Insight Into the Role of Long Noncoding RNA in Cancer Development and Progression

CHAPTER TWO

Insight Into the Role of Long Noncoding RNA in Cancer Development and Progression C.H. Li1, Y. Chen1,2,3,* 1

School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong 3 Shenzhen Research Institute, Chinese University of Hong Kong, Shenzhen, China 2

*

Corresponding author. E-mail address: [email protected]

Contents 1. Introduction 1.1 Molecular Mechanisms of lncRNA 1.2 Cancer-Associated Signaling Pathways 2. Roles of lncRNA During Cancer Development 2.1 Chromosomal Instability 2.2 DNA Damage Response 2.3 Virus-Induced Carcinogenesis 2.4 Carcinogen Stimulation 3. Cancer Cell Survival 3.1 Cancer Metabolism 3.2 Radiation and Oxidative Stress 3.3 Hypoxia 4. LncRNA in Cancer Stem Cell 4.1 Stemness Features 4.2 Renewal 4.3 Transformation of Cancer Stem Cell 5. Insight of Novel lncRNA Roles in Cancer 5.1 Immunity 5.2 Cancer Microenvironment 6. Diagnostic and Prognostic Value of lncRNAs 7. Concluding Remarks Acknowledgment References

International Review of Cell and Molecular Biology, Volume 326 ISSN 1937-6448 http://dx.doi.org/10.1016/bs.ircmb.2016.04.001

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© 2016 Elsevier Inc. All rights reserved.

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Abstract Long noncoding RNA (LncRNA) is a large class of RNA molecules with size larger than 200 nucleotides. They exhibit cellular functions although having no protein-coding capability. Accumulating evidence suggests that long noncoding RNA play crucial roles in cancer biology. Studies showed that deregulation of lncRNA was frequently observed in various types of cancers which contributed heavily to malignant phenotypical changes. Aberration of lncRNA can be induced by a number of factors such as dysregulated signaling pathway, response to catastrophic effect, viral infection, and contact with carcinogens. Meanwhile, alterations of lncRNA expression or function drive subsequent malignant development such as cell transformation or acquisition of stemness characteristics. Here, we give perspectives on recent findings on the involvement of lncRNAs in carcinogenesis and response to adverse tumor environment. Then, we discuss the role of lncRNAs in cancer stem cell which is an important model of cancer emergence. Last, we provide insight on the potential of lncRNAs in modulating environment favorable of cancer development and progression, and evaluate the diagnostic and prognostic value of lncRNAs in cancer management.

ABBREVIATIONS APTR ANRIL ATM BARTs BPDE NRCP CCAT2 CRC CRNDE DBH-AS1 DDR DDSR1 EBV LncRNA-Hh H. pylori HSC HBV HCV HCC HULC HIF1A-AS1 HOTAIR HPV lncRNA-HIF2PUT HIFs HINCUTs

Alu-mediated p21 transcriptional regulator Antisense noncoding RNA in INK4 locus Ataxia-telangiectasia mutated BamHI A rightward transcripts Benzo[a]pyrene-trans-7,8-diol-9,10-epoxide Ceruloplasmin Colon cancer associated transcript 2 Colorectal cancer Colorectal neoplasia differentially expressed DBH antisense RNA 1 DNA damage response DNA damage-sensitive RNA1 Epstein-Barr virus Hedgehog signaling associated lncRNA Helicobacter pylori Hepatic stellate cells Hepatitis-B virus Hepatitis-C virus Hepatocellular carcinoma Hepatocellular carcinoma upregulated long noncoding RNA HIF1A antisense RNA 1 HOX transcript antisense RNA Human papilloma virus Hypoxia inducible factor 2α Hypoxia inducible factors Hypoxia-induced noncoding ultraconserved transcripts

Insight Into the Role of Long Noncoding RNA in Cancer Development and Progression

ICR ICR IL-6 lncRNA-JADE lncRNA-Dreh lncRNA-LET linc-RoR MALAT1 NKILA NORAD oriPtL oriPtR lncRNA-HIF2PUT PCA3 SCAL1 SOX2OT T-ALL HTLV-1 TGFβ1 Col-1 T-UCR UCA1 HBx

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ICAM-1-related RNA ICAM-1-related RNA Interleukin-6 JADE1 adjacent regulatory RNA LncRNA Down-regulated by HBx lncRNA Low Expression in Tumor Long intergenic noncoding RNA, regulator of reprogramming Metastasis associated lung adenocarcinoma transcript 1 NF-κB Interacting LncRNA Noncoding RNA activated by DNA damage Origin of replication leftward transcript Origin of replication rightward transcript Promoter upstream transcript of hypoxia inducible factor 2α Prostate cancer antigen 3 Smoke and cancer-associated lncRNA-1 SOX2 overlapping transcript T-cell acute lymphoblastic leukemia T-lymphotrophic virus Transforming growth factor β1 Type I collagen Ultraconserved region transcripts Urothelial carcinoma associated 1 X protein of HBV

1. INTRODUCTION Advances in genome-wide RNA sequencing technique proved that pervasive transcription occurs within the human genome. Only a small percentage of the transcripts codes for proteins, while a large amount of the remaining RNAs shows noncoding functions. Increasing evidence suggested that RNA molecules that lack protein-coding ability are involved in the communications between various genetic materials (DNA, RNA, and protein) in cells. It is believed that they are the missing puzzle pieces to depict the genomic complexity thoroughly. The noncoding RNAs are further divided into two groups in accordance with the length of RNA molecules. Long noncoding RNA (LncRNA), with length ranging from 200 bp to ∼100 kbp, is the largest subclass of noncoding RNAs. Currently, more than 14,000 lncRNA transcripts are annotated in the Gencode v7 catalog that covers around 9000 intergenic lncRNAs and 5000 exonic and intronic lncRNAs (Derrien et al., 2012). LncRNAs play important roles in various biological processes such as imprinting (Jeon et al., 2012), epigenetic

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regulation (Mattick et al., 2009), apoptosis and cell cycle control (Wapinski and Chang, 2011), transcriptional and translational regulation (Orom et al., 2010), cell development and differentiation (Clark and Mattick, 2011), and aging (Rando and Chang, 2012). Studies have also reported the involvement of lncRNAs in various diseases including cancer. Deregulations of lncRNAs are observed in multiple cancer types that virtually participate in all stages of cancer development including cancer initiation, progression, and metastasis (Gutschner and Diederichs, 2012; Tsai et al., 2011), in which alteration of lncRNAs functions as the drivers of tumor suppressor or oncogenic functions. Aberrations are mostly found in lncRNAs that are critical in malignant phenotypical changes including cell growth, cell cycle control (Kitagawa et al., 2013), apoptosis (Rossi and Antonangeli, 2014), cell migration, invasion, and metastasis (Tsai et al., 2011).

1.1 Molecular Mechanisms of lncRNA Molecular functions of lncRNAs are determined mainly by their regulation on the expression of specific genes. Various modes of molecular interaction have been observed for lncRNA to exhibit their gene-regulating properties, and they cover a wide range of functions from transcriptional to posttranscriptional regulation. Many lncRNAs have protein-binding capability that regulates gene expression at transcriptional level. LncRNA can complex with different protein factors to form functional gene activator or repressor. The activated protein factors will bind to the promoter elements of target genes for gene activation or gene repression. Other than regulating the activity of the protein factor, lncRNA can determine the target specificity of bound proteins. Upon lncRNA-protein interaction, lncRNA can guide the proteins to target genomic regions that are specific to the recognition site of the lncRNAs. Moreover, effect of lncRNA is not confined to a single protein factor. Some proteins when isolated alone have no molecular function, but they have specific roles as a part of a protein complex. LncRNAs can act as a scaffold to recruit various proteins to form a functional protein complex. As such, the complex can possess functions either to activate transcription or suppress transcription. LncRNAs can also act as decoy to remove gene expression regulators from the promoter elements. The lncRNAs compete with the protein binding region at the promoter of target gene. As such, the activating or inhibiting effect of the proteins will be attenuated. At posttranscriptional level, lncRNAs can mediate mRNA modification, affect target mRNA stability and regulate translational efficiency. LncRNA

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is involved in mRNA processing that influence the structure, splicing variant or coding potential of the mRNA. Double-stranded RNA formed by base-pairing between lncRNA and target mRNA can be bound by various double-stranded RNA-binding proteins for further processing. Second, lncRNAs can regulate mRNA stability by either altering the stability of mRNA or depleting/removing the destabilizing factors from the mRNA. For example, binding of lncRNA to the 50 UTR of mRNA may induce staufen-mediated degradation of the mRNA, hence increases the turnover rate of the mRNA (Gong and Maquat, 2011). Some lncRNAs may harbor microRNA-binding site to act as a decoy of microRNA molecules. As stability of mRNA can be determined by microRNA-mediated degradation, the ability of lncRNAs to sequestrate microRNAs prolongs the turnover rate of the mRNA. Attenuation of microRNA-mediated inhibition of mRNA can be also occurred when the lncRNAs bind to the 30 UTR of the mRNA. Upon the lncRNA-30 UTR binding, microRNA-recognition sites positioned on the 30 UTR will be masked and thus microRNA interaction with mRNA will be inhibited. In addition, lncRNAs are implicated in regulation of gene translation. LncRNAs can form stable RNA duplex with target mRNAs, and inhibit the translation. The binding of lncRNAs to the target mRNAs may also recruit translation repressor to stall translation initiation and/or elongation. LncRNAs can also interfere with the translational machinery in order to control translational rate. For example, lncRNAs can alter the interaction between translational initiation factors, and inhibit the assembly of translational initiation complex.

1.2 Cancer-Associated Signaling Pathways Cell signaling pathways that regulate tumorigenic effects are one of the aspects that are frequently investigated. Deregulation of the signaling pathways is implicated in various malignant phenotypes including cancer cell growth, survival, differentiation, and metastasis. Studies have proved that aberrant activations of specific signaling pathways are essential for cancer development and progression, highlighting their importance in cancer biology. Knowledge gained regarding that the roles of lncRNAs in cell signalings will improve the current understanding on the underlying mechanism of cell signaling deregulation, and the effects induced to malignant development (Figs. 1 and 2). Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was significantly upregulated in multiple cancer types. In gallbladder cancer,

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Figure 1 Examples of cancer-associated signaling pathways regulated by lncRNAs.

Figure 2 Emerging roles of lncRNAs in cancer initiation, cancer cell survival, and cancer stem cell.

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inhibition of MALAT1 significantly inhibited the proliferation and metastasis of gallbladder cancer cells both in vitro and in vivo. It was shown that inactivation of ERK/MAPK pathway was resulted upon depletion of MALAT1 in gallbladder cancer cells (Wu et al., 2014). MALAT1 mRNA was also highly expressed in human osteosarcoma tissues, and its expression level was closely correlated with pulmonary metastasis. It is suggested that MALAT1 promoted cell proliferation and cell metastasis through the activation of PI3K/AKT signaling, as inhibition of MALAT1 could lead to reduction of the level of phosphorylated PI3K, and downregulated the expression of PI3K/AKT pathway genes such as AKT, PCNA, and MMP-9 (Dong et al., 2015). MALAT1 could also regulate Wnt/β-catenin signaling in cancer. Treatment of resveratrol in colorectal cancer (CRC) brought out antitumor effect through downregulation of MALAT1 and the subsequent attenuation of Wnt/β-catenin. Reduced expression of MALAT1 resulted in inhibition of CRC cell invasion and metastasis as Wnt/β-catenin signaling was inactivated owing to a decreased nuclear localization of β-catenin (Ji et al., 2013). In bladder cancer, lncRNA urothelial carcinoma associated 1 (UCA1) was shown to promote cancer cell proliferation. It was later suggested that alteration of UCA1 affected PI3K/AKT signaling through phosphorylation of CREB and influenced AKT expression and activity. Inhibition of PI3K pathway by small molecule inhibitor could attenuate the effect of UCA1 and block cell cycle progression (Yang et al., 2012). It is later shown that UCA1 was transactivated by transcriptional factor Ets-2 that potentially activated by Ras/ MAPK signaling. The induction of UCA1 by Ets-2 could account for the functional role of Ets-2 to inhibit apoptosis in bladder cancer cells (Wu et al., 2013). In addition, activation of Wnt signaling by UCA1 promoted the development of chemoresistance. Expression of UCA1 induced the expression of Wnt6 that activated Wnt signaling in cancer cells and subsequently increased the cell viability during cisplatin treatment (Fan et al., 2014). Another lncRNA linc00152 is also reported to mediate the activity of PI3K/ AKT signaling. Linc00152 could promote cell proliferation and tumor growth in gastric cancer and hepatocellular carcinoma (HCC). In gastric cancer, linc00152 directly interacted with EGFR which led to the activation of PI3K/AKT pathway (Zhou et al., 2015). In HCC, linc00152 could activate EpCAM through binding to its promoter, which activated the mTOR pathway in HCC cells for promoting cell growth (Ji et al., 2015). In esophageal squamous cell carcinoma, the antisense transcript of the INK4b-ARF-INK4a gene cluster, named antisense noncoding RNA in

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INK4 locus (ANRIL) was significantly increased in tumor tissues compared to adjacent nontumor tissues. Besides the regulation of tumor suppressor p15 (INK4b), ANRIL also suppressed the transforming growth factor β1 (TGFβ1) signaling in which it promoted the development of esophageal squamous cell carcinoma (Chen et al., 2014). LncRNA HOTAIR directly reduced the expression of WIF-1 and activated the Wnt/β-catenin signaling (Ge et al., 2013). In prostate cancer, linc00963 was involved in cancer cell transition from androgen-dependent to androgen-independent through the EGFR signaling pathway. Linc00963 promoted cell proliferation, motility, and invasion through the induction of EGFR expression and phosphorylation of AKT (Wang et al., 2014c). In melanoma, lncRNA BANCR was overexpressed and promoted cancer cell proliferation. Studies showed that BANCR activated MAPK signaling by interfering with ERK1/2 and JNK pathways (Li et al., 2014a). BANCR was also involved in the proliferation, migration, and apoptosis of lung carcinoma, in which BANCR regulated these malignant phenotypes through the regulation of p38 MAPK and JNK signalings (Jiang et al., 2015). Studies focusing on specific signaling pathways also revealed lncRNAs having important roles during tumorigenesis. Notch signaling plays a central role in T-cell acute lymphoblastic leukemia oncogenesis, and a study was conducted to identify lncRNAs affected by Notch in malignant T cells in hope of developing new therapeutic strategies targeting Notch-signaling hyperactive tumors. LncRNAs directly regulated by Notch were identified in human T-cell acute lymphoblastic leukemia through pharmacological Notch inhibition in T-cell acute lymphoblastic leukemia cell line, Notch active and inactive thymocytes of T-cell acute lymphoblastic leukemia patients (Durinck et al., 2014). In breast cancer, NF-κB signaling is a critical link between inflammation and cancer. A study showed that NF-κB induced the expression of an lncRNA NF-κB Interacting LncRNA (NKILA) that functioned to feedback the activity of NF-κB signaling activity. NKILA was shown to bind to NF-κB/IκB complex and directly masked phosphorylation motifs of IκB, thereby inhibiting IKK-induced IκB phosphorylation and NF-κB activation. As such, NKILA could prevent overactivity of NF-κB pathway in inflammation-stimulated nontumor breast epithelial cells. Low NKILA expression was associated with breast cancer metastasis and poor patient prognosis (Liu et al., 2015a). A hedgehog signaling associated lncRNA, lncRNA-Hh, was transcriptionally regulated by Twist protein in mammosphere cells. LncRNA-Hh directly targeted GAS1 to stimulate the activation of hedgehog signaling. The activated hedgehog signal increased

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GLI1 expression, and enhanced the expression of SOX2 and OCT4 which were critical in maintaining the tumorigenicity of breast cancer cells (Zhou et al., 2016). Hedgehog signaling also plays a role in osteosarcoma development as ubiquitous Hedgehog signaling resembles the early stage of osteosarcoma. It was shown that aberrant Hedgehog signaling led to the overexpression of lncRNA H19, which contributed to the pathogenesis of osteoblastic osteosarcoma (Chan et al., 2014).

2. ROLES OF lncRNA DURING CANCER DEVELOPMENT 2.1 Chromosomal Instability Abnormality in chromosome copy number is consistently observed in cancers, and such aberration is often caused by chromosomal instability. Evidences prove that the induction of chromosomal instability can be triggered by deregulation of critical genes. Recent reports suggested that particular lncRNAs could maintain chromosome integrity, and their deregulation may lead to chromosomal instability. The generation of aneuploidy is a characteristic trait in microsatellite-stable colon cancer, which involves the loss or gain of large portions or whole chromosomes in cancer cells. Colon cancer associated transcript 2 (CCAT2) is an lncRNA highly overexpressed in cancer cells that induced the expression of MYC and Wnt signaling targets. The frequent association between MYC activity with chromosomal instability has been demonstrated, and so it is suggested that CCAT2 lncRNA underlied the chromosomal instability phenotype in microsatellite-stable colon cancer (Ling et al., 2013). More recently, a study showed that inactivation of an lncRNA noncoding RNA activated by DNA damage (NORAD) could trigger dramatic aneuploidy in karyotypically stable cell lines. NORAD RNA is broadly expressed with high abundance, and is conserved among mammalian species. The expression of NORAD is induced after DNA damage. Study showed that NORAD maintained genomic stability by sequestering PUMILIO domain containing proteins, which repressed the stability and translation of mRNAs to which they bound. PUMILIO proteins regulate a large set of targets that determine the fidelity of chromosome transmission. In the absence of NORAD, PUMILIO proteins drived chromosomal instability by hyperactively repressing mitotic, DNA repair, and DNA replication factors (Lee et al., 2015). Currently, the role of NORAD in cancer is not reported

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yet, but it is undoubtedly one of the potential mechanisms unexplored in cancer-associated chromosomal instability phenotype.

2.2 DNA Damage Response The maintenance of genome integrity is essential for the proper function and survival of all organisms. Human cells have evolved prompt and efficient DNA damage response (DDR) to eliminate the detrimental effects of DNA lesions. The DDR involves a complex network of processes that detect and repair DNA damage, in which long noncoding RNAs (lncRNAs), a new class of regulatory RNAs, may play important roles. As mentioned in previous section, lncRNAs such as NORAD can be induced upon DNA damage to maintain chromosome integrity (Lee et al., 2015). Basic and preclinical studies suggested that DDR is one of the primary anticancer barriers during tumorigenesis, while dysregulation of lncRNA may facilitate tumor development by overriding DDR. Indeed, studies have shown the oncogenic roles of lncRNA upon induction by DNA damage. JADE1 adjacent regulatory RNA (lncRNA-JADE) is induced after DNA damage in an ataxia-telangiectasia mutated (ATM)dependent manner. LncRNA-JADE showed important functional link that connected DDR to histone H4 acetylation. LncRNA-JADE transcriptionally activated Jade1, which is a key component in histone acetylation complex containing HBO1, to promote histone H4 acetylation. As the level of lncRNA-JADE was significantly higher in breast tumors compared to normal breast tissues and knockdown of lncRNA-JADE could inhibit breast cancer cell growth, it is believed that overexpression of lncRNA-JADE upon DNA damage may contribute to breast tumorigenesis (Wan et al., 2013). Long intergenic noncoding RNA, regulator of reprogramming (lincRoR) is a stress responsive lncRNA highly expressed in HCC (Takahashi et al., 2014b) and breast cancer (Hou et al., 2014). It is showed that linc-RoR functioned to repress p53 in response to DNA damage. A 28 base sequence of linc-RoR is identified to be essential for p53 repression, as it directly interacted with the heterogeneous nuclear ribonucleoprotein I for the suppression of p53 translation. Inhibition of p53 by linc-RoR led to the attenuation of p53-mediated cell cycle arrest and apoptosis (Zhang et al., 2013). There are other lncRNAs that are associated with DDR, though their associations with cancer are not explored. Induction of ANRIL expression is triggered by DNA damage through the transactivation of transcription factor E2F1 in an ATM-dependent manner. Elevated levels of ANRIL suppress the

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expression of INK4a, INK4b, and ARF at the late-stage of DDR, allowing the cell to return to normal at the completion of the DNA repair (Zhang et al., 2013). Another lncRNA that induced after DNA damage is DNA damage-sensitive RNA1 (DDSR1). DDSR1 expression is induced in an ATM-NF-κB pathway-dependent manner by several DNA doublestrand break agents. It is shown that loss of DDSR1 impaired DDR signaling, and reduced DNA repair capacity by homolog recombination (Sharma et al., 2015b). All these evidences point to the potential role of the DDRassociated lncRNA in tumorigenicity.

2.3 Virus-Induced Carcinogenesis Several viruses are linked to the initiation and development of human cancer, as such they are referred as oncoviruses. Commonly known oncoviruses include hepatitis-B virus (HBV) and hepatitis-C virus (HCV) that induce HCC development; human papilloma virus (HPV) that induces development of cervical cancer, head and neck cancer, oral cancer, and skin cancer; Epstein-Barr virus-(EBV) that induces nasopharyngeal carcinoma and certain types of lymphoma; human T-lymphotrophic virus (HTLV-1) that links with adult T-cell lymphoma. These oncoviruses express viral proteins that interfere with the gene expression network in the host cells, which favors the malignant development or cancer progression of the cells. Reports have shown that some viral proteins were capable of deregulating lncRNAs that promoted cancer development. A large proportion of HCC patients are tested with positive HBV infection, and it has been proved that x protein of HBV (HBx) plays key roles in HCC tumorigenesis. A study has demonstrated that HBV infection could induce differential expression profile of liver lncRNAs in hepatocytes. An lncRNA, named lncRNA downregulated by HBx (lncRNA-Dreh), was identified to be specifically downregulated by HBx protein which led to HCC growth and metastasis. LncRNA-Dreh could combine with the intermediate filament protein vimentin and repressed its expression. As such, loss of lncRNA-Dreh mediated by HBx protein could change the normal cytoskeleton structure that facilitated tumor metastasis (Huang et al., 2013). Another lncRNA named DBH antisense RNA 1 (DBH-AS1) was also shown to involve in HBx-mediated hepatocarcinogenesis. The level of DBH-AS1 was positively correlated with hepatitis B surface antigen and tumor size in HCC tumors. DBH-AS1 functioned to upregulate cell cycle factors CDK6, CCND1, CCNE1 and downregulate p16, p21, and p27. As a

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result, DBH-AS1 increased cell proliferation and tumor growth through accelerating cell cycle progression (Huang et al., 2015). Furthermore, HBV infection could prompt the pathogenesis of preneoplastic event such as cirrhosis through the induction of lncRNA hepatocellular carcinoma upregulated long noncoding RNA (HULC). HULC was significantly upregulated in plasma samples of HBV-related cirrhosis patients. Overexpression of HULC could elevate the frequency of regulatory T cells which contributed to the suppression of immunity and prolonged the cirrhosis status. HULC also regulated the function of regulatory T cells through downregulating the level of p18 directly (Zhao et al., 2015). Study also demonstrated the association between another HCC-associated virus HCV with lncRNA deregulation. HCVactivates STAT3 signaling for accelerating the replication of HCV. It was shown that STAT3 mediated HCV replication via upregulating lnc-IGF2-AS and lnc-7SK. Expression of lnc-7SK and lnc-IGF2-AS were linked with the expression of phosphatidylinositol 4-phosphate which was associated with HCV replication (Xiong et al., 2015). It suggested that lncRNAs were utilized to facilitate viral propagation that linked with HCV-mediated hepatocarcinogenesis. Meanwhile, there were lncRNAs commonly deregulated by both HBV and HCV viruses for HCC development. Linc01419 was significantly overexpressed in both HBV-related and HCV-related HCC when compared with matched nontumor liver tissues that potentially regulated cell cycle of HCC cells (Zhang et al., 2015). HPV virus expresses various viral proteins that play major roles in cervical carcinogenesis. Oncoprotein E7 belongs to one of such proteins that interacts with host cellular molecules and inactivates their regulations. Recently, a study showed lncRNA modulated by HPV protein E7 could induce cervical carcinogenesis. Concurrent high expression of E7 and HOX transcript antisense RNA (HOTAIR) levels were detected in HPV-positive samples. The viral protein could upregulate the expression of HOTAIR, and alter its functions in regulating gene targets. It was demonstrated that E7 could directly interact with HOTAIR that facilitated cancer metastasis (Sharma et al., 2015a). On the other hand, oncovirus may express viral lncRNA in host cells. A study showed that EBV encoded hundreds of viral lncRNAs that were expressed during reactivation (Cao et al., 2015). The EBV latency origin of replication (oriP) was able to transcribed bidirectionally during reactivation that generated both leftward and rightward transcripts (oriPtL and oriPtR). It is shown that the transcripts had noncoding functions via the

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formation of hairpin secondary structures that were recognized by doublestranded RNA binding protein ADAR or multifunctional paraspeckle protein NONO. The binding with NONO indicated that the viral lncRNAs may contribute to global viral lytic gene expression and viral DNA replication. As such, they could interact with cellular innate immune pathways and facilitate progression of the viral lytic cascade (Cao et al., 2015). EBV infected cancers are also observed with high level of viral polyadenylated RNA BamHI A rightward transcripts (BARTs). The BART exons were spliced and polyadenylated in nucleus of host cells that induced change of cellular transcription. The differential expression pattern triggered by BART lncRNAs contributed to the regulation of host cell growth, and it is believed that these viral lncRNAs mediated viral oncogenesis in the presence of a functional immune system (Marquitz et al., 2015).

2.4 Carcinogen Stimulation Exposure to a wide variety of chemicals increases the risk of cancer. Examples of these carcinogens include aflatoxin in certain moulds and benzopyrene in cigarette smoke. Most of them are studied intensively regarding their carcinogenic mechanisms, and researchers begin to investigate their role in the alteration of lncRNAs. Aflatoxin B1 is a carcinogen that increases the susceptibility to HCC, and it is shown that aflatoxin B1 could induce the expression of transcriptional factor E2F1. Aflatoxin B1-induced E2F1 could transcriptionally activate lncRNA H19 in HCC cells and thereby increase cell growth and invasion (Lv et al., 2014). Various kinds of mutagens are found in tobacco that induces various cancer types, and study showed that cigarette smoke extract could induce the change of lncRNA profile in lung cancer cells. Smoke and cancerassociated lncRNA-1 (SCAL1) was shown to be one of the lncRNAs induced by cigarette smoke extract (Thai et al., 2013). Another study also demonstrated the effect of cigarette smoke extract to the change of lncRNA expression that contributed to malignant transformation of lung cancer. It illustrated an lncRNA-mediated modulation that link inflammation with epithelial-mesenchymal transition (Liu et al., 2015b). Benzo[a]pyrene-trans-7,8-diol-9,10-epoxide (BPDE) is one of the important carcinogen in the tobacco that induces lung cancer and esophageal cancer. BPDE covalently binds to DNA that induce differential gene expression. Several studies have illustrated the effect of BPDE exposure to the change of lncRNA expression in cancer. Transformation of human

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bronchial epithelial cell line 16HBE by BPDE could induce the expression of lncRNA AF118081 (Yang et al., 2014b) and LOC728228 (Hu et al., 2015), and it was observed that AF118081 was highly expressed in lung cancer cells and patient samples (Yang et al., 2014b). In addition, transformation of bronchial epithelial cell BEAS-2B could upregulate lncRNA-DQ786227 that functioned to promote cell proliferation, increase colony formation, inhibit apoptosis, and transform the nonmalignant cells to develop tumors in nude mice (Gao et al., 2013). In addition to various chemicals, biological carcinogen is able to promote cancer development through modulating lncRNA expression. Helicobacter pylori is a major gastrointestinal pathogenic bacteria that caused gastric cancer. Studies showed that H. pylori infection could also lead to dysregulation of lncRNA that enhanced H. pylori tumorigenic potential. More than three hundred of lncRNAs were aberrantly expressed upon H. pylori infection in gastric epithelial cells, and subsequent validation showed that lncRNAs n345630, XLOC_004787, n378726, and LINC00473 were downregulated in H. pylori infected cells as well as H. pylori-positive gastric cancer tissues (Zhu et al., 2015). More recently, a report suggested that lncRNA contributed to the modulation of immune response to H. pylori infection. Five lncRNAs XLOC_004562, XLOC_005912, XLOC_000620, XLOC_004122, and XLOC_014388 were validated to be differentially expressed upon H. pylori infection. Among them, the level of XLOC_004122 and XLOC_014388 were lower in gastric mucosal tissues of H. pylori-positive patients, suggesting that the change of these lncRNAs was beneficial to H. pylori-induced tumorigenesis through interfering the immune system (Yang et al., 2015).

3. CANCER CELL SURVIVAL 3.1 Cancer Metabolism Cancer cells reconstruct their metabolism to accommodate the drastic phenotypical change during malignant transformation. The common aim of an altered metabolism in cancer is to acquire necessary nutrients from frequently nutrient-deficient tumor environment. The altered metabolism can either sustain or promote growth, survival, dissemination, and long term maintenance of the cancer cells. One of the common features of the cancer metabolism is the increased uptake of glucose, and metabolization of the glucose through aerobic glycolysis in which glucose is fermentated to lactate.

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This feature is termed as the Warburg effect. This general effect is brought out by aberrant expression of metabolic genes. A study showed that lncRNA H19 was upregulated by EGR1 in liver cancer, thereby leading to the induction of pyruvate kinase M2 in liver cancer cells. Pyruvate kinase M2 is essential for the Warburg effect (Li et al., 2015a). In bladder cancer, increased lncRNA UCA1 level activated mTOR signaling to activate hexokinase 2 which functioned as a mediator of glycolysis (Li et al., 2014b). LncRNA lincRNA-p21 could modulate hypoxia-induced Warburg effect. LincRNA-p21 dissociated Hypoxia inducible factor (HIF)-α protein from VHL protein, and attenuated ubiquitination of HIF-α. The accumulation of HIF-α protein then promoted glycolysis under hypoxia (Yang et al., 2014a). Another lncRNA that regulated Warburg effect is named Colorectal neoplasia differentially expressed (CRNDE) that is activated in early CRC. CRNDE was downregulated during the treatment of insulin and insulin-like growth factors. It was shown that CRNDE regulated gene targets that participated in glucose and lipid metabolism, which could promote the change of metabolism of CRC cells to aerobic glycolysis (Ellis et al., 2014). In ovarian cancer, lncRNA ceruloplasmin (NRCP) was upregulated in tumor tissue which promoted tumor progression. It was reported that NRCP also regulated cancer metabolism via increasing cancer cell glycolysis (Rupaimoole et al., 2015).

3.2 Radiation and Oxidative Stress Radiotherapy is a treatment modality for various cancer types including esophageal squamous cell carcinoma, nasopharyngeal carcinoma, colorectal cancer, and cervical cancer. During the treatment, high energy radiation is emitted to the tumor to damage cancer cells. However, tumor cells frequently survived from the radiation due to the gradual acquisition of radioresistance. Recent studies demonstrated that deregulation of lncRNAs contributed to the development of radioresistant phenotype of cancer cells. In colorectal cancer, lincRNA-21 was frequently reduced in CRC cell lines and human tissues with concomitant increase of β-catenin expression. Study showed that X-ray treatment could induce lincRNA-p21 expression, and subsequently suppressed β-catenin signaling pathway and enforced expression of proapoptotic gene Noxa. The induction of anticancer gene expression enhanced the sensitivity of radiotherapy for CRC (Wang et al., 2014a). Another study also demonstrated the role of lincRNA-p21 in radiationmediated cell death. LincRNA-p21 was transcriptionally induced by ultraviolet B in mouse and human keratinocytes in culture and in mouse skin in

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vivo in a p53 dependent manner. LincRNA-p21 mediated the ultraviolet B-induced apoptosis and/or cell cycle arrest in keratinocytes, while loss of lincRNA-p21 function resulted in the evasion of apoptosis and cell cycle arrest (Hall et al., 2015). As lincRNA-p21 was underexpressed in various cancers, it may have a key role in generating radioresistance during treatments. In nasopharyngeal carcinoma, it was shown that lncRNA MALAT1 regulated radioresistance by modulating cancer stem cell activity. Inhibition of MALAT1 could sensitize nasopharyngeal carcinoma cells to radiation both in vitro and in vivo (Jin et al., 2015). Furthermore, another study investigated the change of lncRNAs profile upon curcumin treatment, as reports suggested that curcumin could sensitize cancer cells to radiation. Curcumin was able to reverse the expression profile of lncRNA induced by ionizing radiation. Particularly, it was shown that lncRNA AK294004 was induced by curcumin that inhibited cyclin D1 (CCND1) expression, that may contribute to curcumin-induced radiosensitization in nasopharyngeal carcinoma cells (Wang et al., 2014d). These evidences suggested that lncRNAs can play important roles in modulating the response of cancer cells exposed to radiation.

3.3 Hypoxia The demand for oxygen is largely increased in order to sustain the growth of tumor. Hypoxia is a condition when the supply of oxygen is insufficient. Adaptive changes occurred in cancer cells to survive the oxygen deficient environment which involves the reprogramming of gene expression network. HIFs are the major players that contributed heavily in hypoxiainduced cancer development and progression, and reports suggested HIFs triggered adaptive mechanisms that involve the deregulation of lncRNAs. Under hypoxic conditions, UCA1 was upregulated in bladder cancer cells, and it is shown that HIF-1α was responsible for transcriptional induction of the lncRNA. HIF-1α could specifically bound to hypoxia responsive elements found in the promoter of UCA1 gene which elevated the expression of UCA1, and upregulation of UCA1 could then increase bladder cancer cell proliferation, migration, invasion, and inhibited apoptosis (Xue et al., 2014). In breast cancer, Ephrin-A3 was induced in response to hypoxia that increased the metastatic potential of the cancer cells. A study had demonstrated a HIF-induced upregulation of Ephrin-A3 that was mediated by lncRNA. HIF indirectly enhanced the level of Ephrin-A3 by first inducing the expression of lncRNA-EFNA3, the lncRNA thereby led to the

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accumulation of Ephrin-A3 (Gomez-Maldonado et al., 2015). Elevated level of Ephrin-A3 could then promote cancer metastasis via enhancing extravastion of the breast cancer cells. Ultraconserved region transcripts (T-UCR), a subclass of lncRNA, were also induced during hypoxia. They were named hypoxia-induced noncoding ultraconserved transcripts (HINCUTs) which were found to be overexpressed in colon cancer clinical samples. Study showed that HIFs partially contributed to the induction of several HINCUT members. Among them, HINCUT-1 was shown to mediate colon cancer development during hypoxia, as HINCUT-1 supported cell proliferation specifically under hypoxic conditions (Ferdin et al., 2013). On the other hand, HIFs were susceptible to lncRNA regulation during hypoxic condition. Linc-ROR level was increased in response to hypoxia in liver cancer that led to the induction of HIF-1α. Knockdown of linc-ROR showed reduced cell viability in hypoxia but not in normoxia, while overexpression of HIF-1α could partially rescue the effect. Furthermore, it was shown that linc-ROR reduced the expression of microRNA miR-145 during hypoxia. As miR-145 functioned to repress the expression of HIF1α, and linc-ROR indirectly upregulated HIF-1α level through attenuating its inhibitor miR-145 (Takahashi et al., 2014a). Studies have shown that hypoxia induced other lncRNAs changes that are independent of HIFs. In HCC, lncRNA H19 was upregulated by hypoxia and played an important role to promote growth after hypoxia recovery. It is also suggested that the function of H19 induced during hypoxia enhanced tumorigenicity of HCC in vivo (Matouk et al., 2007). In gastric cancer, another lncRNA named AK058003, that was frequently upregulated in human gastric cancer, could mediate metastasis of hypoxiainduced cancer cells. Induction of AK058003 by hypoxia reduced the γ-synuclein mRNA and protein level in gastric cancer cells, which promoted metastasis by increasing migration and invasion rate of the cells (Wang et al., 2014e). Meanwhile, hypoxia could lead to the downregulation of lncRNA. Histone deacetylase 3, that reduces histone acetylation at target genes, was induced by hypoxia. It was observed that the deacetylase affected the promoter activity of an lncRNA low expression in tumor (lncRNA-LET), resulted in the inhibition of its transcription. Reduced level of lncRNA-LET contributed to hypoxia-induced cancer cell invasion through stabilizing nuclear factor 90 protein. Hypoxia-mediated silencing of lncRNA-LET may have a major role in cancer as lncRNA-LET was frequently downregulated in multiple cancers including HCC, CRC, and lung cancer (Yang et al., 2013).

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4. LncRNA IN CANCER STEM CELL It is proposed that the heterogeneity of cancer cells may be derived from common ancestral cells, which are capable of self-renewal and possess unlimited proliferative potential. Although these cells comprise only a small proportion of the malignant cell pool, they are believed to propagate into more differentiated cancer cell types that construct the outlook of the tumor and the total population. These cells are referred as the tumor-initiating cells or tumor-propagating cells. Most often, they show stem cell-like characteristics, and hence they are commonly known as cancer stem cells (CSCs). LncRNAs show high cell type and tissue type specificity, and studies have demonstrated their roles in stem cell biology. As such, lncRNAs may also play critical roles in modulating the cancer stem cell phenotypes.

4.1 Stemness Features Pluripotency is an important ability of a cell to acquire stemness features, and various protein factors are shown to play critical roles in determining cell pluripotency. Key protein factors include Oct4, Sox2, Nanog, and c-Myc. They are frequently found in cancer initiating cells, and are considered as the marker of CSC. Thus, lncRNAs that are capable of affecting the expression of these factors are critical in regulating stemness features. An lncRNA gene name human SOX2 overlapping transcript (SOX2OT) was transcribed antisense to one of the key pluripotency factors Sox2. Two SOX2OT variants, SOX2OT-7 and SOX2OT-8, were upregulated in human cancer cells, and their levels were highly correlated with that of SOX2. In particular, SOX2OT-7 played important role in stemness function as its level was decreased upon neuronal-like differentiation similar to SOX2 and other pluripotency regulator OCT4A (Saghaeian Jazi et al., 2015). In glioma, expression of lncRNA MALAT1 enhanced the expression of SOX2, and neural stem cell marker Nestin. Induction of these pluripotency factors by aberrant MALAT1 expression then promoted the proliferation of glioma cells (Han et al., 2015) ICAM-1 was proved to be a cancer stem cell marker in HCC cells and its expression was regulated by pluripotency regulator Nanog (Liu et al., 2013a). Further study showed that level of ICAM-1 was posttranscriptionally regulated by lncRNA ICAM-1-related RNA (ICR) which was identified in ICAM-1+ CSCs in HCC. ICR expression was also regulated by Nanog, and

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this lncRNA regulated CSC properties and contributed to portal vein tumor thrombus development. ICR functioned to form RNA duplex with ICAM1 mRNA, and subsequently elevated ICAM-1 expression by stabilizing ICAM-1 mRNA which modulated the CSC properties of ICAM-1+ HCC cells. Clinically, ICR was critical in HCC as elevated ICR was correlated poor clinical outcomes (Guo et al., 2015b). In colon cancer, an antisense lncRNA was identified to promote cancer stemness feature through upregulating its sense partner gene HIF-2α. The lncRNA was named promoter upstream transcript of hypoxia inducible factor 2α (lncRNAHIF2PUT), which functioned to enhanced HIF-2α expression in cancer cells. HIF-2α is often implicated in CSCs including glioma (Pietras et al., 2014), ovarian cancer (Nozawa-Suzuki et al., 2015) and colon cancer (Santoyo-Ramos et al., 2014). Inhibition of lncRNA-HIF2PUT could lead to the downregulation of stemness markers SOX2, OCT4, and CD44, and impaired spheroid formation in colon cancer cells (Yao et al., 2015).

4.2 Renewal Self-renewal is a process observed in stem cells by which they undergo cell division to generate more stem cells. During self-renewal, the divided cells are able to maintain the essential stem cell function including pluripotency. The self-renewal program is finely regulated by complex gene networks, and recently the role of lncRNAs in self-renewal is unveiled. The hedgehog signaling controls stem cell renewal during embryonic development (Ingham and McMahon, 2001), and study had shown that hedgehog signal regulated CSC maintenance through the induction of pluripotency regulators such as SOX2 and OCT4 (Clement et al., 2007; Gopinath et al., 2013). It was further shown that hedgehog signaling could induce the expression of lncRNAs to promote cancer stem cell renewal. A study showed that lncRNA-Hh contributed in stem cell renewal property that was regulated by TWIST in breast cancer. Particularly, lncRNA-Hh promoted shh-GLI1 pathway to induce the expression of SOX2 and OCT4 in breast cancer cells, which was critical in TWIST-induced maintenance of mammosphere enrichment and self-renewal capacity as well as in vivo tumorigenicity of breast cancer cells (Zhou et al., 2016). CSCs of HCC are suggested to be the cause of cancer cell heterogeneity and frequent tumor recurrence, and a study identified that lncTCF7 played an important role to mediate HCC CSC renewal and maintenance. LncTCF was able to enhance the expression of SOX2, Nanog, and OCT4. LncTCF7

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functioned to induce TCF7 expression by recruiting SWI/SNF complex to TCF7 promoter for transcription. Both lncTCF7 and TCF7 expression were observed in sphere formation of liver cancer cells, implying their importance in CSCs. Subsequently, TCF7 could activate Wnt signaling in cancer cell, and it was shown that lncTCF7-induced Wnt signaling promoted tumorigenicity of HCC by regulating liver cancer stem cell self-renewal (Wang et al., 2015b). Meanwhile, lncRNA can also act as a negative regulator of self-renewal. In colon cancer, large intergenic noncoding RNA p21 (lincRNA-p21) suppressed the stem cell features in purified CSCs. LincRNA-p21 was capable of inhibiting β-catenin signaling, which subsequently reduced the self-renewal propensity of cancer stem cells (Wang et al., 2015a).

4.3 Transformation of Cancer Stem Cell One of the possibilities of CSC emergence is from the transformation of nonmalignant stem cells. It is demonstrated that lncRNA UCA1 may promote liver stem cell malignant transformation through alteration of gene network by histone tail modification. A study showed that UCA1 inhibited trimethylation of H3K27, a suppressive histone marker, at the promoter of several genes such as Sox17, FOXa2, HNF4α, HGF, and Albumin in hepatocyte-like stem cells. UCA1 also triggered the expression HULC and β-catenin which contributed to the malignant growth hepatocyte-like stem cells (Gui et al., 2015). Overexpression of UCA1 led to the increased binding of UCA1 to cyclin D1. The complex then activated lncRNA H19 transcription through the induction of DNA demethylation. Increased H19 expression would enhance the cell telomerase activity by increasing the binding of TERT to TERC and reducing the interaction between TERT with TERRA, which increased the length of telomere (Pu et al., 2015). UCA1 also regulated another pluripotency regulator c-myc expression. The UCA1-cyclin D1 complex was recruited to c-myc promoter by insulator CTCF, which resulted in the enhancement of c-myc expression (Pu et al., 2015). In addition, UCA1 cooperated with SET1A to trigger malignant transformation of hepatocyte-like stem cell by increasing the proliferation of the cells. UCA1 increased phosphorylation of pRB1, and promoted the interaction between SET1A and pRB1. The complex could then induce the trimethylation of H3K4 on specific gene promoter including TRF2. Subsequently, TRF2 expression was activated that may also played a role in telomere extension (Li et al., 2015c). Telomere length

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extension and c-myc expression were believed to be important in the malignant transformation of hepatocyte-like stem cell. In lung cancer, lncRNA HOTAIR demonstrated critical role in inducing the transformation of cancer stem cell. Cigarette smoke extract could induce the generation of cancer stem cell from human bronchial epithelial cells. It was shown that HOTAIR mediated the transformation process, as depletion of HOTAIR could attenuate spheroid formations, and the percentage of side population enrichment. HOTAIR also induced the expression of OCT4, BMI1, CD133, and CD44 which were important in reprogramming of gene network to acquire cancer stem cell properties (Liu et al., 2015b).

5. INSIGHT OF NOVEL lncRNA ROLES IN CANCER 5.1 Immunity Reports have demonstrated the functional roles of several lncRNAs in modulating human immune system. For examples, CD11c+ dendritic cells expressed lncRNAs when they were stimulated by the activator of TLR4 signaling (Guttman et al., 2009). In CD8+ T cells, hundreds of lncRNA genes were expressed that played roles in cell differentiation or activation (Pang et al., 2009). There is a complex interaction between cancer and immune system. Efficient immunity provides effective tumor cell killing, and tumor may develop mechanisms to resist innate immune response. Various mechanisms are observed such as infiltration of neutrophils or macrophages, inhibition of T cell and NK cell, increased frequency of regulatory T cell, which aim to generate an immunosuppressive environment for tumor. Role of lncRNAs in immunity is also implicated in cancer biology. A report showed that two lncRNAs RP11-284N8.3.1 and AC104699.1.1 that were differentially expressed during the development of ovarian cancer, were predicted to function in immune system activation as well as other antitumor processes in the ovarian microenvironment. They were potentially critical in therapeutic treatment as they showed predictive value to ovarian cancer patients’ survival (Guo et al., 2015a). On the other hand, hyperactive immune response that involves the recruitment of particular immune cells may promote cancer development. Mast cell belongs to part of the immunity system, and is commonly observed in various

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tumors. Recruitment of mast cells occurred in prostate tumor after androgen deprivation therapy, and the mast cells triggered cell invasion via downregulation of androgen receptor signals. It is showed that mast cell silenced the expression of androgen receptor through upregulating the level of lncRNA HOTAIR, resulting in an increased rate of complex formation with histone modifier PRC2 complex, and an enhanced binding of the silencing complex on androgen receptor promoter. Epigenetic silencing of androgen receptor then increased MMP9 expression which subsequently promoted prostate cancer invasion (Li et al., 2015b). Currently, knowledge regarding the association of lncRNA and immunity in cancer is lacking. However, given the documented roles of lncRNA in regulating immune cells differentiation and/or maturation, as well as their functions in remodulating cancer microenvironment, it is possible that lncRNA play a role in cancer immunology.

5.2 Cancer Microenvironment Accumulating evidence showed the environmental factors surrounding the tumor interact with cancer cells dynamically. The tumor microenvironment is remodeled by the cancer cells, tumor-associated stromal cells and infiltrating cells to create condition favorable to cancer progression. Various reports have documented the role of lncRNAs mediating the construction of tumor microenvironment, interaction between the tumor and associated cells, and the malignant signal of the components within the microenvironment. Enrichment of cancer-associated fibroblast at the tumor environment contributed heavily to tumor development. In urinary bladder cancer, cancer-associated fibroblasts could release TGFβ1 to tumor stroma, and induce epithelial-mesenchymal transition of urinary bladder cancer cells by activating TGFβ1 signaling. An lncRNA named ZEB2NAT was identified to mediate the stroma-induced tumor progression. ZEB2NAT was essential for TGFβ1-triggered epithelial-mesenchymal transition, as it is shown that the level of ZEB2NATwas positively correlated with TGFβ1 level in clinical samples. Inhibition of ZEB2NAT attenuated the induction of epithelialmesenchymal transition and cell invasion (Zhuang et al., 2015). In HCC, activated hepatic stellate cells (HSC) could promote liver cancer development, and an lncRNA Alu-mediated p21 transcriptional regulator (APTR) was identified that functioned to activate the HSCs. Depletion of APTR inhibited the activation of HSCs and abrogated TGF-β1-induced upregulation of α-SMA in HSCs. Knockdown of APTR could also inhibit cell

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proliferation and cell cycle in primary HSCs (Yu et al., 2015). On the other hand, activation of HSCs could lead to the downregulation of lncRNA HIF1A antisense RNA 1 (HIF1A-AS1) in the stellate cells. It was shown that loss of HIF1A-AS1 in TGFβ1-induced activation of hepatic stellate cells was attributed by the reduction of TET3 protein. Loss of TET3 induced the increase of α-SMA, and promoted cell growth. Downregulation of HIF1AAS could lead to the increased cell proliferation and reduced apoptotic rate, that was also observed in loss of TET3 (Zhang et al., 2014). Moreover, TGFβ1-induced activation of HSCs also inhibited the expression of lncRNA MEG3. The suppression of MEG3 by TGFβ1 was found to be dose dependent and time dependent. MEG3 played a role in regulating HSC proliferation, as re-expression of MEG3 in HSCs could activate p53 and trigger the release of cytochrome c, and lead to the apoptosis of the HSCs (He et al., 2014). Components constituted within the tumor microenvironment may drive malignant development through mediating lncRNAs. In colon cancer, inflammatory cytokine CCL5 was secreted by infiltrating dendritic cells into the tumor stroma, which stimulated cell migration, invasion, and epithelial-mesenchymal transition in colon cancer cells. It is shown that CCL5 in tumor stroma activated Snail signaling of the cancer cells through the upregulation of lncRNA MALAT1. MALAT1 then induced the expression of Snail which contributed to cell migration and invasion (Kan et al., 2015). In HCC, proinflammatory cytokine interleukin-6 (IL-6) in tumor microenvironment could promote the development of HCC cells. Recently, a novel tumor-inducing mechanism of IL-6 that was mediated by lncRNA was discovered. IL-6 could induce the expression of lncTCF7 by activating transcriptional factor STAT3. Activated STAT3 then bound to the promoter region of lncTCF7. The IL6-lncTCF7 pathway was critical in promoting HCC cell invasion and epithelial-mesenchymal transition (Wu et al., 2015). Type I collagen (Col-1) containing interstitial extracellular matrix, that is aberrantly enriched in the tumor microenvironment, could promote tumor progression through mediating lncRNA expression in cancer cells. The expression of lncRNAs was regulated by the tumor promoting Col-1. In particular, Col-1 could induce the expression of lncRNA HOTAIR via increasing the promoter activity of HOTAIR promoter (Zhuang et al., 2013). Cancer cells also adopted lncRNA-mediated mechanism in modulating tumor microenvironment. Studies illustrated the functional role of lncRNA released to the extracellular matrix. LncRNA H19 was enriched in a

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subpopulation of hepatoma cells that expressed CD90 epitope, and was packaged into hepatoma derived exosomes. H19 was released to the stromal together with the exosomes, and could then modulate endothelial cells through promoting angiogenic phenotype and cell-to-cell adhesion (Conigliaro et al., 2015). Another study demonstrated that the exosomes released by lung cancer cells could inhibit osteogenic and adipogenic differentiation of the mesenchymal stem cells. Mesenchymal stem cells are important component of the tumor environment and are attracted to the tumor sites frequently. It is showed that the differentiation of mesenchymal stem cells could be mediated by the differential changes of lncRNAs induced by lung cancer cells. The exosomes could induce the differential expression of more than 2000 lncRNAs, and it was speculated that the change of lncRNA pattern played a role in regulating mesenchymal stem cell differentiation (Wang et al., 2016).

6. DIAGNOSTIC AND PROGNOSTIC VALUE OF lncRNAS Aberrant expressions of lncRNAs are frequently observed in various cancer types which are associated with tumor initiation, cancer progression and metastasis. As such, the levels of cancer-associated lncRNA have the potential as the biomarkers for cancer diagnosis and outcome prediction. LncRNAs as biomarkers have superiority than mRNAs due to their higher tissue and cellular specificity. For example, lncRNA PCGEM1 is specifically expressed in prostate tissue and prostate cancer (Srikantan et al., 2000). Upregulation of another lncRNA HULC is also specific to cancer derived in liver (Panzitt et al., 2007). Practically, lncRNAs released by tumor cells can be detected in the bodily fluids of the patients such as blood, plasma and urine (Gao et al., 2015; Wang et al., 2006), hence minimally invasive detection of the lncRNAs is possible. LncRNAs with high tissue specificity are good candidate as diagnostic markers. Studies showed that lncRNA Prostate cancer antigen 3 (PCA3) was upregulated in prostate tumor tissues compared to nontumor tissues (Hessels and Schalken, 2009). It is shown that PCA3 expression could only be detected in prostate cancer but not in other cancer types, which highlight its tumor specificity (Bussemakers et al., 1999). The expression level and the specificity of PCA3 for prostate cancer diagnosis were high, and it showed better diagnostic characteristics than the conventional biomarker hTERT (de Kok et al., 2002). Moreover, the detection of PCA3 showed better

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specificity than prostate specific antigen mRNA (Tinzl et al., 2004). For bladder cancer diagnosis, studies showed that lncRNA-UCA1 showed great potential as the diagnostic marker. Its level was high in bladder tumor tissues, and detection of lncRNA-UCA1 could distinguish bladder cancer from other urinary-related diseases (Wang et al., 2006). LncRNA-UCA1 could also be detected in urine, and the level was associated with advanced tumor stage (Srivastava et al., 2014). On the other hand, there are several lncRNAs which include HOTAIR and MALAT1 that are deregulated in multiple cancer types. While their diagnostic potential is limited, studies demonstrated that they showed good prognostic characteristics to predict patient survival, tumor recurrence or cancer relapse. MALAT1 is reported to be overexpressed in lung cancer (Schmidt et al., 2011), colorectal cancer (Zheng et al., 2014), gastric cancer (Wang et al., 2014b), and HCC (Lai et al., 2012). High expression of MALAT1 was significantly correlated to poor patient disease-free survival and overall survival (Zheng et al., 2014). Overexpression of MALAT1 could be a marker to predict tumor recurrence in HCC after liver transplantation (Lai et al., 2012). High expression of HOTAIR can be observed in breast cancer (Gupta et al., 2010), lung cancer (Liu et al., 2013b), pancreatic cancer (Kim et al., 2013), and colorectal cancer (Kogo et al., 2011). High levels of HOTAIR were associated with shorter patient survival in breast cancer (Kogo et al., 2011), and tumor recurrence in HCC after liver transplantation (Yang et al., 2011). The level of HOTAIR is often associated with the metastatic potential of the tumor. A reduction of probability of metastasis free survival was observed in breast cancer with high HOTAIR level (Gupta et al., 2010). Level of HOTAIR also positively associated with liver metastasis in colorectal cancer (Kogo et al., 2011).

7. CONCLUDING REMARKS In this review, we highlighted the association between diverse cancerassociated events and the deregulation of lncRNAs. It is intriguing that there are far broader roles of lncRNAs in mediating cancer development. The alteration of lncRNAs in response to adverse effect suggested that lncRNAs can act as critical driver of carcinogenesis. In addition, the influence of lncRNAs deregulation is not limited to the cancer cells only, but also affect the environmental factors (ie, immunity, tumor microenvironment) which facilitate tumorigenesis. This opens up new avenues for investigating

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any unexplored mechanisms related to cancer development. With the improvement in RNA targeting therapeutics, it is believed that lncRNAbased treatment against cancer is promising provided that the critical lncRNA candidates are identified (Li and Chen, 2013). Currently, only a small proportion of lncRNAs relative to the huge population are studied, and their precise biochemical characteristics, structural features, and molecular functions required in depth investigation. Better understanding on lncRNAs can prompt the rapid progression from lncRNA basic research to translational research on cancer therapeutics and management.

ACKNOWLEDGMENT The work described in this chapter was supported by grants from the Research Grants Council-General Research Fund of Hong Kong Special Administrative Region, China (CUHK462211, CUHK462713, and 14102714), National Natural Science Foundation of China (81101888 and 8142730), Shenzhen Basic Research Program (JC201105201092A) and Direct Grant from CUHK to YC.

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