Cancer Letters 361 (2015) 13–21

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Cancer Letters j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

Mini-review

Long noncoding RNAs: Novel players in colorectal cancer Dong Han a,b,1, Meng Wang c,1, Ning Ma a, Ya Xu a, Yuting Jiang a, Xu Gao a,* a

Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China Heilongjiang Medical Science Academy, Harbin, China c Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China b

A R T I C L E

I N F O

Article history: Received 15 January 2015 Received in revised form 1 March 2015 Accepted 2 March 2015 Keywords: Long noncoding RNAs Colorectal cancer (CRC) Tumorigenesis Therapeutic targets

A B S T R A C T

Colorectal cancer (CRC) is the most common type of cancer in the world. Despite its commonness, the underlying mechanism of CRC is not completely understood. Long noncoding RNAs (lncRNAs) have received increased attention with the development of whole genome and transcriptome sequencing technologies. Recent findings reveal that lncRNAs are implicated in serial steps of cancer development. These lncRNAs interact with DNA, RNA, protein molecules and/or their combinations, acting as an essential regulator in chromatin organization, and transcriptional and post-transcriptional regulation. In this review, we highlight recent findings of emerging roles for lncRNAs in CRC and discuss rapid translational lncRNA research for clinical application in diagnosis, prognosis and potential treatment. © 2015 Elsevier Ireland Ltd. All rights reserved.

Introduction Colorectal cancer (CRC) is one of the most common malignancies in the world. More than 1 million individuals will develop CRC each year, and the disease-specific mortality rate is nearly 33% in the developed world [1]. Initiation of CRC is a complex biological process, involving multiple genomic and epigenomic alterations, occurring over an extended time period of usually a decade. Screening for CRC from curable early stages has the potential to reduce both the incidence and mortality of the disease [2]. Despite substantial progress in understanding the molecular mechanisms and treatment for CRC in recent years, the overall survival rate of CRC patients has not changed dramatically. Intensive investigations over the last few decades have focused on the role of protein-coding genes in the pathogenesis of CRC. Nevertheless, only ~1% of the human genome encodes proteins, leaving another ~4–9% that is transcribed to yield many short or long RNAs with limited proteincoding capacity [3]. Thus, a lot of non-protein coding RNAs (ncRNAs) are transcribed from genome, such as small interfering RNAs (siRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), small nucleolar RNA (snoRNA) and long noncoding RNAs (lncRNAs). lncRNAs are most commonly defined as an RNA transcript of more than 200 nucleotides (nt) and located in nuclear or cytosolic fractions. They are usually transcribed by RNA polymerase II but have no open reading frame and map to intronic and intergenic regions. Moreover, lncRNAs display epigenetic features similar to

* Corresponding author. Tel.: +86 451 86661684; fax: +86 451 8708 6131. E-mail address: [email protected] (X Gao). 1 These authors contributed equally to the work and should be regarded as joint first authors. http://dx.doi.org/10.1016/j.canlet.2015.03.002 0304-3835/© 2015 Elsevier Ireland Ltd. All rights reserved.

protein-coding genes, such as trimethylation of histone 3 lysine 4 (H3K4me3) at the transcriptional start site (TSS) and trimethylation of histone 3 lysine 36 (H3K36me3) throughout the gene region [4]. It has been estimated that approximately 15,000 lncRNAs are present in the human genome, but the GENCODE v19 catalog of human lncRNAs contains 13,870 lncRNA genes that produce 23,898 lncRNAs [5]. Recent studies have demonstrated that lncRNAs play important roles in carcinogenesis and cancer metastasis and aberrant expression of lncRNAs has been identified in CRC [6,7]. LncRNAs may function as oncogenes or tumor suppressors in the cancer initiatome [8] and, therefore, CRC can no longer be considered as a simple model of malignancy. In the present review, we summarize recent progress in the genome-wide analysis of lncRNAs in CRC and the dysregulation of lncRNAs in CRC tissues or cells. We briefly delineate the regulatory network mediated by lncRNAs and the implication of lncRNAs for diagnosis, assessment and treatment of CRC. We suggest that lncRNAs add a novel, but informative layer to our understanding of the complexity of CRC development.

Classification and characteristics of lncRNAs LncRNAs are non-coding transcripts ranging from 200 to 100,000 nucleotides in length [9]. The estimated number of individual lncRNAs in the human genome sharply increased from 7000 to 23,000 and it is expected to exceed the number of protein-coding genes [10]. LncRNAs are transcribed at any region in the genome by RNA polymerase II/III and are either polyadenylated or nonpolyadenylated [11]. In order to gain greater insights into the function of lncRNAs, it will be important to understand the underlying structural features that allow lncRNAs to mediate their biological effects.

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Fig. 1. Overview of five broad categories of lncRNAs. (A) Intergenic lncRNA: lies as an independent unit within the genomic interval between two protein-coding genes. (B) Intronic: transcribed from inside of an intron of a protein-coding gene. (C) Bidirectional: transcribed from the promoter of a protein-coding gene and in opposite direction and, in general, within a few hundred base pairs. (D) Sense or (E) Antisense: transcribed in the same or opposite direction of coding genes, and overlapped with one or more coding exons.

LncRNAs may undergo an alternative splicing procedure like protein coding RNAs and they may mature into secondary and even tertiary structures [12]. Much like proteins, whose structural features are quite conserved across evolution, it is likely that, while lncRNA primary nucleotide sequences may have diverged, their structural elements have remained constant in higher eukaryotes [13]. From the genetic point of view lncRNAs can be classified into the following categories (Fig. 1): (a) Intergenic lncRNAs, also termed large intervening non-coding RNAs or lincRNAs, are lncRNAs with separate transcriptional units from protein-coding genes. One definition required lincRNAs to be 5 kb away from protein-coding genes. (b) Intronic lncRNAs are lncRNAs that initiate inside an intron of a protein-coding gene in either direction and terminate without overlapping exons. (c) Bidirectional lncRNAs are transcripts that initiate in a divergent fashion from the promoter of a protein-coding gene; the precise distance cutoff that constitutes bidirectionality is not defined but is generally within a few hundred base pairs. (d) Sense lncRNAs are lncRNAs whose sequence overlaps with the sense strand of a protein-coding gene. (e) Antisense lncRNAs, which initiate inside or 3′ of a protein-coding gene, are transcribed in the opposite direction of protein-coding genes and overlap at least one coding exon [11]. Recently, researchers concluded two major differences between the spliced and polyadenylated lncRNAs and the messenger RNAs. Firstly, their exon–intron structure of lncRNAs is simpler, with nearly half of lncRNAs only bearing two exons [11]. Secondly, although lncRNAs show exquisite patterns of tissue specificity, their expression levels are significantly lower than those of protein-coding genes [12]. Median expression levels of lncRNAs (steady states of transcripts) are ~10 times lower than those of mRNAs [13]. Importantly,

lncRNAs show prominent tissue specificity. These characteristics appear critical for their functional analysis. In past years, along with in-depth studies of lncRNAs, several lncRNA databases have been constructed (Table 1). These databases can facilitate further functional research on lncRNAs. LncRNAs deregulated in CRC The cancer transcriptome is more complex than was previously believed. lncRNAs can act as organizational factors of subcellular structures and regulate the localization or activity of proteins. Recent studies have identified large numbers of lncRNAs

Table 1 Public lncRNA databases. Name

Website

Reference

ChIPBase Starbase linc2GO

http://deepbase.sysu.edu.cn/chipbase/ http://starbase.sysu.edu.cn/ http://www.bioinfo.tsinghua.edu.cn/~liuke/ Linc2GO http://www.mircode.org/mircode/ http://gyanxet-beta.com/lncedb/ http://www.microrna.gr/LncBase http://genome.igib.res.in/lncRNome/ http://www.ncrna.org/frnadb/ http://www.lncipedia.org/ http://www.lncrnadb.org/ http://www.noncode.org/ http://nred.matticklab.com/cgi-bin/ncrnadb.pl http://cmbi.bjmu.edu.cn/lncrnadisease

[14] [15,16] [17]

mircode lnCeDB Diana-lncBase lncRNome fRNAdb LNCipedia lncRNAdb NONCODE NRED LncRNADisease

[18] [19] [20] [21] [22] [23] [24] [25] [26] [27]

D. Han et al./Cancer Letters 361 (2015) 13–21

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Fig. 2. Functional mechanisms of lncRNAs in CRC. CRC-related lncRNAs can participate in diverse biological processes by various means including epigenetic regulation, splicing regulation, transcriptional and post-transcriptional regulation. CCAT1-L can interact with CTCF and modulate chromatin conformation at the genome regions (epigenetic regulation). MALAT-1 can change the cellular levels of phosphorylated forms of SR proteins, finally modulating alternative splicing of various pre-mRNAs (splicing regulation). CCAT2 can up-regulate MYC, miR-17-5p, and miR-20a through TCF7L2-mediated transcriptional regulation (transcriptional regulation). Additionally, H19 can give rise to the miR-675, then regulating CRC carcinogenesis through the target genes of miR-675 (miRNA precursor). MALAT1 can bind to SFPQ and release PTBP2 from the SFPQ/PTBP2 complex, eventually initiating the oncogenic function of PTBP2 (lncRNA-protein interaction). Moreover, PVT-1 can enhance the stability of NOP2 protein, thus promote proliferation and stem cell-like property of cancer cells (post-transcriptional regulation).

playing important regulatory roles at various levels, including chromosome modification [28], transcription in nucleus, and posttranscriptional processing in the cytoplasm [29]. In Fig. 2, we provide an overview of lncRNA functions participated in CRC development. However, additional functions and detailed signaling pathways of lncRNAs remain to be clarified. Here, we discuss aberrant expression of lncRNAs in CRC. We summarize well-studied CRC-related lncRNAs in Table 2, and the list is increasing with many lncRNAs newly identified in different types of cancers. Genetic variation Surprisingly, emerging studies revealed that the presence of largeand small-scale mutations in the lncRNA primary sequence is highly correlated with cancer. Several lines of evidence have shown that single nucleotide polymorphisms (SNPs) in lncRNAs may influence the process of splicing and stability of mRNA conformation, resulting in the modification of its interacting partners [53,54]. Furthermore, germline mutations, as well as SNPs in lncRNAs were found to occur more frequently in patients with colon cancer and chronic leukemia than in the general population [55]. Several reports have showed that SNPs in the 8q24 chromosomal region are related to CRC risks. For example, Haiman and colleagues found the rs6983267 SNP, mapping to the 8q24.21 chromosomal region, consistently associated with an increased risk of CRC [56]. Additionally,

the increased cancer risk from this SNP variant was also observed in other cancer types, including prostate, ovarian, and inflammatory breast cancers [57,58]. The genomic region spanning rs6983267 was found to contain DNA enhancer elements and the allelic variants were shown to confer different binding affinity to TCF7L2 (transcription factor 7-like 2 [T-cell specific, HMG-box]), a transcription factor that plays a central role in the transcriptional activation of WNT target genes [59,60]. All these suggest that rs6983267 itself resides in a functional element that directly participates in colon cancer pathogenesis. Recently, Ling et al. [30] found a novel lncRNA transcript that maps to the highly conserved 8q24.21 region encompassing rs6983267, named CCAT2 and was overexpressed in microsatellitestable CRC samples. In the study on heterogeneous cell line models and CRC samples, they suggested that rs6983267 status affected the CCAT2 expression, providing an additional mechanism linking the risk allele of rs6983267 with higher CRC risk. Besides, they found CCAT2 was closely associated with MYC expression levels, suggesting that the SNP status may also affect CCAT2’s function as an RNA transcript. Finally, Li et al. [31] conducted a case–control study and genotyped 5 SNPs in the lncRNA PRNCR1 in 908 subjects including 313 cases with CRC and 595 control subjects. They found that the rs13252298 and rs1456315 were associated with significantly decreased risks of CRC, and patients with the rs7007694C and rs16901946G had decreased risks to develop poorly differentiated CRC, whereas patients with the rs1456315G had an increased risk

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Table 2 Representative lncRNAs implicated in CRC. More and more lncRNAs are found to be oncogenes or tumor suppressors, adding a new layer of complexity to the molecular architecture of CRC. Well-studied CRC-associated lncRNAs are summarized, but the list is increasing with many new lncRNAs identified in the near future. LncRNA

Genomic location

Classification

Expression pattern

Function in tumorigenesis

Potential mechanism

Reference

CCAT2

8q24.21

Sense

Up

Oncogene

[30]

PRNCR1 MALAT1

8q24.21 11q13.1

Sense Sense

NA Up

NA Oncogene

CCAT1 CCAT1-L

8q24.21 8q24

Sense Sense

NA Up

NA Oncogene

HOTAIR

12q13.13

Antisense

Up

Oncogene

H19

11p15.5

Lincrna

Up

Oncogene

PVT-1

8q24

Sense

Up

Oncogene

GAS5 lincRNA-p21

1q25.1 6p21.2

Sense Lincrna

Down Down

Tumor suppressor Tumor suppressor

CRNDE ncNRFR

16q12.2 1p13.2

Lincrna Sense

Up Up

Oncogene Oncogene

ncRuPAR

5q13.3

NA

Down

Tumor suppressor

LIT1 RP11-462C24.1 PCAT-1

11p15.5 4q25 8q24.21

Antisense Antisense Sense

NA NA NA

NA NA NA

Promotes tumor growth, metastasis, and chromosomal instability. Upregulates MYC, miR-17-5p, and miR-20a through TCF7L2-mediated transcriptional regulation. SNPs in the lncRNA PRNCR1 contributes to susceptibility to CRC. Promotes cell proliferation and migration through binding to SFPQ and releasing PTBP2 from the SFPQ/PTBP2 complex, or Wnt/bcatenin signaling pathway. NA Knockdown of CCAT1-L reduces long-range interactions between the MYC promoter and its enhancers. Interacts with CTCF and modulates chromatin conformation at these loop regions. CRC patients had higher HOTAIR expression in blood than healthy controls. Increases cancer invasiveness and metastasis in a manner dependent on PRC2. Promotes cell proliferation through downregulation of H19-derived miR-675 targeting RB. DTA-H19 plasmid administered intra-arterially delays the tumor growth. Increases proliferation and invasion capabilities through downregulating caspase3 and smad4 expression. Induces apoptosis and growth arrest by titrating away GR. Upregulated after X-ray treatment and activation of p53. Enhances the sensitivity of radiotherapy by targeting Wnt/β-catenin. Increase CRC tumorogenesis in a manner dependent on PRC2. Overexpression in non-transformed, conditionally immortalized mouse colonocytes results in malignant transformation and inhibits the function of the tumor suppressor let-7. Inhibits tumor progression by downregulating protease activated receptor-1 (PAR-1). NA NA NA

[31] [32–36]

[37] [38]

[39,40]

[41–43]

[44] [45] [46] [47] [48]

[49] [50] [51] [52]

NA, data not available.

to develop poorly differentiated CRC. Since certain single nucleotide mutations in protein-coding genes can completely change protein structure or function, the effects of genetic variations in lncRNAs may be more difficult to detect. Here, we suggest that better annotation of lncRNA structures should improve the detection of genome variations that affect lncRNAs.

[36] demonstrated that MALAT1 could promote growth and migration in CRC cells by competitively binding to tumor suppressor gene SFPQ and releasing SFPQ from the SFPQ/PTBP2 complex, which led to increased SFPQ-detached proto-oncogene PTBP2. Taken together, all the works above imply MALAT1 might serve as a potential therapeutic target in CRC.

MALAT-1 CCAT family Lung adenocarcinoma transcript 1 (MALAT-1) is a long noncoding RNA consisting of more than 8000 nt expressed from chromosome 11q13. In 2003, Ji and colleagues [32] demonstrated that MALAT1 was highly expressed in non-small cell lung cancer and the high expression of MALAT1 was associated with metastasis and poor prognosis. In 2011, Xu et al. [33] and the team identified the functional motif of MALAT-1 in CRC. In their work, MALAT-1 was divided into five segments, each overlapping and covering the entire length of the MALAT-1. They found a motif of the 3′ end MALAT-1 gene (6918 nt–8841 nt) played an important role in the biological processes of human colorectal malignancies. Additionally, Zheng and colleagues [34] evaluated MALAT-1 expression in 146 stage II/III CRC patients and 23 paired normal colonic mucosa samples. Results showed that expression of MALAT-1 was up-regulated in CRC tissues, and a higher expression level of MALAT-1 might serve as a negative prognostic marker in stage II/III CRC patients. Recently, some studies have revealed the exact mechanism of MALAT-1 on CRC. For example, a work of Ji [35] showed that knockdown of MALAT1 inhibited the translocation of β-catenin from the cytoplasm to the nucleus, resulting in decreased c-Myc and MMP-7 expression, while MALAT1 overexpression did the opposite, indicating the MALAT1 mediated wnt/β-catenin signal pathway participated in the invasion and metastasis of CRC. Besides, another work of Ji and colleagues

Human 8q24 has recently been reported to express several lncRNAs in different human tumors. For example, PRNCR1 binds to the androgen receptor (AR) and is involved in the AR-mediated gene activation in prostate cancers [53,61]. Notably, two CRC-specific lncRNAs transcribed from 8q24 were recently reported. CCAT1 is 2600 nt in length and is a highly specific marker for CRC [27], and its upregulation is evident in both pre-malignant conditions and through all disease stages in CRC [37,62]. Additionally, Ling and colleagues showed that CCAT2, a 340 nt ncRNA transcribed from the MYC-335 region, appeared to enhance invasion and metastasis through MYC-regulated miR-17-5p and miR-20a [30]. Their work showed that MYC, miR-17-5p, and miR-20a were up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. Recently, Xiang and colleagues [38] reported a novel 5200 nt human colorectal cancer-specific lncRNA CCAT1-L was transcribed from a super-enhancer region of MYC (MYC-515), and played a role in MYC transcriptional regulation. They demonstrated that CCAT1-L localized to its site of transcription and functioned in the maintenance of chromatin looping between the MYC promoter and its enhancers in coordination with CTCF. These results reveal a novel connection between the chromatin organization regulated by an lncRNA and MYC expression in a specific human cancer.

D. Han et al./Cancer Letters 361 (2015) 13–21

HOTAIR One of the mechanisms of action of lncRNAs is to epigenetically regulate gene expression such as HOTAIR which regulates genome modification. HOTAIR is transcribed in the opposite direction of the HOXC gene at the HOXC locus on chromosome 12q13.13. It is reported that HOTAIR interacts on its 5′ end with Polycomb repressive complex 2 to remodel chromatin and ensure silencing of HOX genes during embryonic development, whereas on 3′ end HOTAIR interacts with histone demethylase [63]. In recently years, studies have shown that HOTAIR is significantly overexpressed in many cancers, including breast cancer, hepatocellular cancer and laryngeal squamous cell carcinoma [64,65]. To determine the function of HOTAIR in CRCs, Kogo and colleagues [40] utilized cDNA microarray data from a subset of 32 CRC samples obtained by laser microdissection (LMD). They showed that HOTAIR expression levels were higher in cancerous tissues than in corresponding noncancerous tissues, and there was a close correlation between expression of HOTAIR and members of the PRC2 complex (SUZ12, EZH2, and H3K27me3). Importantly, Svoboda and colleagues [39] analyzed HOTAIR lncRNA levels not only in tumors but also in blood of sporadic CRC patients, and in association with their overall survival. They found that CRC patients had higher HOTAIR expression in blood than healthy controls. Besides, their work also showed that HOTAIR levels positively correlated between blood and tumor. They suggested that HOTAIR blood levels might serve as a potential surrogate prognostic marker in sporadic CRC. H19 The lncRNA H19 is one of the earliest-discovered non-coding RNAs in the mammalian genome. IGF2 and H19 are two oppositely expressed genes, located adjacent to each other at 11p15.5 [66]. In the majority of human tissues the imprinting of IGF2 depends on a differentially methylated region (DMR) located upstream of H19 promoters [67]. Aberrant DNA methylation is capable of modifying imprinted gene expression and may contribute to the causes of CRC. As known, alteration of the normal imprinting status is a common abnormality in embryonic and adult cancers, involving the loss of origin-specific gene expression, also called loss of imprinting (LOI). LOI is found in various types of adult malignancies including CRC [68]. However, whether LOI in CRC involves hypomethylation or hypermethylation is vague. Cui and colleagues [69] performed genomic sequencing analysis. Their results suggested hypomethylation of the sixth CTCF-binding site in the DMR of IGF2/H19 was linked to LOI and the common IGF2-H19 enhancer competition model for IGF2 imprinting did not apply to human CRC. Tian and colleagues [41] obtained the same result. Contradictorily, Nakagawa et al. [42] found that the LOI of IGF2 correlated with biallelic hypermethylation of five CpG sites in the CTCFbinding element. Besides the important imprinted involvement in the LOI of H19/ IGF2 loci, H19 is upregulated in a number of tumors, including bladder [70], glioma [71] and prostate cancers [72], suggesting the onco-genetic role of H19 in carcinoma. In 2004, Fellig and colleagues found that H19 was highly expressed in more than half of hepatic metastases derived from a range of carcinomas including CRC. Recently, H19 was reported to be the primary miRNA precursor of miR-675 in both human and mice [73]. In the work of Tsang et al. [43], it was reported that H19-derived miR-675 regulated the CRC development through downregulation of its target RB. Since many kinds of human carcinoma demonstrated overexpression of the H19 gene, regional administration of the plasmid seems to be a promising therapeutic approach. Ohana et al. [74] and Sorin et al. [75] showed that the DTA-H19 plasmid administered intra-arterially significantly delayed the tumor growth and even resulted in tumor

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regression in high percentage of the treated animals with liver metastases of colon cancer. Notably, besides H19 being the primary miR-675 precursor, there is another microRNA embedded in the IGF2/H19 imprinting region, where miR-483 is splicing from IGF2 [76]. Recently, two lncRNAs were newly found in this region: PIHIT [77] and 91H [78]. Deng and colleagues [79] found that upregulation of 91H promotes tumor metastasis and predicts poor prognosis for patients with CRC. Ma et al. [80] declared in their work that whether these two lncRNAs could regulate the CTCF and other factors, and whether miR-483 and miR675 could regulate these lncRNAs remains to be determined. Taken together, H19 is an lncRNA from an important imprinting region and has many potential functions in carcinogenesis. More effects are needed to better elucidate the mechanism of H19 in the progression of CRC. Other lncRNAs Plasmacytoma variant translocation 1 (PVT1) lncRNA is located in chromosome region 8q24.21, relatively close to the transcription factor c-Myc. These two genes are co-amplified in CRC cell lines [81]. The PVT1 gene is transcribed to several mature RNAs by alternative splicing, including a cluster of six annotated microRNAs: miR-1204, miR-1205, miR-1206, miR-1207-5p, miR-1207-3p, and miR-1208 [82]. PVT1 is overexpressed in several cancers [83,84]. Besides, upregulation of PVT1 contributes to tumor survival and chemoresistance [85] while its downregulation inhibits cell proliferation and induces a strong apoptotic response [83]. It has been proposed that PVT1 regulates c-Myc expression but also that PVT1 is regulated by c-Myc [86]. Takahashi and colleagues [44] found that PVT1 generated anti-apoptotic activity in CRC cells by activating the TGF-β signaling pathway and apoptotic signals. Their results revealed that the PVT-1 expression level was an independent risk factor for overall survival of CRC patients and the abnormal expression of PVT-1 was a prognostic indicator for CRC. However, it is still not clear whether the role of PVT1 lncRNA depends exclusively on being an miRNA host gene. Recently, Wang and colleagues [87] revealed a novel mechanism of PVT1 in HCC: promoting proliferation and stem cell-like property by stabilizing NOP2. In the future, further studies are required to understand the exact role of PVT1 in tumorigenesis and to determine whether the miRNAs encoded by PVT1 mediate its functionality. To date, only a few tumor suppressor-like lncRNAs have been reported in CRC. The growth arrest-specific transcript 5 (GAS5) is encoded at 1q25 and is about 630 nucleotides in length. It was reported working as a tumor suppressor to sensitize cells to apoptosis [88–90]. Overexpression of GAS5 led to increased apoptosis and slower cell cycle [91]. Kino et al. found that GAS5 was upregulated during growth arrest induced by serum starvation or the lack of growth factors. GAS5 bound the DNA binding domain of glucocorticoid receptor (GR) directly, preventing GRs from binding to DNA, thus modulating cell survival and metabolism [92]. Recently, Yin and colleagues [45] showed that lower expression of GAS5 was significantly correlated with large tumor size, low histological grade and advanced TNM stage in CRC. Further experiments revealed that overexpressed GAS5 significantly repressed the proliferation both in vitro and in vivo. In a word, these results suggested that GAS5 can play an essential role in normal growth arrest and apoptosis. lncRNAs have also shown their tumorigenic potential by modulating transcription of p53 [93]. Linc-RNA-p21 is a 3 kb lncRNA transcriptionally activated by p53. It collaborates with p53 in order to control gene expression in response to DNA damage. Silencing of linc-RNAp21 depresses the expression of hundreds of genes through interaction with heterogeneous nuclear rib nucleoprotein K (hnRNP-K), thus promoting apoptosis of abnormal cells or restraining tumors [94]. Additionally, lincRNA-p21 can inhibit the

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translation of target mRNAs. A work of Yoon et al. [95] showed that in the absence of HuR, lincRNA-p21 was stable and interacted with the mRNAs CTNNB1, JUNB and translational repressor Rck, repressing the translation of the targeted mRNAs. Recently, Zhai and colleagues [46] demonstrated that activation of p53 increased the level of lincRNA-p21 in CRC cells. Besides, their results showed lincRNAp21 was significantly lower in CRC specimens compared with paired normal samples, and lincRNA-p21 level was found to be associated with CRC stage, tumor tissue invasion, and vascular invasion, indicating the potential anti-tumor role of lincRNA-p21 in CRC. CRNDE was originally discovered as an upregulated lncRNA in CRC, whereas it shows little to no expression in normal colon epithelium [47]. Khalil et al. demonstrated CRNDE to be a lncRNA that interacted with chromatin-modifying complexes [96]. Besides, CRNDE appears to play a role in early development, and its expression is altered upon differentiation of stem cells and various types of progenitor cells [97]. It is known that transcripts from the CRNDE locus undergo extensive alternative splicing to generate a number of isoforms. Ellis and colleagues showed that transcripts containing intronic sequence localized in the nucleus, while those completely lacking intronic sequences were enriched in the cytoplasm. Recently, another work of Ellis et al. [98] investigated the effects of insulin/IGF on CRNDE expression. They demonstrated CRNDE was an lncRNA regulated by PI3K/Akt/mTOR and Raf/MAPK pathways, the canonical downstream signaling cascades of insulin and IGF1/ 2. Furthermore, they showed knockdown of the intronic region mediated by siRNA within CRNDE transcripts in CRC cells affected the expression of insulin/IGF-related pathway genes, in a pattern suggestive of the Warburg effect. It is the first report exploring the relationship between lncRNA and glucose and lipid metabolism in a manner that aids the development of a cancer phenotype. Shi and colleagues [51] selected 92 patients for a prospective analysis of association between lncRNA expression and clinical characteristics. Their results showed that the expression level of lncRNA RP11-462C24.1 was lower in CRC tissues compared with adjacent normal samples, indicating the potential roles of RP11462C24.1 in tumorigenesis and progression of CRC. Similarly, a work of Ge and colleagues [52] explored the expression of prostate cancerassociated ncRNA transcripts 1 (PCAT-1) in 108 CRC clinical samples and matched 81 adjacent normal tissues. Results showed that PCAT-1 expression in CRC tissues was significantly upregulated compared with the matched normal tissues, and a significant association exsited between PCAT-1 expression and distant metastasis. Notably, Franklin and colleagues [48] found a novel lncRNA from the Nras locus of the mouse genome and they designated it as non-coding Nras Functional RNA (ncNRFR). Functional analysis in their work showed that overexpression of ncNRFR in non-transformed, conditionally immortalized mouse colonocytes appeared to perturb the growth of normal colonic epithelial cells, leading to a more transformed state, perhaps through inhibition of let-7 function. Potential clinical applications of lncRNAs in CRC LncRNAs are emerging from the “desert region” of the genome as a new source of biomarkers to characterize disease recurrence and progression, for the reason that many lncRNAs have restricted species-specific and cancer-specific expression patterns. Besides, a significant increased or decreased expression level for lncRNA is often detected in tumors compared with normal tissues. Moreover, some types of lncRNAs are demonstrated to be present in body fluid, like urine and plasma, and this may shed light on the role of circulating or secretory lncRNAs on diagnosis. For example, Svoboda and colleagues [39] demonstrated that CRC patients had higher HOTAIR expression in blood than healthy controls. HOTAIR levels positively correlated between blood and tumor, indicating HOTAIR blood levels may serve as a potential prognostic marker in sporadic CRC.

Similar results were found for the existence of lncRNA PCA3 in prostate cancer patient urine samples and HULC in HCC patient blood [99,100]. But the exact mechanism for the release of lncRNAs into body fluid is still not well defined. Exosomes are nanovesicles secreted into the extracellular environment containing proteins, messenger RNAs and microRNAs, suggesting they play a role as mediators in cell-to-cell communication [101]. Some studies suggested lncRNAs may be packaged into microparticles, including exosomes, microvesicles and apoptotic bodies. Specifically, Gezer and colleagues [102] have shown the presence and differential abundance of lncRNA molecules in secreted exosome. They found some oncogenic lncRNAs with low expression levels were rich in secreted exosomes in MCF7 and Hela cells, such as HOTAIR, CCND1-ncRNA, and lincRNA-p21. Given this specificity and good accessibility, lncRNAs may be superior biomarkers to many protein-coding biomarkers. Accumulating evidence has demonstrated that lncRNA variants might be associated with risk of disease, including cancer. We have discussed above that there’s a large “gene desert” region upstream of the cMYC oncogene on chromosome 8q24, harboring several lncRNAs, where dozens of SNPs have been identified to be associated with the risk of CRC. The specific SNP in a certain lncRNA may indicate the potential CRC risk for a healthy person. Apart from being biomarkers, lncRNAs may also provide new targets for CRC therapy. A lncRNA H19 with oncogenic properties is upregulated in a wide range of tumors including CRC and it is an interesting target of alternative cancer treatment. The specificity expression of imprinted H19 is conferred by a regulatory sequence. Accordingly, a plasmid composed of the H19 gene regulatory element that drives the expression of diphtheria toxin (DT-A) gene has been developed and it is undergoing clinical testing as a treatment for CRC and other cancers [103,104]. Moreover, Kam and colleagues [105] showed that a well designed peptide nucleic acid (PNA)-molecular beacon (PNA-MB) complementary to lncRNA-CCAT1 can be used as a tool for imaging cell lines and detecting malignancies in human CRC biopsies in situ, indicating the potential diagnostic application of lncRNAs in CRC. Taken together, although the research of lncRNAs is presently at its infancy and only a small number of lncRNAs have been characterized, dysregulated lncRNAs in CRC could still become an important factor for both the diagnosis and prognosis of CRC. Prospect CRC is the second- and third-most commonly diagnosed cancer in females and males respectively, and more than 1.2 million patients are diagnosed with colorectal cancer every year. Understanding the defect in the gene regulatory network at the genomic level is urgently needed. Recent studies of miRNA and lncRNA have highlighted the importance of the non-coding part of the human genome. Functional studies have indicated some lncRNAs are involved in human carcinogenesis, acting as either oncogenes or anti-tumor genes. Among these, most cancer-related lncRNAs have the same expression pattern and biological function, independent of the cancer type. However, it is still important to note that some exact lncRNAs are reported playing different roles in distinct cancer types. Taking H19 as an example, it is over-expressed and acts as an oncogene in bladder [70], glioma [71] and colorectal [43,79] cancers; however, it still works as a tumor-suppressor in hepatocellular cancer [106]. This difference may be due to H19 different molecular mechanisms. H19 contains a microRNA (miR-675) in the first exon, which is responsible for its oncogenic activity by regulating target genes of miR-675 [73]. Oppositely, as reported in HCC [106], H19 was downexpressed and associated with the protein complex hnRNP U/PCAF/ RNAPol II, activating the miR-200 family by increasing histone acetylation, thus contributing to suppression of tumor metastasis.

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Since lncRNAs have been reported to be involved in all aspects of gene regulation, including epigenetic regulation, nuclear and cytoplasmic trafficking, transcription, mRNA splicing and translation, there are still significant gaps in our current understanding of lncRNA function. One exact lncRNA may have diverse biological functions in the whole genome. As shown in Table 1, we just list the reported CRCrelated lncRNAs. There are still a number of famous cancer-related lncRNAs whose functions associated with CRC needed to be uncovered, such as ANRIL [107], HULC [108] and MEG3 [109] and so on. Although lncRNA research still remains in its infancy, we cannot ignore the potential opportunity of lncRNA to develop novel biomarkers for CRC diagnosis and therapy. Thus, more effects are needed to better elucidate the function and critical mechanisms of colon-specific lncRNAs in the progression of CRC. In the future, systematic identification of lncRNAs and fine understanding of their mechanisms may pave new way for designing therapeutics for CRC, which may yet place lncRNAs at center stage in CRC biology. Acknowledgements This work was supported by the Natural Science Foundation of Heilongjiang Province for youth (QC2013C089), Science and Technology Research Project of Education Department in Heilongjiang Province (12531226), Postdoctoral Foundation of Heilongjiang Province (LBH-Z12172/LBH-TZ0415), Research Foundation for the Doctoral Program of Higher Education (20122307110002), Science and Technology Project of Heilongjiang Province (2013G1002) and Harbin (2014RFXGJ053) and Yu weihan academician fund for distinguished young Scholars of Harbin medical university. We apologize to all researchers whose relevant contributions were not cited due to space limitations. Thanks for anonymous reviewers’ constructive comments and suggestions. Conflict of interest No potential conflicts of interest were disclosed. References [1] D.M. Parkin, F. Bray, J. Ferlay, P. Pisani, Global cancer statistics, 2002, CA Cancer J. Clin. 55 (2005) 74–108. [2] J.M. Walsh, J.P. Terdiman, Colorectal cancer screening: scientific review, JAMA 289 (2003) 1288–1296. [3] C.P. Ponting, P.L. Oliver, W. Reik, Evolution and functions of long noncoding RNAs, Cell 136 (2009) 629–641. [4] R. Kurokawa, Long noncoding RNA as a regulator for transcription, Prog. Mol. Subcell. Biol. 51 (2011) 29–41. [5] A.L. Walsh, A.V. Tuzova, E.M. Bolton, T.H. Lynch, A.S. Perry, Long noncoding RNAs and prostate carcinogenesis: the missing ‘linc’?, Trends Mol. Med. 20 (2014) 428–436. [6] J.R. Prensner, A.M. Chinnaiyan, The emergence of lncRNAs in cancer biology, Cancer Discov. 1 (2011) 391–407. [7] T. Gutschner, S. Diederichs, The hallmarks of cancer: a long non-coding RNA point of view, RNA Biol. 9 (2012) 703–719. [8] C.J. Wu, Understanding the Role of Long Noncoding RNAs in the Cancer Genome, 1st ed., Springer, New York, 2013. [9] K.C. Wang, H.Y. Chang, Molecular mechanisms of long noncoding RNAs, Mol. Cell 43 (2011) 904–914. [10] L.L. Chen, G.G. Carmichael, Long noncoding RNAs in mammalian cells: what, where, and why?, Wiley interdisciplinary reviews, RNA 1 (2010) 2–21. [11] H. Jia, M. Osak, G.K. Bogu, L.W. Stanton, R. Johnson, L. Lipovich, Genome-wide computational identification and manual annotation of human long noncoding RNA genes, RNA 16 (2010) 1478–1487. [12] T. Derrien, R. Johnson, G. Bussotti, A. Tanzer, S. Djebali, H. Tilgner, et al., The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression, Genome Res. 22 (2012) 1775–1789. [13] M.N. Cabili, C. Trapnell, L. Goff, M. Koziol, B. Tazon-Vega, A. Regev, et al., Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses, Genes Dev. 25 (2011) 1915–1927. [14] J.H. Yang, J.H. Li, S. Jiang, H. Zhou, L.H. Qu, ChIPBase: a database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-Seq data, Nucleic Acids Res. 41 (2013) D177–D187.

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