Emerging role of non-coding RNA in oral cancer

Cellular Signalling 42 (2018) 134–143

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Cellular Signalling journal homepage: www.elsevier.com/locate/cellsig

Review

Emerging role of non-coding RNA in oral cancer☆ a,⁎

Fatemeh Momen-Heravi , Shashi Bala a b

T

b,⁎⁎

Division of Periodontics, Section of Oral and Diagnostic Sciences, Columbia University College of Dental Medicine, New York, NY 10032, USA Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA

A R T I C L E I N F O

A B S T R A C T

Keywords: lncRNAs Circular RNAs miRNAs Extracellular RNAs Exosomes Oral cancer Oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is characterized by genomic and epigenomic alterations. However, the mechanisms underlying oral squamous cell carcinoma tumorigenesis and progression remain to be elucidated. Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and extracellular RNAs (exRNAs) are emerging groups of regulatory RNAs, which possess low or no protein-coding potential. Emerging lines of evidence indicates that deregulated expression of lncRNAs and circular RNAs are associated with the induction and progression of various cancers, including oral cancer, through epigenetic, transcriptional, and post-transcriptional alterations. In this review, we highlight the expression and functional roles of extracellular RNAs, lncRNAs, and circular RNAs in oral squamous cell carcinoma and discuss their potential clinical applications as diagnostic or prognostic biomarkers, and therapeutic targets.

1. Introduction The discovery of non-coding RNA added a new layer to our understanding of biological processes. The term non-coding RNA (ncRNAs) encompasses microRNA (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and intronic RNAs [1]. The literature indicates that there may be a lack of potential for these RNAs to encode proteins or peptides. Although ncRNAs do not encode proteins, they are master regulators of gene expression through various mechanisms [1–3]. In the field of cancer research, it has become apparent that aberrations within the noncoding genome drive fundamental cancer phenotypes in addition to the best-known protein coding mutations [4,5]. Oral squamous cell carcinoma (OSCC) is a major global health problem [6]. Some of the most widely recognized risk factors of OSCC are tobacco use and alcohol consumption [6]. Recently, infection of high risk HPV was introduced as a novel risk factor in subsets of patients who were exposed to the disease [7]. Traditionally, the expression of protein-coding genes [messenger RNAs (mRNAs)] has been the focus of cancer studies for decades. Recently, this approach has been challenged due to the discoveries that small proportions of human transcriptome are protein-coding genes [8]. Specifically, Ensemble1 (v76) statistics reveals that only 34% of human transcriptome are protein coding genes and 66% are non-coding genes including long

intergenic non-coding RNAs, antisense RNAs, pseudogenes, and microRNAs (miRNAs) [8]. Recent evidence has also indicated a fundamental role of non-coding RNAs in almost all stages of gene expression process such as at the levels of cellular physiologic processes, and in the development of different human diseases including cancers [9]. Thus, an understanding the function of different non-coding RNAs including lncRNAs, circRNAs, and ExRNAs provides an opportunity to understand underlining biological events involved in different cancers including OSCC. This understanding might ultimately lead to development of novel new therapies and diagnostic tools. Here, we aim to review the characteristic and functions of oral cancer related non-coding RNAs. In this perspective, we provide an overview of the current state of noncoding RNA biomarker identification in cancer phenotypes, catalog the molecular roles for lncRNAs in cellular processes, and review the emerging roles for lncRNAs, circRNAs, and extracellular RNAs in oral cancer pathophysiology. 2. Extracellular RNA and exosome-associated RNA in oral squamous cell carcinoma Exosomes are the smallest (30–100 nm) vesicles and most heavily studied subpopulation of extracellular vesicles [10,11]. These particles are generated by the exocytosis of multivesicular bodies (MVBs) [12] (Fig. 1). Early endosomes can be targeted for ubiquitin-dependent

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Competing financial statement: Authors declare no competing financial interests. Correspondence to: S. Bala, Department of Medicine, LRB208, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA. Correspondence to: F. Momen-Heravi, Section of Oral, Diagnostic, and Rehabilitation Sciences, Columbia University College of Dental Medicine, 630 W. 168 St., New York, NY 10032, USA. E-mail addresses: [email protected] (F. Momen-Heravi), [email protected] (S. Bala). ⁎

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http://dx.doi.org/10.1016/j.cellsig.2017.10.009 Received 6 July 2017; Received in revised form 28 September 2017; Accepted 15 October 2017 Available online 19 October 2017 0898-6568/ © 2017 Elsevier Inc. All rights reserved.

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Ceramidedependent

Membrane budding

ESCRTdependent

Protein DNA mRNA, ncRNA

ARF6

miRNA

SNAREs RAB 7 MVB

Extracellular vesicles

RAB 27 Secretory pathway

TSG 101, CD63 Fig. 1. Biogenesis of extracellular vesicles. Extracellular vesicles (EVs) are comprised of various types of vesicles including exosomes, microvesicles, macrovesicles. Exosomes are formed by internalization of the endocytic membrane and formation of multivesicular bodies (MVB inside the cell). The fusion of the MVBs with plasma membrane results in their release. Microvesicles are formed and released by plasma membrane. Exosomes/microvesicles carry various mRNA, miRNA, ncRNA, DNA, proteins and are emerging as a new inter or intra (cellcell/organ) communicatior.

Ex-RNAs biomarker approaches are emerging. Interestingly, most miRNAs are shown to be enriched in the exosomal fraction of saliva and serum rather than the exosome depleted fraction [26]. Momen-Heravi et al. reported the differential expression of extracellular miRNA in saliva of patients with OSCC, patients with OSCC in remission (OSCCR), patients with oral lichen planus compared to healthy subjects [27]. Using genome wide study and NanoString nCounter miRNA expression assay and real-time quantitative polymerase chain reaction, we found miRNA-27b was significantly upregulated in saliva of patients with OSCC compared to other groups [27]. Furthermore, miRNA-27b showed higher sensitivity and specificity in detecting OSCC compared to other miRNAs tested [27]. Another study found that salivary miRNA31 was significantly elevated in all the stages of OSCC irrespective of the tumor size [28]. Moreover, the levels of miRNA-31 were higher in saliva as compared to plasma, suggesting local production of miRNA-31 at the tumor site [28]. Interestingly after excision of oral carcinoma, salivary miRNA-31 was amazingly reduced, signifying that most of the upregulated salivary miRNA-31 came from tumor tissues [28]. Zahran et al. reported a highly significant increase in salivary miRNA-21 and miRNA-184 in saliva of OSCC patients when compared to healthy and disease controls [29]. Conversely, miRNA-145 levels showed a highly significant decrease in OSCC. Where as recurrent aphthous stomatitis (RAS) cases showed no significant difference from normal controls in any measured miRNA (P > 0.05). Interestingly, the only microRNA to discriminate between OSCC and oral potentially malignant disorders was miRNA-184 [29]. Transcriptomic analyses of human saliva derived exosomes revealed that 509 mRNA core transcripts were present [30]. Experimentally, in vitro co-culture of salivary exosomes with human oral keratinocytes altered the gene expression of the recipient cells, indicating a crucial role of exosomes in horizontal gene transfer [30]. Another study showed that exosome number, exosome size, and inter-exosome are increased in the saliva of patients with oral cancer [31]. Interestingly, oral cancer exosomes exhibited significantly increased CD63 surface densities and displayed irregular morphologies [31]. These studies suggest that RNA content in the exosomes might be a potential resource for oral cancer diagnostics and also as new oral cancer biomarkers. However, precise mechanisms via which exosomes play role in OSCC initiation and progression have yet to be determined.

interactions in one of three endosomal sorting complexes required for transport (ESCRT-0, ESCRT-I and ESCRT-II), which lead to the recycling of the endosome or, alternatively, its progression towards a late endosomal pathway [12]. Late endosomal pathways are dependent on MVBs, are ubiquitin-independent, and lead to the formation and sorting of exosomes [13]. Exosomes have been isolated from almost all cell types as well as mucosal and endogenous biofluids and have been implicated in key processes like growth and development, immune response, blood coagulation, and various stages of tumorigenesis [14–17]. Exosomes carry various molecular cargos including nucleic acids, proteins, and lipids and provide a snapshot of cells at the time of release [18]. The lipid bilayer structure of exosomes protects cargo from degradation enzymes such as RNases [19]. Low-abundance molecular analytes specific to the disease can be enriched in exosomes and have been recovered from exosomes [19]. These characteristics position EVs as a new, highly appealing class of biomarkers with strong diagnostic potential in the context of personalized medicine [20,21]. Up to 76% of all map able reads generated by RNA-Seq on exosomes were miRNA transcripts [22]. miRNAs demonstrated fundamental roles in normal development, differentiation, growth and in pathogenesis of different diseases [23]. They also play pivotal roles in cancer initiation and progression [23]. PCR based array methods identified the role of miRNA-26a and miRNA-26b in OSCC cells [24]. In OSCC, loss of tumorsuppressive miRNA-26a/b enhances cancer cell migration and invasion via regulation of TMEM184B [24]. This study provided new insights into the potential role of miRNA-26a/b in OSCC oncogenesis and metastasis [24]. miRNAs were also detected in the extracellular vesicles in OSCC. In this context miRNA-21 was detected in exosomes derived from OSCC under hypoxic conditions and significantly enhanced snail and vimentin expression while significantly decreasing E-cadherin levels both in vitro and in vivo studies [25]. Moreover, circulating exosomal miRNA-21 levels were associated with HIF-1α/HIF-2α expression, T stage, and lymph node metastasis in patients with OSCC [25]. These findings suggest that the hypoxic microenvironment may stimulate tumor cells to generate miRNA-21-rich exosomes that are delivered to normoxic cells to promote prometastatic behaviors [25]. Further investigations into the therapeutic value of exosomal miRNA inhibition are needed for oral cancer treatment. Saliva is a readily available biofluid, therefore salivary exosomes/

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lncRNA Firre with the chromatin remodelers, CTCF and cohesion, is one of the elucidated mechanisms, which change chromatin conformation in the process of X chromosome inactivation. As a result, inactive chromosome X positions near the nucleolus and preserves H3K27me3 methylation [41]. Other lncRNAs exert their inhibitory mechanisms by binding to miRNAs which can sequester these biomolecules and reduce their inhibitory potential on their targets [32]. 4. Long noncoding RNA in oral squamous cell carcinoma In this decade the role of miRNA in oral squamous cell carcinomas (OSCC) has been extensively investigated, however, functional role of lncRNAs in such tumors remains unclear. In this section, we aim to review the potential role of lncRNAs in OSCC. We will summarize the latest findings about the biological functions and molecular mechanisms of lncRNAs in OSCC initiation and progression. We will also explore the possibility of using the lncRNA as diagnostic and prognostic markers as well as therapeutic targets in the clinical setting. We will catalog each lncRNA that has been shown to play a role in OSCC with regards to its general characteristics and roles in OSCC. The biological function and molecular mechanisms of each specific lncRNA and clinical utility in OSCC are outlined in Table 1. Many lncRNAs are deregulated in cancers including head and neck cancer [9]. Distinct lncRNA expression profiles between oral cancer tumors and normal human tissue has been identified [42,43]. Among lncRNAs associated with cancer, some of lncRNAs works as oncogenes while the others work as tumor suppressors by participating in different cellular processes such as proliferation, differentiation, and tumor invasion and metastasis [43]. In fact, some of the OSCC-associated lncRNAs showed well-characterized roles in cancer development and progression, suggesting that those lncRNAs can be used as new biomarkers and monitoring tools as well as potential therapeutics targets in OSCC treatment. Various functions of lncRNAs in OSCC pathogenesis are reviewed in Fig. 4. Here, we review the characteristic and functions of oral cancer related non-coding RNAs.

Fig. 2. Various functions of long non-coding RNA (lncRNA). lncRNAs execute different functions such as chromatin modifications, transcriptional activator or repressor, miRNA sponge and RNA splicing regulator.

3. Long non-coding RNA in cancer lncRNAs are functionally defined as transcripts > 200 nt in length with no protein-coding potential [4,32]. They number in the tens of thousands, many of which are uniquely expressed in differentiated tissues or specific cancer types [4,32]. RNA polymerase II execute the transcription of lncRNAs and their expression is generally tissue-specific [4,32]. lncRNAs are the essential components of different biological processes including stem-cell biology, development, and differentiation. Deregulation of lncRNAs is shown to be closely associated with development of human diseases including various types of cancer [4,32]. Thus, lncRNAs are the focus of current cancer research and functional annotation of lncRNAs is an emerging line of research. Commonly, lncRNAs employ different mechanisms to execute their cellular functions. Such as lncRNAs exert their functions by affecting chromatin remodeling and methylation, and act as a sponge for miRNA inhibition and modulate stability of protein complexes [2,33–34] (Fig. 2). The various methods to identify lncRNAs are summarized in Fig. 3. It has been identified that some lncRNAs such as TARID, AS1DHRS4 and Kcnq1ot1 recruit DNA methyltransferases directly to modify chromatin conformation, or they modify nucleosome positioning through SWI/SNF complex as in the case of SChLAP1 [35–37]. Polycomb repressive complex-2 (PRC2) is histone methyltransferase, one of the most studied regulated proteins by non-coding RNA and has been shown to be the intermediate target of lncRNAs [38]. PRC2 resulted in the inactivation of chromatin by inducing inhibitory H3K427me3 histone marks [38]. Alternatively, activation of the chromatin by certain lncRNAs such as CCAT1 and HOTTIP result in modulating chromosome looping and affecting gene promoters [39,40]. lncRNA Firre is involved in maintaining X chromosome inactivation [41]. Binding of X-linked

5. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) 5.1. Characteristics of MALAT1 MALAT1, a highly conserved lncRNA, is located on chromosome 6p24.3 in humans and is 8.7 kb long [44]. Multiple promoters play roles in MALAT1 transcription and produce different MALAT1 transcript variants [45]. MALAT1 has the unique stability because of its structure as a triple-helical, and having expression and nuclear retention element (ENE)-like structures which forms by a triple-helical structure of multiple U·A-U base triples and a single C·G-C base triple [46]. MALAT1 plays a role in RNA metabolism as highlighted by its localization in nuclear speckles [46]. An upregulation of MALAT1 is reported in cancer tissues and MALAT1 also modulates the expression of cell cycle genes and is required for G1/S and mitotic progression Fig. 3. Current long non-coding RNA (lncRNA) measurement methods. There are various methods/ technologies to identify lncRNAs such as RNA sequencing, lncRNAs microarrays and RT2 lncRNA PCR array or lncRNA specific PCR assay.

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Table 1 Deregulation of lncRNAs in OSCC. lncRNA

Expression

Functional role/mechanism

Clinical application

References

MALAT1

Up-regulated

Potential therapeutic target.

[49,53]

lincRNA-ROR

Up-regulated

Prognostic value to predict the therapeutic response.

[63]

CCAT1 LINC00152

Up-regulated Up-regulated Down-regulated Up-regulated Up-regulated Up-regulated Up-regulated Up-regulated Up-regulated Up-regulated

May be a predictor for poor treatment response. Potential biomarker for early detection and prognosis prediction of TSCC. Therapeutic target for OSCC Not yet determined. Prognostic predictor. New target for the diagnosis and therapy of OSCC. Predicted target for tongue carcinoma therapies Not yet determined. Prognosis biomarker. Not yet determined.

[63] [79]

MEG3 AC132217.4 MIR31HG LINC00668 Inc-sox5 TUC338 LNC00673 UCA1 NKILA FTH1P3

Down-regulated Up-regulated

EMT-mediated cell migration and invasion via regulating N-cadherin, Vimentin and E-cadherin Acts as a sponge for miRNA-145-5p to modulate c-Myc, Kl, Sox2, and Oct4 genes May acts as a sponge for miRNA-155-5p and let7b-5p lncRNA levels are correlated with cancer progression, advanced stage, cancer relapse, and invasion. Regulates cell proliferation, cell cycle and apoptosis. Promotes cell migration and EMT via IGF2 levels. HIF-1α co-activator Acts as CeRNA for miRNA-297 to regulate VEGFA regulation Regulates apoptosis and cell cycle. Enhances proliferation and reduced apoptosis. Promotes tumor invasion and metastasis. Promotes tumor invasion and metastasis possibly through WNT/βcatenin pathway. Inhibits the phosphorylation of IKβα NF-kβ, and inhibits EMT. Acts as a molecular sponge for miRNA-224 to modulate frizzled 5 expression.

Prognosis biomarker. Potential therapeutic target

[96] [97]

[85,86,87] [88] [89] [90] [91] [92] [93] [94,95]

Abbreviations: EMT, epithelial mesenchymal transition.

role by increasing proliferation and metastasis of tongue cancer and could serve as a potential therapeutic target in human tongue cancer. Increased levels of MALAT1 were also found in the tongue squamous cell carcinoma tissue (TSCC) [51]. The level of MALAT1 was correlated with cervical lymph node metastasis in TSCC patients [51]. Another study revealed that enhanced MALAT1 expression was inversely correlated with upregulation of certain small proline rich proteins which affect metastasis ability of cancerous cells [52]. A recent study revealed differentially expressed lncRNAs between OSCC and healthy control oral mucosa in a transcriptome approach [53]. 14 lncRNAs were found to be significantly differentially expressed in OSCC that may be involved in oral cancer carcinogenesis [53]. The novel findings of this study was that out of the 14 validated lncRNAs, more than half (8 out of 14) have never been reported to be associated with cancer before. The novel lncRNAs found in this study are LOC441178, COX10-AS1, PCBP1AS1, FLG-AS1, MLLT4-AS1, LINC01315, LOC100506990, and CCL15CCL14. LOC441178 [53]. These newly discovered lncRNAs need further investigation to exploit them as potential OSCC biomarkers and/or therapeutic targets. In summary, these findings provide the mechanistic insights into the role of MALAT1 in regulating OSCC metastasis, and suggest that MALAT1 is an essential prognostic factor and therapeutic target for OSCC.

through modulating oncogenic transcription factor B-MYB (mybl2) [44]. MALAT-1 depleted cells are sensitive to p53 levels, indicating that p53 is one of the key molecules involved in the downstream effects of MALAT1 [47]. MALAT1 regulates growth control genes and post-transcriptional regulation of some genes such as RNPS1, PRP6 and SON through alternative splicing by MALAT1 has been reported [48]. Taken together, these studies highlight the role of MALAT1 in modulation of gene expression at the both transcriptional and post-transcriptional levels. 5.2. MALAT1 in oral squamous cell carcinoma Recently Zhou et el., found that MALAT1 is overexpressed in OSCC tissues compared to normal oral mucosa [49]. Knockdown of MALAT1 by small interfering RNA in OSCC cells lines (TSCCA and Tca8113) depicted its role in maintaining epithelial-mesenchymal transition (EMT) mediated cell migration and invasion [49]. Mechanistically, MALAT1 knockdown significantly suppressed N-cadherin and Vimentin expression but induced E-cadherin expression in vitro [49]. In a tongue cancer cell line, MALAT1 targeted miRNA-124 and promoted cancer growth through modulation of jagged1 (JAG1) [50]. Knockdown of MALAT1 suppressed the growth and metastasis of tongue cancer cell lines [50]. This study revealed that MALAT1 might play an oncogenic

Fig. 4. Various functions of lncRNAs in Oral Squamous Cell Carcinoma. Recent studies have revealed the role of lncRNA in OSCC. lncRNA are involved in the tumor proliferation, metastasis, EMT processes, OSCC progression, relapse and invasion. Some lncRNAs act as tumor suppressor in OSCC and other induces hypoxia and also acts as miRNA sponges to promote OSCC.

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6. Long intronic noncoding RNA ROR (lincRNA-ROR)

chromatin looping and consequently could interact with the MYCpromoter, which leads to regulation of c-Myc expression in cis manner [69,70]. CCAT1 mediated down-regulation of c-Myc is correlated with a poor prognosis in hepatocellular carcinoma and gastric cancer [71,72]. Competing function of CCAT1 through down-regulation of miRNA-1555p, let-7b-5p and miRNA-490-3p by sequestration and miRNA-218-5p by epigenetic regulation have been reported [34,73–75].

6.1. Characteristics of Linc-ROR Linc-ROR is a 2.6 kb lncRNA located at 18q21.31 and is composed of abundant retrotransposons elements such as LINE, SINE and LTR elements [54]. The location of lincRNA-ROR is a binding site for pluripotency transcription factors such as Sox2, Oct4, and Nanog [55]. lincRNA acts as competing endogenous RNA and demonstrates a fundamental impact on differentiation of human embroyonic stem cells through sponging miRNA-145 at the post-transcriptional level [55,56]. Transcription factors associated with linc-ROR are expressed in various tumors and are associated with an undifferentiated phenotype [57]. Similarly, Linc-RoR acts as circRNA and linc-ROR miRNA-145 axis inhibits mediation of the differentiation of endometrial cancer stem cells [58]. lincRNA-ROR is significantly upregulated in triple negative breast cancer and regulates GTPase ADP-ribosylation factor 6 (Arf6), a regulator of E-cadherin localization and cell-cell adhesion via exerting its effect on miRNA-145 [59]. Regulation of EMT by linc-ROR has been described where it acts as a circRNA for miRNA-205. Linc-ROR increases the half-life of ZEB2 via having its effect on miRNA-205 [60]. Linc-RoR is also a strong negative regulator of p53 and suppresses p53 during DNA damage through direct interaction with hnRNP I and inhibits p53-mediated cell cycle arrest and apoptosis [61]. These studies suggest that lincRNA-ROR is mostly associated with less differentiated cell populations, and deregulation of linc-ROR has been reported in various types of cancers, implying a crucial role of this lncRNA in cancer and might be a potential therapeutic target in near by future [58,59,62].

7.2. CCAT1 in OSCC A recent study reported a significant overexpression of CCAT1 in 27% (16/60) of oral tumors [63]. Tumors over expressing CCAT1 showed high levels of c-Myc and significantly down regulation of miRNA-155-5p and let7b-5p levels. Patients with high levels of CCAT1 showed poor therapeutic outcomes. The CCAT1 amplified samples were mostly tumors with aggressive phenotypes and the CCAT1 elevated levels were observed in the patients with history of tobacco smoking [63]. These results suggest that CCAT1 acts as an endogenous sponge for miRNA-155-5p and let7b-5p, and may account for poor treatment response. 8. Long intergenic non-coding RNA 00152 (LINC000152) 8.1. Characteristics of LINC000152 Long intergenic non-coding RNA 00152 (LINC00152) is mapped on chromosome 2p11.2 and has a transcript length of 828 nucleotides [76]. Recent studies suggest an imperative role of this lncRNA in gastric cancer. Increased expression of LINC00152 is reported in gastric cancer [76]. LINC00152 binds to the enhancer of zeste homolog 2 (EZH2) and induces tumor cell cycle progression by silencing the expression of p15 and p21 in gastric cancer [77]. Functional analysis showed that knockdown of LINC00152 resulted in the inhibition of cell proliferation, induces cell cycle arrest at G1 phase, triggers late apoptosis, diminishes EMT, and inhibits invasive tumor phenotype in gastric cancer [78].

6.2. Linc-ROR in OSCC The expression profiling of long non-coding RNA revealed linc-RoR as a prognostic biomarker in oral cancer [63]. Further investigation of 11 selected long non-coding RNAs that were associated with cell proliferation, metastasis, and tumor suppression in oral squamous cell carcinomas and normal tissues revealed that 9 lncRNAs were significantly overexpressed in tumors from subjects with tobacco chewing history [63]. Linc-RoR, a regulator of reprogramming, implicated in tumorigenesis, was overexpressed in undifferentiated tumors and showed strong association with tumor recurrence and poor therapeutic response. Through its sponging effect on miRNA-145-5p, linc-RoR modulates the post-transcriptional control of its target genes c-Myc, Kl, Sox2, and Oct4, which contributes to the formation and maintenance of undifferentiated states [63]. This study demonstrated the association of linc-RoR overexpression in undifferentiated oral tumors and its prognostic value to predict the therapeutic response.

8.2. LINC00152 in OSCC

7. Colon Cancer-associated transcript-1 (CCAT1)

LINC00152 was highly expressed in primary oral squamous cell carcinoma samples harvested from tongue tissue [79]. Increased levels of LINC00152 in tumors were significantly correlated with cancer progression, advance stage, cancer relapse, and invasion [79]. KaplanMeier survival analysis showed significant association between increased levels of LINC00152 with poor overall survival and disease-free survival in patients with oral cancer [79]. These findings suggest that LINC00152 might serve as a potential biomarker for early detection and prognosis prediction of TSCC [79]. However, mechanism underlying the role of LINC00152 in TSCC or OSCC is yet to be identified. Furthermore, these results should be replicated in other populations.

7.1. Characteristics of CCAT1

9. Maternally expressed gene 3 (MEG3)

Colon cancer-associated transcript-1 (CCAT1), also known as cancer-associated region long noncoding RNA-5 (CARLo-5) or CCAT1-S, has a length of 2628 nucleotides and maps to chromosome 8q24.21 [64]. The first report regarding the role of CCAT was described in colon cancer [65]. Knock-down of CCAT1 by siRNA leads to the induction of G1 phase cell arrest and proliferation inhibition. CCAT1 is believed to mediate cell proliferation by inhibiting the expression of CDKN1A mRNA, which is a crucial regulator of G1 arrest [66,67]. An inverse relation between the expression of CCAT1 and p16, p21, p27, which are GO/G1 arrest markers, has been reported [66]. Silencing of CCAT1 leads to up-regulation of E-cadherin and subsequently downregulates fibronectin and vimentin, which are critical hallmarks of EMT [68]. CCAT1 can interact with a transcriptional enhancer MYC-335 through

9.1. Characteristics of MEG3 Maternally expressed gene 3 (MEG3) is the first lncRNA to be discovered to have tumor suppressor properties. MEG3 expresses in many normal human tissues [80] and its expression is lost in many human cancers and tumor cell lines [81]. Loss of MEG3 expression in tumors can be a result of gene deletion, promoter hypermethylation, or hypermethylation of the intergenic differentially methylated region [81]. Mechanistic studies showed that re-expression of MEG3 prevent tumor cell proliferation in culture and tumor colony formation [82,83]. The observed growth inhibition is controlled by MEG3 mediated apoptosis. MEG3 causes the accumulation of p53 protein and regulates expression of p53 target genes [84]. 138

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epithelial-mesenchymal transmission [96]. In vivo experimental metastasis model showed that NKILA suppressed lung metastasis of OSCC in NOD/SCID mice [96]. LncRNA ferritin heavy chain 1 pseudogene 3 (FTH1P3) was also found to be over expressed in OSCC and associated with less survival of patients [97]. FTH1P3 acted as competitive endogenous RNA by sponging miRNA-224-5p and consequently modulating the expression of frizzled class receptor 5, which acts as oncogene in OSCC [97]. In conclusion, different lncRNAs exert various functions in pathogenesis of OSCC. The pivotal role of abnormal lncRNAs expression in OSCC development and progression suggests that lncRNAs can be used as therapeutic targets. Using small interfering RNA (siRNAs) or newly discovered genome engineering with CRISPER technology to fine tune cancer promoting lncRNAs seems to be an attractive therapeutic approach for cancer therapy. In the case of tumor-suppressor lncRNAs (e.g. MEG3) transfection of an lncRNA vector in cancer cells can inhibit tumor growth. lncRNAs orchestrate multiple intricate functions at the multiple biological levels, however, only a small fraction of lncRNA profile and function has been investigated in OSCC. More research has to be done in this field pertinent to OSCC. Moreover, there is a need for the better functional characterization of lncRNAs and discovering their utility in clinical setting in well-controlled studies.

9.2. MEG3 and OSCC It has been shown that miRNA-26a and lncRNA MEG3 expression were both significantly reduced in tongue squamous cell carcinoma compared with matched nonmalignant tissues [85]. The low expression of both these non-coding RNAs signified poor outcome in patients with OSCC [85]. Functionally, overexpression of miRNA-26a or MEG3 in SCC-15 and CAL27 cells inhibited cell proliferation and cell cycle progression and triggered cell apoptosis [85]. Moreover, HPV-induced MEG3 downregulation has been suggested as an advantageous tumorigenesis mechanism in cervical cancer and it might play a role in HPVrelated OSCC [86]. These results underline the role of MEG3 as a cancer suppressor lncRNA, especially in the context of HPV-related OSCC. A recent study found that MEG3 was significantly decreased in OSCC and overexpression of MEG3 in CAL27 cells inhibited the proliferation and metastasis of cancer cells and promoted apoptosis [87]. Importantly, MEG3 played a role as a tumor suppressor by inhibiting the WNT/βcatenin axis. This study implies that MEG3 inhibits the growth and metastasis of OSCC by regulating the WNT/βcatenin signaling pathway. These studies indicate that MEG3 modulation might act as a potential therapeutic target for OSCC therapy. 10. Other lncRNAs in OSCC

11. Circular RNAs Besides the above-discussed well-characterized lncRNAs, less-studied lncRNAs also showed pathological roles in OSCC. AC132217.4, an intergenic lncRNA was significantly up-regulated and promoted cell migration and EMT induction by increasing IGF2 levels in OSCSC [88]. Mechanistically, KLF8 binds to the upstream sequence of AC132217.4 and by activating its transcription accelerates OSCC carcinoma metastasis through AC132217.4-IGF2 axis [88]. MIR31HG is a hypoxia-inducible lncRNA and acts as HIF-1α co-activator that regulates the HIF1α transcriptional network [89]. Enhanced levels of MIR31HG were associated with poor clinical outcomes and poor prognosis in oral cancer [89]. Additionally, levels of hyaluronan synthase 2 antisense 1 (HAS2-AS1) in OSCC tumors were closely associated with lymph node metastasis and hypoxic tumor status through modulation of HIF1-α [89]. Long intergenic non-coding RNA 668 (LINC00668) expression was up regulated, which was correlated with tumor invasion, and downregulation of miRNA-297 in OSCC tumors [90]. Specifically, LINC00668 acted as circRNA for miRNA-297 to facilitate VEGFA expression and propagate OSCC progression [90]. Another lncRNA, Incsox5, which is stabilized by RNA binding protein, HuR, promoted Tca8113 (a tongue carcinoma cell line) tumor progression [91]. Tongue squamous cell carcinoma cells (CAL-27, SCC-9 cell lines) showed overexpression of lncRNA TUC338 which led to enhanced proliferation and reduced apoptosis of malignant cells [92]. It has been reported that long intergenic non-coding RNA 673 (LINC00673) was significantly overexpressed in a significant proportion of human OSCC biopsies and correlated with poor clinical outcomes [93]. Knockdown of LINC00673 significantly inhibited cell migration and invasion in OSCC [93]. The non-coding RNA urothelial carcinoma-associated 1 (UCA1) has been shown to be upregulated in oral squamous cell carcinoma and promoted tumor metastasis and proliferation through the modulation of the WNT/β-catenin signaling pathway [94]. The overexpression of UCA1 in tumor tissue was confirmed by another study, which showed significantly higher expression of UCA1 in tongue squamous cell carcinoma compared to the adjacent normal tissue [95]. A correlation between UCA1 and cancer metastasis was observed in TSCC [95]. Long non-coding RNA NKILA was down regulated in OSCC cancer tissue compared to the matched non-cancerous tissue [96]. Low NKILA expression in the cancer tissue significantly correlated with patient poor prognosis and tumor metastasis. Mechanistically, NKILA inhibited the phosphorylation of Ikβα and NF-kβ activation as well as induction of

Circular RNAs (circRNAs) are a subset of non-coding RNAs that has recently been emerged as a new regulator of gene expression [98]. They form a covalently closed continuous loop without 5′ caps and 3′ tails and present in tissue-specific manner in mammalian cells [99]. Biogenesis and emerging role of circular RNAs is extensively reviewed elsewhere [100,101,102]. The snap shot of biogenesis and role of circular RNAs is depicted in Fig. 5. Briefly, circRNAs are produced from precursor mRNA by back-splicing of genes by RNA polymerase II and are often expressed at the low levels [100]. The regulation of circRNA biogenesis depends on the cis and trans regulatory elements that control splicing [100]. Thousands of circRNAs accumulate in the brain, and hundreds are up-regulated during the human epithelial–mesenchymal transition (EMT) [100]. Most circRNAs are comprised of several exons, usually two or three. In addition, multiple circRNAs, with the internal intron included or excluded, can be produced from the same gene by alternative splicing [100,101,102] (Fig. 5). Recent studies have revealed that some circRNAs play important physiological functions and regulate gene expression at the multiple levels [34,103,104]. CircRNAs can function as miRNA sponges. For instance, ciRS-7 (circular RNA sponge for miRNA-7) is produced from the vertebrate cerebellar degeneration-related 1 (CDR1) antisense transcript, acts as RNA sponge for miRNA-7 [105]. The nuclear circular RNAs in the cell is circular intronic RNAs (ciRNAs), which are derived from lariat introns [106]. Abundantly expressed ciRNAs, such as ci-ankrd52 and ci-sirt7 are localized to nucleus and interact with the elongating Pol II complex [100]. Depleting these ciRNAs is shown to decrease the transcription levels of ankyrin repeat domain 52 and sirtuin 7 genes [106]. This study suggests that ciRNAs promote Pol II transcription and have a role in transcription regulation, though the mechanism of action is not well understood [106]. 12. Circular RNAs and cancer Although circRNAs were first described around two decades ago through identifying spliced transcripts of a candidate tumor suppressor, they were considered to be a result of splicing errors that had no apparent function [107]. With the introduction of sequencing and advanced genomic methods a large number of circRNAs have been discovered [108]. circRNAs confer numerous advantages in understanding and monitoring regulatory networks. First, circRNAs are more stable compared to mRNAs in vivo due to their resistance to RNase activity 139

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Fig. 5. Circular RNA biogenesis and their functions in cellular processes. Many circular RNAs (circRNAs) can be generated from a single genomic locus. circRNAs are produced by non-canonical splicing process (backsplicing). circRNAs can consist of one or more exons and can even have unspliced intronic sequences. Colored bars (exons) black lines (introns). Recently, different roles of circRNAs is emerging such as post -transcriptional regulator, miRNA sponge as well as translational repressor.

Fig. 6. Future perspectives and challenges of salivary lncRNAs, circRNA, and EVRNAs as cancer biomarkers and potential therapeutics.

in vitro and in vivo [110]. Luciferase reporter assays revealed direct interaction of circRNA_100290 with miRNA-29 family members [110]. CDK6 was identified as a direct target of miRNA-29b through EGFP/ RFP reporter assays [110]. These findings are indicative of the competing endogenous function of circRNA_100290 to regulate CDK6 expression through sponging effect on miRNA-29b family.

[99]. Second, circRNAs are more abundant than linear mRNA and in some cases this abundance is > 10 times [109]. Third, circRNAs have tissue specificity that make them ideal candidates for biomarker discovery and cancer biology studies [108]. 12.1. Circular RNAs in OSCC

13. Concluding remarks

New evidence suggests that circRNAs are closely associated with different types of cancers [110]. Since this field is relatively new, there are very few studies in the context of circRNAs RNAs in OSCC. Recently a comprehensive study of circRNAs in human OSCC using circRNA and mRNA microarrays was carried out where it was identified that many circRNAs were differentially expressed between OSCC tissue and paired non-cancerous matched tissue [110]. circRNA_100290 acts as a critical regulator in OSCC progression [110]. Functional studies showed that knockdown of circRNA_100290 decreased the expression of CDK6, and induced G1/S arrest and inhibited proliferation of OSCC cell lines both

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