dysregulated in NPC and play important roles in NPC occurrence, progression, and even treatment. lncRNAs, which are up-regulated in NPC, may act as oncogene to promote growth, migration, invasion, chemo-, and radio-resistance, while others may possess anti-tumor properties [42-48] (Fig. 1). This indicates distinct role of different lncRNAs in NPC occurrence and progression, and may provide a missing piece of the otherwise well-known oncogenic and tumor suppressor network puzzle. In addition, altered expressions of lncRNAs in NPC may differ in various patient populations, for example, high levels of lnc-C22orf32-1 and lnc-AL355149.1-1 were significantly associated with the male not female NPC patients. In addition, recurrent NPC was demonstrated a distinctive lncRNA expression pattern as compared to that in primary tumors. LncRNA lnc-BCL2L11-3 was significantly increased, while substantial reductions of lnc-AL355149.1-1 and lnc-ZNF674-1 were found in the recurrent NPC tissues in comparing to that in the primary one. Thus, the distinctive lncRNA identified in the primary and recurrent NPC may imply a distinctive mechanism underlying for tumor growth and metastasis [49]. This may be the reasons for further emphasizing the necessity of personalized treatment for the patients with NPC using lncRNA expression profiles as one of indicators. Given their numerous putative roles of development and progression, a thorough understanding the impact of lncRNAs dysregulation and functions in NPC is expected to shed light on useful biomarkers and therapeutic targets for the clinical management of this malignancy. The biological functions and molecular mechanisms of specific lncRNAs in NPC are summarized (Table 1).

Growing evidence demonstrates that lncRNAs play an important role in cancer origination and progression. Among those, the tumor suppressor role of lncRNAs has been found in several cancer types [50-52]. Downregulation of a lncRNA, maternally expressed gene 3 (MEG3), was identified in NPC suggesting a possible role of tumor suppressor in cancer such as NPC. MEG3 is an imprinted gene belonging to the imprinted DLK1-MEG3 locus located at chromosome 14q32.3, a common deleted region in NPC. Both losses of DNA copy numbers and aberrant promoter methylation result in MEG3 inactivation. The expression of MEG3 gene is low in the numbers of human tumors and cell lines. Multiple mechanisms such as deletion of gene, promoter hypermethylation, and hypermethylation of the intergenic differentially methylated region contributed to the loss of MEG3 expression in tumors. Interestingly, MEG3 expression could be rescued by the treatment of a demethylation agent. Besides, ectopic expression of MEG3 in NPC cells resulted in repression of cell proliferation, colony formation, induction of cell cycle arrest, and tumorigenicity in vitro and in vivo. This characterized MEG3 as a tumor suppressive in NPC may consider as IncRNA-targeted epigenetic therapy against this disease [53]. Nevertheless, the mechanism of MEG3 as a tumor suppressor warrants further studies. LncRNA-LET, a recently identified 1ncRNA, has also been shown to act as a tumor suppressor in NPC as well [54, 55]. LET inhibited proliferation, adhesion and invasion of NPC in vitro by enhancing its expression. By contrast, decreased LET expression could promote the proliferation, adhesion and invasion of NPC [55]. The reduced LET expression was significantly correlated with advanced clinical stage, larger tumor size, increased lymph node tumor burden, and poor survival in patient with NPC. Knockdown of LET promoted proliferation and inhibited apoptosis in NPC cells [56]. Importantly, lncRNA-LET was repressed by enhancer of zeste homologue 2 (EZH2), a histone methyl transferase subunit of a polycomb repressor complex (PRC), and a a master epigenetic regulator [57], -mediated H3K27 histone methylation on the LET promoter, and the expressions of EZH2 and lncRNA-LET were significantly inversely correlated in NPC [58]. These observations indicated a pivotal role for lncRNA-LET in NPC cell proliferation. The expression of lncRNA LINC0086 was also reduced in NPC, resulting in increased proliferation and decreased apoptosis in NPC cells [59]. LINC0086q expression was associated with histological grades, lymph node metastasis, and clinical stages in patients with NPC. LINC0086 showed to decrease in miR-214 expression by directly interacting with miR-214 in the 3’-UTR region. Furthermore, the reduced LINC0086 on cell growth of NPC were reversed by exogenously expressed miR-214 in vitro and in vivo suggesting a potential new diagnostic and therapeutic biomarker for NPC [59]. LOC401317 was highly induced by p53 transgene expression. Investigating its function in vitro and in vivo as a candidate tumor suppressor showed that LOC401317 was directly transcribed by p53 through a p53-binding site adjacent to its potential promoter region, and that LOC401317 inhibited cell cycle progression by increasing p21 and decreasing cyclin D1/E1 expressions, and promoted apoptosis through the induction of poly(ADP-ribose) polymerase and caspase-3 cleavage [60]. Nevertheless, current available information regarding this and other tumor suppressor lncRNAs involving in pathogenesis of NPC is limited, thus the true roles and functions of these lncRNAs in NPC still remains to be determined.

Based on their large number and expression specificity in a variety of cancers, vast amounts of lncRNAs are likely to serve as oncogenic role, which is involved in the increased proliferation and migration of cancers through distinct mechanisms [61-64]. LncRNA HOX transcript antisense intergenic RNA (HOTAIR) acts as an oncogene and is aberrantly expressed in multiple types of cancer, and has been considered as predictive factor for poor prognosis in a variety of cancers [65, 66]. HOTAIR regulated multiple signaling and targets via distinct mechanisms, thereby promoting growth and progression of cancer [65, 67]. Expression of HOTAIR was extremely abundant in NPC cells and clinical samples [68, 69], high expression levels of HOTAIR are correlated with poor prognosis in NPC patients, and HOTAIR mediates the migration and invasion of NPC cells [69]. Furthermore, HOTAIR also promoted angiogenesis through directly activating the transcription of angiogenic factor VEGFA as well as GRP78-mediated induction of VEGFA and Ang2 expressions in NPC cells [68]. Studies have demonstrated that upregulation of lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) played an oncogenic role in various tumors, including NPC [54, 70-72]. LncRNA ANRIL, which encodes a 3834-nt RNA that contains 19 exons at the antisense orientation of the INK4B-ARF-INK4A gene cluster, could promote NPC progression by increasing cell proliferation and transformation, reprogramming cell glucose metabolism, and inducing side-population stem-like cancer cells. This may partially account for ANRIL-induced stem-like NPC cells and tumorigenesis [73]. In addition, knockdown of ANRIL repressed tumorigenicity and enhanced DDP-induced cytotoxicity through regulating microRNA let-7a in NPC cells, this provided a promising therapeutic strategy for NPC patients [54]. Moreover, silencing of ANRIL repressed proliferation, promoted apoptosis, and improved radiosensitivity in NPC cells via functioning as a miR-125a sponge [74]. LncRNAs also play critical roles in regulating chemo-resistance in multiple types of cancers. The lncRNA CCAT1 is upregulated in NPC, resulting in significantly enhancing paclitaxel resistance in NPC cells [75]. The upregulated CCAT1 showed to sponge miR-181a, whereas miR-181a could directly bind to CCAT1 in NPC cells. This study demonstrated that lncRNA CCAT1 affected the sensitivity of paclitaxel in NPC cells through miR-181a/CPEB2 associated signaling cascade [75]. LncRNA-regulator of reprogramming (ROR), a recently identified lncRNA, has been shown to be involved in initiation, progression and metastasis of several tumors including NPC [47, 76-78]. LncRNA-ROR, located at chromosome 18q21.31, was first discovered in induced pluripotent stem cells (iPSCs) and was directly regulated by stem cell (SC) markers SOX2, OCT4, NONOG, which were crucial for progression of various human malignancies including NPC [79]. LncRNA-ROR was reported to be highly associated with the proliferation and metastasis of NPC [47]. Importantly, the enrichment of lncRNA-ROR played a key role in chemoresistance through mechanism by which lncRNA-ROR suppressed p53 signal pathway [47]. LncRNA Ewing sarcoma associated transcript 1 (EWSAT1) has been identified as an oncogene, as a downstream target of EWS and transcription factor FLI1 (EWS-FLI1), dysregulation of EWSAT1 is closed correlated with tumor progression in Ewing sarcoma [80]. Recently, high-through input analysis reveals that EWSAT1 is also highly expressed in NPC. EWSAT1 was reported as a direct target of miR-326/330-5p clusters, and there was an interactive repression between them. EWSAT1’s function as an oncogene to facilitate tumor progression was attributed to its ability to acting as a ceRNA for miR-326/330-5p clusters, and subsequently activating the cyclin D1 signaling pathway in NPC [81]. NEAT1 (nuclear paraspeckle assembly transcript 1, also known as MENε/β), a lncRNA, serves as a crucial regulator in several cancers [82, 83]. NEAT1 drives oncogenic growth by altering the epigenetic landscape of target gene promoter to favor transcription, resulting in cancer progression. Highly expression of NEAT1 was found in NPC tissues and cell lines. Interestingly, NEAT1 expression was positively associated with advanced stages but negatively correlated with OS in patients with NPC. The resistance of NPC to radiotherapy is a major problem in clinical treatment. Knockdown of NEAT1 could sensitize NPC cells to radiation in vitro. NEAT1 may also induce EMT phenotype, which is a key contributor to radioresistance [84]. In addition, there was a physical interaction between NEAT1 and miR-204 in NPC cells. NEAT1 could counteract the suppressive effect of miR-204 on Zinc finger E-box binding homeobox 1 (ZEB1) promoter, and silencing of NEAT1 decreased ZEB1 expression in NPC cells. Interestingly, enforced expression of ZEB1 restored the effects of NEAT1 on radiosensitivity and EMT phenotype. Thus, NEAT1 regulated EMT phenotype and radio-resistance by modulating the miR-204/ZEB1 axis in NPC [85]. LncRNA X inactivate-specific transcript (XIST) acts as an important regulator in tumor progression, and dysregulation of XIST was closed related to tumor initiation, growth and progression [86, 87]. XIST was also up-regulated in NPC tissues and high expression of XIST contributed to a poor survival, indicating an independent prognostic factor of XIST for NPC patients. In addition, overexpression of XIST enhanced, while silencing of XIST reduced the NPC cell growth. Mechanistically, XIST up-regulated the expression of miR-34a-5p targeted gene E2F transcriptional activator E2F3 via acting as a competitive ‘sponge’ of miR-34a-5p. Thus, XIST functioned as an oncogene through up-regulating E2F3 and sponging miR-34a-5p in NPC cells [88]. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), also known as nuclear-enriched transcript 2 (NEAT2), is a lncRNA consisting of more than 8700 nt located on chromosome 11q13 and acts as a transcriptional regulator for various genes including those involved in cell proliferation, migration and metastasis. Several studies have shown that the aberrant expression of MALAT1 is found in various cancer types, and associated with clinical progression in human cancers including NPC [89-91]. LncRNA MALAT1 was highly expressed in 5-8F cells with a high metastatic potential compared to that in normal nasopharyngeal epithelium cells. Excessive expression of MALAT1 suppressed the expression of E-cadherin, promoted the expression of vimentin, thereby enhancing the proliferation, invasion, and metastasis of NPC cells [92]. Conversely, knockdown of MALAT1 could sensitize NPC cells to radiation both in vitro and in vivo. Furthermore, there was reciprocal repression between MALAT1 and miR-1, MALAT1 regulated radioresistance by modulating cancer stem cell (CSC) activity through regulating miR-1/slug axis [93]. The above studies suggested that MALAT1 could act as a therapeutic target for NPC patients. In performing lncRNA expression profiling on metastatic and primary NPC tumors, one study have identified the different expressed lncRNAs between these samples. Among these lncRNAs, ENST00000438550 expression was demonstrated to be significantly correlated with NPC disease progression. A survival analysis showed that a high expression level of ENST00000438550 was an independent indicator of disease progression in NPC patients [94]. Overexpression of lncRNA LINC00312, also called NAG7, an estrogen receptor repressor and NPC-associated gene, inhibited the proliferation, invasion, and migration in NPC cells [95-97]. Thus, LINC00312 is a negative regulator of growth in NPC cells. Importantly, expression of LINC00312 was inversely correlated with tumor size but positively related to lymph node metastasis. Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with a number of human malignancies. LINC00312 was strongly negatively correlated with EBER-1, a small non-coding viral RNA abundantly expressed in cancer cells transcribed by EBV, in NPC. Furthermore, LINC00312 was an independent risk factor for in multivariate analyses implying a potential biomarker for metastasis, progression and prognosis in NPC [42]. NPC-associated gene NAG7 was a novel candidate tumor suppressor gene associated with NPC. Exogenously expressed NAG7 gene showed to inhibit proliferation by delaying the progression of G1 into S in cell cycle and inducing cell apoptosis of NPC cells through reduction of expression of cyclin D1 and E expressions [43]. Also, as a consequence of elevated NAG7 expression, the adhesion, migration, and invasive capabilities of HNE1 NPC cells in vitro and in vivo were enhanced. NAG7 was a significant negative regulator of protein expression of estrogen receptor alpha, activated both the c-Jun N-terminal kinase-2 (JNK2)/ activator protein1 (AP-1)/matrix metallopeptidase 1 (MMP1), and the upstream H-Ras/p-cRaf pathways [98]. In addition, other lncRNAs have also been implicated as oncogenic in NPC, including LOC100129148, LINC01420, ENST00000470135, n375709, H19, Lentivirus-mediated lncRNA HNF1A antisense RNA (HNF1A-AS), actin filament associated protein 1 antisense RNA1 (AFAP1-AS1). H19 inhibited E-cadherin expression and promoted cell invasion of NPC cells via the miR-630/EZH2 pathways in NPC cells [99]. Knockdown of HNF1A-AS suppressed proliferation and migration of NPC cells [100]. AFAP1-AS1 knockdown increased AFAP1 protein expression, thereby inhibiting the NPC cell migration and invasive capability [101]. Recently, high-through put analysis revealed that lncRNA LOC100129148 was highly expressed in NPC. LOC100129148 was up-regulated in NPC tissues and cell lines, and increased expression of LOC100129148 resulted in poor survival. Overexpressed LOC100129148 induced, but silenced LOC100129148 hampered cell proliferation in NPC cells. Mechanistically, LOC100129148 enhanced the expression of KLF12, a member of the Kruppel-like family of transcription factors, through competitive ‘sponge’ for miR-539-5p to stimulate growth of NPC cells [102]. NPC patients with high lncRNA LINC01420 expression level showed poor overall survival as well, and knockdown LINC01420 inhibited NPC cell migration and invasion in vitro [103]. Depletion of ENST00000470135 also illustrated significant inhibitory effect on NPC cell migration, invasion and proliferation in vitro [104]. Paclitaxel chemoresistance restricted the therapeutic efficacy and prognosis of patients with NPC. Cell growth experiments demonstrated that inhibition of lncRNA n375709 increased the paclitaxel sensitivity in both NPC 5-8F (high tumorigenic and metastatic) and 6-10B (low tumorigenic and metastatic) cells, suggesting that n375709 was involved in the regulation of NPC paclitaxel resistance [105]. Nevertheless, due to the fact that limited information are available for the roles of these lncRNAs involving in the occurrence, growth and progression of NPC, the functions and detailed mechanism underlying the involvement of these lncRNAs still remained to be determined. We reasoned that some of these lncRNAs play key roles in NPC progression and some are candidate biomarkers for the diagnosis and/or prognosis of NPC. Thus, more studies are still needed to further elucidate their true roles and functions in cancer biology including NPC in the near future.

In recent years, lncRNAs are rapidly being recognized as important regulators of gene expression in cancer. The evolutionary conservation, diversity and complexity of lncRNAs indicate that they exert significant regulatory control on cell growth. Therefore, LncRNAs could represent goldmines for basic scientific research, biomarker and drug discovery, and potential therapeutics. We should point out that despite of more than 100, 000 lncRNAs are currently identified, in comparison to protein-coding genes or others such as miRNAs, the functions and mechanisms of the majority of lncRNAs are still poorly understood. Although the recent application of next-generation sequencing to a growing number of cancer transcriptomes has revealed thousands of lncRNAs, in which aberrant expression are associated with different cancer types, few have been functionally characterized. Notably, these lncRNAs may play key roles in gene regulation and thus influence various aspects of cellular homeostasis and functions, including proliferation, metastasis or genomic stability. Therefore, strategies leading to identification of more specific cancer-related lncRNAs and characterizing the imminent applications of these findings to the clinic are highly warranted. Recent years brought significant progress in the understanding of the biology of lncRNAs, and even some initial developments in their therapeutic application, however, the lncRNA field especially link to NPC still need to be elucidated.

By regulating both transcriptional and post-transcriptional events, lncRNAs may play a critical role in cancers which in turn has stimulated aspects of novel drug discovery. Several features of lncRNAs support the use of lncRNAs as therapeutic targets. The specific expression pattern of lncRNAs in certain types of tissues or cells provides a unique opportunity for delicate regulation of lncRNA-targeting therapeutics. In addition, chromatin modification represents one of the main mechanisms of action of lncRNAs, thus a rationale for targeting the interaction of lncRNAs with epigenetic factors may be feasible. Moreover, since many lncRNAs are located in the nucleus and regulate neighboring gene expression, specific gene-locus regulation can be achieved by lncRNA manipulation. Currently, a variety of lncRNA therapeutics is being investigated, and several companies are also actively developing lncRNA-targeting therapeutics for treatment of human diseases including cancer. However, the development of lncRNA-targeted therapies is challenged by several obstacles such as the successful delivery of the therapeutic agent to the target tissues, and the safety evaluation of lncRNA-based therapeutics, including the potential immune response of the delivery system, toxicity caused by the chemical modification, and unexpected off-target effects, among others. In that, we predict that new lncRNA-targeting anti-cancer drugs with improved specificity and efficacy will enter the clinical stage and finally be used, in combination with chemo-, radio-, and even targeted therapies for the treatment of cancer patients including NPC in the near future [106]. This may also suggest a promising area of lncRNAs design as a potential for discovery of targets as well as a therapeutic strategy.

Finally, while some of these lncRNAs involving in the NPC occurrence, growth and progression, the detailed mechanism underlying the involvement of these lncRNAs in NPC still remained to be determined. Further insight into the biological functions of lncRNAs in NPC pathogenesis will unveil to understand this malignancy by aiding in identification of essential disease processes to provide useful prognostic biomarkers for NPC. Moreover, studies to better understand the molecular mechanisms of lncRNAs expression and regulation may offer promise for the innovation of early diagnostic approaches, and the development of more potential therapeutics for NPC.

Nasopharyngeal carcinoma (NPC); long non-coding RNAs (lncRNAs); Global burden of disease cancer collaboration (GBDCC); Overall survival (OS); Epstein-Barr virus (EBV); Non-protein coding RNAs (ncRNAs); Encyclopedia of DNA Elements (ENCODE); MicroRNAs (miRNAs); maternally expressed gene 3 (MEG3); LncRNA HOX transcript antisense intergenic RNA (HOTAIR); Antisense non-coding RNA in the INK4 locus (ANRIL); Regulator of reprogramming (ROR); Induced pluripotent stem cells (iPSCs); Ewing sarcoma associated transcript 1 (EWSAT1); EWS and transcription factor FLI1 (EWS-FLI1); Nuclear paraspeckle assembly transcript 1, also known as MENε/β) (NEAT1); Zinc finger E-box binding homeobox 1 (ZEB1); X inactivate-specific transcript (XIST); Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1); Nuclear-enriched transcript 2 (NEAT2); Cancer stem cell (CSC); C-Jun N-terminal kinase-2 (JNK2); Activator protein1 (AP-1); Matrix metallopeptidase 1 (MMP1); HNF1A antisense RNA (HNF1A-AS); Actin filament associated protein 1 antisense RNA1 (AFAP1-AS1); Zeste homologue 2 (EZH2); Polycomb repressor complex (PRC); Vascular endothelial growth factor (VEGF); Angiopoietin-2 (Ang2).

This work was supported in part by the grants from the National Nature Scientific Foundation of China (81272614, 81403216), the Science and Technology Program of Guangzhou (201607010385), the Discipline of Integrated Chinese and Western Medicine in Guangzhou University of Chinese Medicine (A1-Af-D018161Z1513), the Special Science and Technology Join fund from Guangdong Provincial Department of Science and Technology-Guangdong Academy of Traditional Chinese Medicine (2012A032500011, 2014A020221024), and the Specific Research Fund for TCM Science and Technology of Guangdong Provincial Hospital of Chinese Medicine (YK2013B2N13, YN2015MS19).

The authors claim no conflicts of interest.