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Long non-coding RNA in bladder cancer
Journal Pre-proofs Review Long non-coding RNA in bladder cancer Yuepeng Cao, Tian Tian, Weijian Li, Hanzi Xu, Chuanfei Zhan, Xuhong Wu, Chao Wang, Xiaoli Wu, Wanke Wu, Shuyun Zheng, Kaipeng Xie PII: DOI: Reference:
S0009-8981(20)30017-6 https://doi.org/10.1016/j.cca.2020.01.008 CCA 15988
To appear in:
Clinica Chimica Acta
Received Date: Revised Date: Accepted Date:
13 October 2019 7 January 2020 8 January 2020
Please cite this article as: Y. Cao, T. Tian, W. Li, H. Xu, C. Zhan, X. Wu, C. Wang, X. Wu, W. Wu, S. Zheng, K. Xie, Long non-coding RNA in bladder cancer, Clinica Chimica Acta (2020), doi: https://doi.org/10.1016/j.cca. 2020.01.008
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© 2020 Published by Elsevier B.V.
Long non-coding RNA in bladder cancer
Yuepeng Cao1，2†, Tian Tian3 †, Weijian Li4, Hanzi Xu5，Chuanfei Zhan1, Xuhong Wu1, Chao Wang1, Xiaoli Wu2, Wanke Wu2, Shuyun Zheng1* , Kaipeng Xie2* 1
Department of Critical Care Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of
Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China 2
Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing
Medical University, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing, China. 3
Department of Child Health Care, The First Affiliated Hospital of Nanjing Medical
University, Nanjing, China 4
Department of Urology, Drum Tower Hospital, Medical School of Nanjing
University, Institute of Urology, Nanjing University, Nanjing, China 5
Department of Radiotherapy, jiangsu Cancer Hospital, Jiangsu Institute of Cancer
Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
Correspondence Kaipeng Xie, Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing, China. E-mail: [email protected]. Shuyun Zheng, Shuyun Zheng1* Department of Critical Care Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China Email: [email protected] † These authors contributed equally to this work.
Abstract
Bladder cancer (BC) is the ninth most common malignant disease and ranks fourteenth in cancer mortality worldwide. Moreover, among cancers, the incidence and mortality of BC in males increased to the 6th and 9th place, respectively. The overall survival (OS) declines dramatically as the cancer progresses, especially when urothelial cells transition from noninvasive to invasive. It is well known that epithelial cells can acquire invasive properties and a propensity to metastasize through the epithelialto-mesenchymal transition (EMT) process in tumourigenesis and progression. However, the potential molecular mechanisms and key pathways are still unclear. As the sequencing technology advances, long non-coding RNAs (lncRNAs) have been proven to play an important role in regulating biological processes and cellular pathways. Here, we reviewed important lncRNAs, such as H19, UCA1 and MALAT1, that participate in the malignant phenotype of BC and regulate EMT signalling networks in the invasion-metastasis cascade during BC development. We further discuss MALAT1, PCAT-1 and SPRY4-IT1, and also urine and blood exosomal H19 and PTENP as potential noninvasive biomarkers. Moreover, antisense oligonucleotides (ASOs) and a double-stranded DNA plasmid (BC-819) have been designed for use in preclinical cancer models and clinical trials in patients. Therefore, the results of investigations have gradually prompted the utility of lncRNAs. Keywords: Long noncoding RNA; Metastasis; Bladder cancer; EMT
Introduction Bladder cancer (BC) is one of the most frequently diagnosed cancers worldwide, with nearly 430 000 new patients each year [1]. Based on the histological origin, approximately 90% of bladder cancers are urothelial carcinoma [2]. However, unlike other epithelial cancers with a single linear progression, bladder cancer is divided into two subgroups, non-muscleinvasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) [3]. The two are not different just in the depth infiltration but have distinctly different characteristics and outcomes [4]. NMIBC is characterized by a high rate of local recurrence [5, 6]. While NMIBC can be treated by endoscopic resection, 20% of NMIBC patients will progress to muscle-invasive bladder cancer within 5 years [7, 8]. MIBC cases are more likely to have lymphatic and lung metastasis [9]. Moreover, despite undergoing radical surgery, the 5-year survival of MIBC is lower than 50% [10]. Therefore, it is important to identify the molecular features behind progression and early metastasis. In the last decade, research institutions, especially The Cancer Genome Atlas (TCGA), have generated comprehensive panoramic maps of bladder cancer [11]. It is known that more than 90% of the human genome is transcribed, while only 1-2% encodes proteins. The majority of RNA transcripts do not encode proteins and are called noncoding RNAs [12]. LncRNAs are a class of noncoding RNA transcripts that are longer than
200 nucleotides [13]. Although they do not encode proteins, lncRNAs have been suggested to play regulatory roles in biological processes, especially in oncogenesis and progression [14-16]. H19, located on chromosome 1lpl 5.5, was the first not translated gene found in bladder cancer more than two decades ago [17, 18]. At that time, the authors only found a correlation between H19 expression and bladder cancer recurrence, while its biological role in bladder cancer remained unclear [19]. With the development of technology, more lncRNAs have been detected that are differentially expressed in bladder cancer [20, 21]. UCA1 (urothelial carcinoma associated 1) is another landmark lncRNA [22, 23]. Clinical data showed that UCA1 was specific and sensitive in the diagnosis of bladder cancer [21]. Until the first decade of the 21st century, there were few functional studies on lncRNAs in bladder cancer. In recent decades, biological research of lncRNAs in bladder cancer has grown explosively [24-28]. Compared to that in paired adjacent tissues, the expression of BLACAT2, SNHG6, and HOTAIR was increased, while the expression of CASC2a, XIST and NBAT1 was decreased in bladder cancer [29-34]. Taking clinical features into account, LSINCT5, CALML3-AS1 and ZFAS1 were positively correlated with the advanced clinical stage and lymph node distal metastasis [35-37]. The increased expression levels of CALML3-AS1, H19 and SNHG5 were associated with poor prognosis [36, 38, 39]. Moreover, lncRNAs have also been identified to play important
roles in the formation and progression of cancers. For example, increased BLACAT2, SNHG16, and HOTAIR expression promoted cell invasion, migration and metastasis [29, 31, 40] , while decreased CASC2a, XIST and NBAT1 expression was negatively correlated with invasion, migration and metastasis of bladder cancer cells [32, 34, 41]. However, the mechanisms of lncRNAs in the progression and metastasis of bladder cancer remain unknown. Lymphatic metastasis is a significant sign of poor prognosis in bladder cancer [42, 43]. Despite treating MIBC cases with radical cystectomy and pelvic lymph node dissection, more than 50% of patients will eventually develop distant metastasis [44]. Once the cancer becomes metastatic, the 5-year overall survival suddenly drops to 6% [9]. Metastasis is also known as the invasion-metastasis cascade, which consists of sequential and interrelated steps, whereby malignant cells disseminate from the primary tumour to distant organs [45]. One accepted explanation for the invasion and dissemination aspects of metastasis in cancer is EMT. EMT is a specific biological conversion process that contains a series of biochemical changes, such as disrupted intercellular junctions, loss of apical–basal polarity, reorganization of the cytoskeleton, and increased cell motility [46]. Thus, through undergoing the EMT process, epithelial cells acquire increased motility and develop an aggressive phenotype that favours invasion and metastasis [47]. Recently, a growing number of lncRNAs have been found to play regulatory roles in tumour
invasion/metastasis processes through EMT-based mechanisms in bladder cancers [48-52]. A comprehensive genomic analysis of NMIBC and MIBC cases demonstrated large differences in biological processes, including molecular processes, epithelial mesenchymal transition, and outcome [53, 54]. This review summarizes some of the EMT-related lncRNAs involved in bladder cancer and their potential applications in cancer therapy (Table 1). Biological functions of lncRNAs in bladder cancer LncRNAs can be classified into different categories based on their genomic localization, subcellular localization, and function. According to their location in the genome, lncRNAs are classified into five types: sense, antisense, bidirectional, intergenic and intronic lncRNAs. For example, H19, UCA1 and MALAT1 are intergenic lncRNAs [55-57]; BLACAT1, SPRY4-IT1 and lncRNA-LET are intronic lncRNAs [58-60]; and SNHG16 and GAS5 are antisense lncRNAs [40, 61], although a transcript of GAS5 may also be a bidirectional lncRNA [62]. Moreover, according to their subcellular location, lncRNAs are classified as nuclear lncRNAs and cytoplasmic lncRNAs. Both ISH and subcellular fractionation assays suggested that BLACAT2 and LBCS localized in the nuclei of bladder cancer cells [29, 63]. In contrast, ARAP1-AS1 and LSINCT5 were enriched in the cytoplasm of BC cells [35, 64]. Moreover, according to their functions, lncRNAs are classified as signalling, decoy, guide, and
scaffold lncRNAs. For example, LNMAT1 promoted lymphatic metastasis of bladder cancer by recruiting hnRNPL to the CCL2 promoter, which activated CCL2 expression [65]. DBCCR1-003 could bind to DNMT1 and prevent DNMT1-mediated methylation of DBCCR1 in BC. Then, overexpression of DBCCR1-003 led to a significant inhibition of bladder cancer cell growth and apoptosis [66]. SPRY4-IT1 promoted proliferation and metastasis of bladder cancer cells by upregulating EZH2 by sponging miR-101-3p [67]. In addition, regardless of their classifications, lncRNAs can exert their functions at the level of transcription, post-translation and epigenetic regulation. As a regulatory gene, lncRNA can exert a great influence on biological processes, including affecting apoptosis, the cell cycle, cell development and diff erentiation. For instance, Luo et al demonstrated that upregulated H19 increased bladder cancer cell proliferation[68]. GAPLINC was significantly increased in bladder cancer tissues compared with normal tissues. GAPLINC silencing promoted cell cycle arrest at G1 phase and inhibited migration and invasion ability [69]. Similarly, knockdown of SNHG16 also resulted in cell cycle arrest at G1 phase and promoted bladder cancer cell apoptosis [40]. Overexpressed BLACAT2 induced intratumoral/peritumoral lymphangiogenesis and promoted bladder cancer cell invasiveness by binding with WDR5 [29]. Additionally, upregulation of MEG3 not only inhibited cell invasion and
migration but also improved the cisplatin chemosensitivity of bladder cancer cells [70]. Role of lncRNAs in regulating invasion and metastasis in bladder cancer The death rate of bladder cancer patients with lymph node metastasis is markedly increased from 18.6% to 77.6% within 5 years compared to that of patients without lymph node metastasis. Moreover, bladder cancer patients with extranodal lymph node metastasis have an even worse prognosis. Metastasis involves a complex multistep process in cancer progression, whereby cancer cells acquire invasive properties and disseminate to other sites (Figure 1). In the cancer progression process, lncRNAs have been revealed to play crucial regulatory roles in promotion and inhibition. Herein, we discuss lncRNAs with the two opposite effects. 1. LncRNAs promote invasion and metastasis in bladder cancer The lncRNA UCA1 was the first discovered oncogenic lncRNA in bladder cancer [21]. It has been fully demonstrated that upregulation of UCA1 is associated with enhanced invasion and migration [71]. LncRNA H19 is also a well-known imprinted gene and is expressed in many cancers, including bladder cancer. Luo et al suggested that H19 expression levels are significantly upregulated in the most metastasized bladder cancer tissues and invasive cell lines. They also found that H19 increases bladder cancer metastasis by enhancing EZH2 expression and downregulating E-
cadherin [38]. Lv et al. also found that H19 and DNMT3B exhibited higher co-expression in bladder cancer tissues and cells. Moreover, H19 directly binds to miR-29b-3p (miR-29b) and inhibits the expression of its target DNMT3B to exert malignant transformation effects [72]. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression was associated with high tumour stage, advanced histological grade and positive lymph node metastasis [73]. One possible mechanism demonstrates that MALAT1-mediated bladder cancer progression is partly associated with specific suppression of miR-125b and activates target genes through the “MALAT1-miR-125b-Bcl-2/MMP-13” axis [74]. Furthermore, TP73-AS1, SNHG6, BLACAT2 and PVT1 are significantly upregulated in LN-metastatic bladder cancer and play oncogenic roles in bladder cancer progression. 2. LncRNAs inhibit invasion and metastasis in bladder cancer The number of studies on lncRNAs that suppress bladder cancer metastasis is slowly increasing. In general, the expression levels of lncRNAs GAS5, CASC2 CASC2a and LOWEG were negatively correlated with lymph node metastasis and clinical stage. LINC00641 is a novel lncRNA that inhibits bladder cancer cell proliferation, invasion and migration. The authors demonstrated that LINC00641 exerted its inhibitory effects through the miR-197-3p/KLF10/PTEN/PI3K/AKT axis [75]. PTENP1 was located in exosomes from plasma and was significantly reduced in BC
tissues. When BC cells were exposed to exosomal PTENP1, their malignant ability of invasion and migration was reduced through increased cell apoptosis. Exosome–transmitted PTENP1 suppresses the expression of PTEN by binding to microRNA-17 [76]. Similarly, overexpression of GAS5 reduced cell viability and induced cell apoptosis in the bladder by inhibiting EZH2 transcription in bladder cancer cells [62]. However, some lncRNAs, such as XIST and NBAT1, also have opposing effects in bladder cancer progression. Roles of lncRNAs in the regulation of EMT signalling networks in the invasion-metastasis cascade A large numbers of lncRNAs have been suggested to participate in the EMT process [77-79]. Thus, we summarized the signalling pathways of lncRNAs associated with EMT in bladder cancer progression (Figure 2). 1. TGF-β signalling pathway It is well-known that TGF-β signalling is a major signalling pathway in malignant progression [80]. When TGF-β signalling is activated, the expression of EMT-TFs and their downstream factors, including Snail, Slug and Twist, are upregulated. LncRNA-ATB was the first lncRNA found to be activated by TGF-β [81]. LncRNA-ATB promoted cell proliferation, invasion and migration by acting as a sponge of miR-126 [82]. HOTAIR expression level was found to be higher in BC tissues and cell lines [83]. Knockdown of HOTAIR reduced the expression of EMT genes,
including MMP1, SNAI1, TWIST1, ZEB1 and ZO1 in BC cell lines [31]. Furthermore, the authors found that MALAT1 is a vital mediator of TGFβ–induced EMT, involving the TGF-β/malat1/suz12 pathway. Zhuang et al found that cancer-associated fibroblasts secreted TGFβ1, which induced EMT and invasion of BC cells. Then, they revealed that TGFβ1 induced EMT through the TGFβ1-ZEB2NAT-ZEB2 axis [66]. 2. Wnt/β-catenin signalling pathway When the canonical signal of Wnt is activated, the degradation of β-catenin is inhibited, and the expression of EMT-TF genes is triggered after βcatenin enters the nucleus, thereby reducing the expression of E-cadherin [84]. E-cadherin is a critical molecule for epithelial cell-to-cell adhesion and loss of E-cadherin expression is a hallmark of EMT [85]. Many lncRNAs have been identified that participate in regulating the Wnt/βcatenin signalling pathway. The upregulated H19 promotes BC metastasis by associating with zeste homologue 2 (EZH2) and inhibiting E-cadherin expression [38]. Downregulated MALAT-1 levels were associated with reduced ZEB1, ZEB2 and Slug expression. TOPFlash and FOPFlash proved that MALAT-1 promotes BC cell migration by activating Wnt/βcatenin signalling [86]. SNHG16 contributes to the progression of bladder cancer by regulating the miR‐ 98/STAT3/Wnt/β‐ catenin axis [30]. 3. PI3K/Akt signalling pathway Among the pathways regulated by lncRNAs in EMT, the PI3K/Akt
signalling pathway is indispensable. Wang et al suggested that HULC could mediate BC cell proliferation and apoptosis by enhancing the expression of ZIC2 through activation of the PI3K/AKT pathway [87]. LINC00641, a novel tumour suppressor, could inhibit BC cell proliferation, migration and invasion. Mechanistically, LINC00641 could bind with miR-197-3p to enhance KLF10 expression, leading to suppression of the PTEN/PI3K/AKT pathway [75]. Knockdown of DUXAP10 in T24 and 5637 cells had an antitumour effect by interfering with the PI3K/AKT/mTOR signalling pathway [88]. PTEN is a negative regulator of the PI3K/Akt signalling pathway [89]. LncRNA-RP11-79H23.3 increased PTEN expression by sponging hsa-miR-107. Decreased RP1179H23.3 contributed to the progression of BC by activating the PI3K/Akt signalling pathway [90]. 4. Other pathways In addition, lncRNAs can regulate other pathways, including the hypoxia/HIF-1α pathway, NOTCH pathway, JNK pathway and p53 pathway [91-93]. LncRNA-ARAP1-AS1 activates the NOTCH signalling pathway in BC cells by sponging miR-4735-3p [64]. XIST can promote migration and induce EMT by reducing the expression of p53 through binding to TET1 [33]. LncRNAs function as potential biomarkers and gene therapy targets in bladder cancer
1. Potential biomarkers of EMT With the development of sequencing technologies, dysregulation of lncRNA expression has been detected more accurately during every step of the malignant process. Their abundance and stable distribution in tissues, blood and urine make lncRNAs ideal biomarkers. As EMT is a potential process during metastasis, lncRNAs that participate in EMT are valuable for predicting metastasis. For example, GAS6‐ AS2 was shown to be upregulated in BC tissues, and its increased levels were positively correlated with cancer stages [94]. Similarly, serum exosomal H19 and plasma exosomal PTENP1 were suggested as noninvasive biomarkers for BC diagnosis and prognosis [76, 95]. Specifically, the specificity and sensitivity of PTENP1 to predict bladder cancer were 84.2% and 65.4%, respectively. Additionally, for bladder cancer, urine is a natural and suitable sample. RT-PCR of urine sediments indicated that UCA1 was a very sensitive (91.8%, 78 of 85) and specific (80.9%, 76 of 94) unique marker for bladder cancer [21]. MALAT1, PCAT-1 and SPRY4-IT1 in urine exosomes can also serve as potential biomarkers for diagnosis and predict the recurrence of bladder cancer [96]. 2. Potential therapeutic strategies The Cancer Genome Atlas (TCGA) conducted comprehensive integrative molecular analyses of 9,125 tumours from 33 cancer types and charted the major common pathways, including Notch, PI-3-kinase/Akt, RTK-RAS,
TGF signalling, p53 and Wnt/β-catenin [97]. Although the tumour subtypes and original organs are different, some important similar genomic changes have been discovered. The integrated analysis also uncovered three most frequently dysregulated pathways in bladder cancer: p53/cell cycle regulation (89%), RTK/RAS/PI3K signalling (71%), and chromatin remodelling pathways in 52% of cases [98]. Interestingly, these signalling pathways are mostly related to the pathways regulated by lncRNAs, such as HOTAIR, XIST and H19. Given their structure and regulatory function in transcription, lncRNAs may have potential therapeutic applications. At present, some technologies, including antisense oligonucleotides (ASOs), siRNAs and small molecules, have been used to target lncRNAs to inhibit cancer progression and metastasis [99-102]. The most straightforward therapeutic strategy is targeting the RNA sequence directly [103]. The siRNA strategy can lead to intense downregulation of the targeted lncRNA and has recently gained momentum as a treatment modality [104, 105]. However, RNAi cannot be employed to knock down nuclear localized lncRNAs, and in those cases antisense oligonucleotides (ASOs) are a more suitable strategy MALAT1 is localized in many nuclear cancer cells, including bladder, cervical and pancreatic cancer [106, 107]. MALAT-1 ASOs have shown efficacy in a preclinical cancer model [108]. Moreover, BC-819 (DTA-H19) is a double-stranded DNA plasmid that was used to target H19 in bladder cancer cells [109]. The research demonstrates that
bladder cancer can be successfully treated via intravesical instillation of H19-DTA-P4-DTA [110]. The efficacy and toxicity of BC-819 instillations have been tested in a phase 2 clinical trial on 47 patients with recurrent bladder cancer. Patients expressing H19 received a 6-week induction course of BC-819. In all patients, the median time to recurrence was 11.3 months, and the recurrence time was 22.1 months when analysed by response status at 3 months. These results demonstrate that BC-819 could be used as a potential agent for cancers that express H19 [111, 112]. Conclusions In general, great attention has been paid to the role of lncRNAs in the diagnosis, treatment and prognosis of diseases by sequencing techniques. An increasing number of studies on cancers have indicated that lncRNAs may primarily contribute to cancer via their aberrant expression and may be associated with tumour development, progression and tumour metastasis, which can increase cancer-related deaths. In this review, we concentrated on the role of lncRNAs in bladder cancer. We introduced the biological functions of lncRNAs in bladder cancer and how lncRNAs may regulate invasion and metastasis in bladder cancer. In addition, we discussed the roles of lncRNAs in the regulation of EMT signalling networks in the invasion-metastasis cascade and indicated their potential as biomarkers and gene therapy targets in bladder cancer. Abbreviations:
ALML3-AS1: Human calmodulin-like protein3- antisense RNA 1; ARAP1-AS1:
ARAP1
antisense
RNA
1;
ASOs:
Antisense
oligonucleotides; BC: Bladder cancer; BC-819: DTA-H19,which contains diphtheria toxin controlled under the H19 promoter; BLACAT1: Bladder cancer associated transcript 1; BLACAT2: Bladder cancer-associated transcript 2; CALML3-AS1: Calmodulin-like-protein3- antisense RNA 1; CASC2: Cancer susceptibility candidate2; CASC2a: Cancer susceptibility candidate2a; CCL2: Chemokine (C-C motif) ligand 2; DBCCR1-003: Deleted in bladder cancer chromosome region 1; DNA: Deoxyribonucleic acid; DNMT1: DNA methyltransferase 1; DNMT3B: Deoxyribonucleic acid methyltransferases3B; EMT-TF: Epithelial-to-mesenchymal transition inducing transcription factors (EMT-TFs); EZH2: Zeste homolog 2; FOPFlash : The negative control of wnt signaling reporter; GAPLINC: Gastric adenocarcinoma predictive long intergenic noncoding RNA ; GAS5: Growth arrestspecific 5; H19: Long non-coding RNA H19; HOTAIR: HOX transcript antisense intergenic RNA; HOTAIR: HOX Transcript Antisense RNA; HULC: Highly upregulated in liver cancer; LBCS: Low expressed in Bladder Cancer Stem cell; LINC00641: Long intergenic non-coding RNA 641; LncRNAs: Long non-coding RNAs; LncRNA-LET: Long noncoding RNA (lncRNA) low expression in tumor (LET); LSINCT5: Long Stress Induced Non-Coding Transcripts
5;MALAT1: Metastasisassociated lung adenocarcinoma transcript 1; MIBC: Muscle-invasive bladder cancer; MMP1: Matrix metalloproteinase 1; mTOR：Mechanistic target of rapamycin; NBAT1: Neuroblastomaassociated transcript 1; NMIBC：Non-muscle-invasive bladder cancer; OS: overall survival; EMT: epithelial-to-mesenchymal transition; PCAT-1 and SPRY4-IT1: SPRY4 intronic transcript 1; PCAT-1: Prostate cancerassociated transcript 1 ; PI3K/Akt: Phosphatidylinositol 3-kinase-protein kinase B ; PTENP: Phosphatase and tensin homolog deleted on chromosome ten ; PTENP1: Phosphatase and tensin homolog pseudogene 1; PVT1: Plasmacytoma variant translocation 1; RTK-RAS: Receptor tyrosine kinases ; RT-PCR: real-time Polymerase Chain Reaction；siRNA: Small interfering RNA; SNAI1: Zinc finger Snail 1; SNHG16: Small Nucleolar RNA Host Gene 16; SNHG5: Small Nucleolar RNA Host Gene 5; SNHG6: SnoRNA host gene 6; SPRY4-IT1: Sprouty4-Intron 1; T24 and 5637: Bladder cancer cell lines (T24 、 5637); TCGA: The Cancer Genome Atlas; TGF-β: Transforming growth factor-β; TOPFlash: Wnt signaling reporter ; TP73-AS1: P73 antisense RNA 1: TWIST1: Twist basic helix-loop-helix transcription factor 1; WDR5: WD repeat domain 5;urothelial carcinoma associated 1; XIST: X-inactive specific transcript; XIST: X-inactivespecific transcript; ZEB1: Zinc finger E-box binding homeobox 1; ZIC2: Zinc family member 2; ZO1: Zona occludens protein-1; ZFAS1: Zinc
finger antisense 1; Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials Not applicable Competing interests The authors declare that they have no competing interests Funding This research was supported by the National Natural Science Fund of China (81772712, 81702569, 81801413), the Natural Science Foundation of Jiangsu Province (BK20170151)，Nanjing Medical Science and Technique Development Foundation (JQX18009). Authors’ contributions YP C, TT and WJ L wrote the manuscript. HZ X, CF Z, XH W, C W, XL W and WK W provided critical revision.SY Z and KP X Modified the manuscript at last. All authors read and agreed to the final manuscript. Acknowledgements None to declare.
References [1] A.M. Kamat, N.M. Hahn, J.A. Efstathiou, S.P. Lerner, P.-U. Malmström, W. Choi, C.C. Guo, Y. Lotan, W. Kassouf, Bladder cancer, The Lancet 388(10061) (2016) 2796-2810. [2] M.G.K. Cumberbatch, I. Jubber, P.C. Black, F. Esperto, J.D. Figueroa, A.M. Kamat, L. Kiemeney, Y. Lotan, K. Pang, D.T. Silverman, A. Znaor, J.W.F. Catto, Epidemiology of Bladder Cancer: A Systematic Review and Contemporary Update of Risk Factors in 2018, Eur. Urol.
(2018).
[3] R.H. Martinez Rodriguez, O. Buisan Rueda, L. Ibarz, Bladder cancer: Present and future, Med. Clin. (Barc.) 149(10) (2017) 449-455. [4] K. Inamura, Bladder Cancer: New Insights into Its Molecular Pathology, Cancers (Basel) 10(4) (2018). [5] V.T. Packiam, S.C. Johnson, G.D. Steinberg, Non-muscle-invasive bladder cancer: Intravesical treatments beyond Bacille Calmette-Guerin, Cancer 123(3) (2017) 390-400. [6] V. Soukup, O. Capoun, D. Cohen, V. Hernandez, M. Babjuk, M. Burger, E. Comperat, P. Gontero, T. Lam, S. MacLennan, A.H. Mostafid, J. Palou, B.W.G. van Rhijn, M. Roupret, S.F. Shariat, R. Sylvester, Y. Yuan, R. Zigeuner, Prognostic Performance and Reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in Non-muscle-invasive Bladder Cancer: A European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel Systematic Review, Eur. Urol. 72(5) (2017) 801-813. [7] M. Babjuk, Bladder Cancer in the Elderly, Eur. Urol. 73(1) (2018) 51-52. [8] S.L. Woldu, A. Bagrodia, Y. Lotan, Guideline of guidelines: non-muscle-invasive bladder cancer, BJU Int. 119(3) (2017) 371-380. [9] S.A. Funt, J.E. Rosenberg, Systemic, perioperative management of muscle-invasive bladder cancer and future horizons, Nat. Rev. Clin. Oncol. 14(4) (2017) 221-234. [10] M. Abufaraj, G. Dalbagni, S. Daneshmand, S. Horenblas, A.M. Kamat, R. Kanzaki, A.R. Zlotta, S.F. Shariat, The Role of Surgery in Metastatic Bladder Cancer: A Systematic Review, Eur. Urol. 73(4) (2018) 543-557. [11] N. Cancer Genome Atlas Research, J.N. Weinstein, E.A. Collisson, G.B. Mills, K.R. Shaw, B.A. Ozenberger, K. Ellrott, I. Shmulevich, C. Sander, J.M. Stuart, The Cancer Genome Atlas Pan-Cancer analysis project, Nat. Genet. 45(10) (2013) 1113-20. [12] An integrated encyclopedia of DNA elements in the human genome, Nature 489(7414) (2012) 5774. [13] J.S. Mattick, J.L. Rinn, Discovery and annotation of long noncoding RNAs, Nature structural & molecular biology 22(1) (2015) 5-7. [14] L. Yang, H. Wang, Q. Shen, L. Feng, H. Jin, Long non-coding RNAs involved in autophagy regulation, Cell Death Dis. 8(10) (2017) e3073. [15] Q. Huang, J. Yan, R. Agami, Long non-coding RNAs in metastasis, Cancer Metastasis Rev. 37(1) (2018) 75-81. [16] Y. Xie, W. Dang, S. Zhang, W. Yue, L. Yang, X. Zhai, Q. Yan, J. Lu, The role of exosomal noncoding RNAs in cancer, Mol. Cancer 18(1) (2019) 37. [17] B. Tycko, Genomic imprinting: mechanism and role in human pathology, Am. J. Pathol. 144(3) (1994) 431-43. [18] M. Elkin, A. Shevelev, E. Schulze, M. Tykocinsky, M. Cooper, I. Ariel, D. Pode, E. Kopf, N. de Groot, A. Hochberg, The expression of the imprinted H19 and IGF-2 genes in human bladder carcinoma, FEBS Lett. 374(1) (1995) 57-61.
[19] I. Ariel, O. Lustig, T. Schneider, G. Pizov, M. Sappir, N. De-Groot, A. Hochberg, The imprinted H19 gene as a tumor marker in bladder carcinoma, Urology 45(2) (1995) 335-8. [20] M.J. Cooper, M. Fischer, D. Komitowski, A. Shevelev, E. Schulze, I. Ariel, M.L. Tykocinski, S. Miron, J. Ilan, N. de Groot, A. Hochberg, Developmentally imprinted genes as markers for bladder tumor progression, The Journal of urology 155(6) (1996) 2120-7. [21] X.S. Wang, Z. Zhang, H.C. Wang, J.L. Cai, Q.W. Xu, M.Q. Li, Y.C. Chen, X.P. Qian, T.J. Lu, L.Z. Yu, Y. Zhang, D.Q. Xin, Y.Q. Na, W.F. Chen, Rapid identification of UCA1 as a very sensitive and specific unique marker for human bladder carcinoma, Clin. Cancer Res. 12(16) (2006) 4851-8. [22] J. Luo, J. Chen, H. Li, Y. Yang, H. Yun, S. Yang, X. Mao, LncRNA UCA1 promotes the invasion and EMT of bladder cancer cells by regulating the miR-143/HMGB1 pathway, Oncol. Lett. 14(5) (2017) 5556-5562. [23] Y. Wang, W. Chen, C. Yang, W. Wu, S. Wu, X. Qin, X. Li, Long non-coding RNA UCA1a(CUDR) promotes proliferation and tumorigenesis of bladder cancer, Int. J. Oncol. 41(1) (2012) 276-84. [24] L.J. Li, J.L. Zhu, W.S. Bao, D.K. Chen, W.W. Huang, Z.L. Weng, Long noncoding RNA GHET1 promotes the development of bladder cancer, Int. J. Clin. Exp. Pathol. 7(10) (2014) 7196-205. [25] J. Tan, K. Qiu, M. Li, Y. Liang, Double-negative feedback loop between long non-coding RNA TUG1 and miR-145 promotes epithelial to mesenchymal transition and radioresistance in human bladder cancer cells, FEBS Lett. 589(20 Pt B) (2015) 3175-81. [26] T. Ye, W. Ding, N. Wang, H. Huang, Y. Pan, A. Wei, Long noncoding RNA linc00346 promotes the malignant phenotypes of bladder cancer, Biochem. Biophys. Res. Commun. 491(1) (2017) 79-84. [27] D. Yu, C. Zhang, J. Gui, RNA-binding protein HuR promotes bladder cancer progression by competitively binding to the long noncoding HOTAIR with miR-1, Onco Targets Ther. 10 (2017) 26092619. [28] F. Zhu, X. Zhang, Q. Yu, G. Han, F. Diao, C. Wu, Y. Zhang, LncRNA AWPPH inhibits SMAD4 via EZH2 to regulate bladder cancer progression, J. Cell. Biochem. 119(6) (2018) 4496-4505. [29] W. He, G. Zhong, N. Jiang, B. Wang, X. Fan, C. Chen, X. Chen, J. Huang, T. Lin, Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis, The Journal of clinical investigation 128(2) (2018) 861-875. [30] F. Feng, A. Chen, J. Huang, Q. Xia, Y. Chen, X. Jin, Long noncoding RNA SNHG16 contributes to the development of bladder cancer via regulating miR-98/STAT3/Wnt/beta-catenin pathway axis, J. Cell. Biochem. 119(11) (2018) 9408-9418. [31] C. Berrondo, J. Flax, V. Kucherov, A. Siebert, T. Osinski, A. Rosenberg, C. Fucile, S. Richheimer, C.J. Beckham, Expression of the Long Non-Coding RNA HOTAIR Correlates with Disease Progression in Bladder Cancer and Is Contained in Bladder Cancer Patient Urinary Exosomes, PloS one 11(1) (2016) e0147236. [32] Z. Li, K.-E. Wang, X.-L. Zhou, J. Zhou, C.-H. Ye, Long Non-Coding RNA Cancer Susceptibility Candidate 2a (CASC2a) Is a Marker of Early Recurrence After Radical Cystectomy in Patients with Urothelial Carcinoma of the Bladder, Med. Sci. Monit. 24 (2018) 438-447. [33] B. Hu, G. Shi, Q. Li, W. Li, H. Zhou, Long noncoding RNA XIST participates in bladder cancer by downregulating p53 via binding to TET1, J. Cell. Biochem.
(2018).
[34] Z. Liu, D. Xie, H. Zhang, Long noncoding RNA neuroblastoma-associated transcript 1 gene inhibits malignant cellular phenotypes of bladder cancer through miR-21/SOCS6 axis, Cell Death Dis. 9(10) (2018) 1042. [35] X. Zhu, Y. Li, S. Zhao, S. Zhao, LSINCT5 activates Wnt/beta-catenin signaling by interacting with NCYM to promote bladder cancer progression, Biochem. Biophys. Res. Commun. 502(3) (2018) 299-306.
[36] F. Wang, Y. Zu, W. Huang, H. Chen, H. Xie, Y. Yang, LncRNA CALML3-AS1 promotes tumorigenesis of bladder cancer via regulating ZBTB2 by suppression of microRNA-4316, Biochem. Biophys. Res. Commun. 504(1) (2018) 171-176. [37] J.S. Wang, Q.H. Liu, X.H. Cheng, W.Y. Zhang, Y.C. Jin, The long noncoding RNA ZFAS1 facilitates bladder cancer tumorigenesis by sponging miR-329, Biomed. Pharmacother. 103 (2018) 174-181. [38] M. Luo, Z. Li, W. Wang, Y. Zeng, Z. Liu, J. Qiu, Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression, Cancer Lett. 333(2) (2013) 213-21. [39] Z. Ma, S. Xue, B. Zeng, D. Qiu, lncRNA SNHG5 is associated with poor prognosis of bladder cancer and promotes bladder cancer cell proliferation through targeting p27, Oncol. Lett. 15(2) (2018) 19241930. [40] X. Cao, J. Xu, D. Yue, LncRNA-SNHG16 predicts poor prognosis and promotes tumor proliferation through epigenetically silencing p21 in bladder cancer, Cancer Gene Ther. 25(1-2) (2018) 10-17. [41] R. Xu, X. Zhu, F. Chen, C. Huang, K. Ai, H. Wu, L. Zhang, X. Zhao, LncRNA XIST/miR-200c regulates the stemness properties and tumourigenicity of human bladder cancer stem cell-like cells, Cancer cell international 18 (2018) 41. [42] A. Siefker-Radtke, B. Curti, Immunotherapy in metastatic urothelial carcinoma: focus on immune checkpoint inhibition, Nature reviews. Urology 15(2) (2018) 112-124. [43] C. Chen, Y. Luo, W. He, Y. Zhao, Y. Kong, H. Liu, G. Zhong, Y. Li, J. Li, J. Huang, R. Chen, T. Lin, Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer, The Journal of clinical investigation
(2019).
[44] F.A. Yafi, A.G. Aprikian, J.L. Chin, Y. Fradet, J. Izawa, E. Estey, A. Fairey, R. Rendon, I. Cagiannos, L. Lacombe, J.B. Lattouf, D. Bell, D. Drachenberg, W. Kassouf, Contemporary outcomes of 2287 patients with bladder cancer who were treated with radical cystectomy: a Canadian multicentre experience, BJU Int. 108(4) (2011) 539-45. [45] J.E. Talmadge, I.J. Fidler, AACR centennial series: the biology of cancer metastasis: historical perspective, Cancer research 70(14) (2010) 5649-69. [46] T.T. Liao, M.H. Yang, Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness, Mol. Oncol. 11(7) (2017) 792-804. [47] B. De Craene, G. Berx, Regulatory networks defining EMT during cancer initiation and progression, Nature reviews. Cancer 13(2) (2013) 97-110. [48] S. Grelet, L.A. Link, B. Howley, C. Obellianne, V. Palanisamy, V.K. Gangaraju, J.A. Diehl, P.H. Howe, A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression, Nat. Cell Biol. 19(9) (2017) 1105-1115. [49] R. Mitra, X. Chen, E.J. Greenawalt, U. Maulik, W. Jiang, Z. Zhao, C.M. Eischen, Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition, Nat Commun 8(1) (2017) 1604. [50] Z. Fu, C. Chen, Q. Zhou, Y. Wang, Y. Zhao, X. Zhao, W. Li, S. Zheng, H. Ye, L. Wang, Z. He, Q. Lin, Z. Li, R. Chen, LncRNA HOTTIP modulates cancer stem cell properties in human pancreatic cancer by regulating HOXA9, Cancer Lett. 410 (2017) 68-81. [51] X. Yan, D. Zhang, W. Wu, S. Wu, J. Qian, Y. Hao, F. Yan, P. Zhu, J. Wu, G. Huang, Y. Huang, J. Luo, X. Liu, B. Liu, X. Chen, Y. Du, R. Chen, Z. Fan, Mesenchymal Stem Cells Promote Hepatocarcinogenesis via lncRNA-MUF Interaction with ANXA2 and miR-34a, Cancer research 77(23) (2017) 6704-6716. [52] Z. Tuo, J. Zhang, W. Xue, LncRNA TP73-AS1 predicts the prognosis of bladder cancer patients and functions as a suppressor for bladder cancer by EMT pathway, Biochem. Biophys. Res. Commun. 499(4)
(2018) 875-881. [53] J. Hedegaard, P. Lamy, I. Nordentoft, F. Algaba, S. Hoyer, B.P. Ulhoi, S. Vang, T. Reinert, G.G. Hermann, K. Mogensen, M.B.H. Thomsen, M.M. Nielsen, M. Marquez, U. Segersten, M. Aine, M. Hoglund, K. Birkenkamp-Demtroder, N. Fristrup, M. Borre, A. Hartmann, R. Stohr, S. Wach, B. Keck, A.K. Seitz, R. Nawroth, T. Maurer, C. Tulic, T. Simic, K. Junker, M. Horstmann, N. Harving, A.C. Petersen, M.L. Calle, E.W. Steyerberg, W. Beukers, K.E.M. van Kessel, J.B. Jensen, J.S. Pedersen, P.U. Malmstrom, N. Malats, F.X. Real, E.C. Zwarthoff, T.F. Orntoft, L. Dyrskjot, Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma, Cancer Cell 30(1) (2016) 27-42. [54] A.G. Robertson, J. Kim, H. Al-Ahmadie, J. Bellmunt, G. Guo, A.D. Cherniack, T. Hinoue, P.W. Laird, K.A. Hoadley, R. Akbani, M.A.A. Castro, E.A. Gibb, R.S. Kanchi, D.A. Gordenin, S.A. Shukla, F. SanchezVega, D.E. Hansel, B.A. Czerniak, V.E. Reuter, X. Su, B. de Sa Carvalho, V.S. Chagas, K.L. Mungall, S. Sadeghi, C.S. Pedamallu, Y. Lu, L.J. Klimczak, J. Zhang, C. Choo, A.I. Ojesina, S. Bullman, K.M. Leraas, T.M. Lichtenberg, C.J. Wu, N. Schultz, G. Getz, M. Meyerson, G.B. Mills, D.J. McConkey, J.N. Weinstein, D.J. Kwiatkowski, S.P. Lerner, Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer, Cell 171(3) (2017) 540-556.e25. [55] I. Ariel, M. Sughayer, Y. Fellig, G. Pizov, S. Ayesh, D. Podeh, B.A. Libdeh, C. Levy, T. Birman, M.L. Tykocinski, N. de Groot, A. Hochberg, The imprinted H19 gene is a marker of early recurrence in human bladder carcinoma, Mol. Pathol. 53(6) (2000) 320-3. [56] M. Xue, W. Chen, A. Xiang, R. Wang, H. Chen, J. Pan, H. Pang, H. An, X. Wang, H. Hou, X. Li, Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNAUCA1, Mol. Cancer 16(1) (2017) 143. [57] D. Jiao, Z. Li, M. Zhu, Y. Wang, G. Wu, X. Han, LncRNA MALAT1 promotes tumor growth and metastasis by targeting miR-124/foxq1 in bladder transitional cell carcinoma (BTCC), Am. J. Cancer Res. 8(4) (2018) 748-760. [58] W. He, Q. Cai, F. Sun, G. Zhong, P. Wang, H. Liu, J. Luo, H. Yu, J. Huang, T. Lin, linc-UBC1 physically associates with polycomb repressive complex 2 (PRC2) and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer, Biochim. Biophys. Acta 1832(10) (2013) 1528-37. [59] X.L. Zhao, Z.H. Zhao, W.C. Xu, J.Q. Hou, X.Y. Du, Increased expression of SPRY4-IT1 predicts poor prognosis and promotes tumor growth and metastasis in bladder cancer, Int. J. Clin. Exp. Pathol. 8(2) (2015) 1954-60. [60] J. Zhuang, L. Shen, L. Yang, X. Huang, Q. Lu, Y. Cui, X. Zheng, X. Zhao, D. Zhang, R. Huang, H. Guo, J. Yan, TGFbeta1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer, Theranostics 7(12) (2017) 3053-3067. [61] M. Avgeris, A. Tsilimantou, P.K. Levis, T. Tokas, D.C. Sideris, K. Stravodimos, A. Ardavanis, A. Scorilas, Loss of GAS5 tumour suppressor lncRNA: an independent molecular cancer biomarker for short-term relapse and progression in bladder cancer patients, Br. J. Cancer 119(12) (2018) 1477-1486. [62] M. Wang, C. Guo, L. Wang, G. Luo, C. Huang, Y. Li, D. Liu, F. Zeng, G. Jiang, X. Xiao, Long noncoding RNA GAS5 promotes bladder cancer cells apoptosis through inhibiting EZH2 transcription, Cell Death Dis. 9(2) (2018) 238. [63] X. Chen, R. Xie, P. Gu, M. Huang, J. Han, W. Dong, W. Xie, B. Wang, W. He, G. Zhong, Z. Chen, J. Huang, T. Lin, Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2, Clin. Cancer Res.
(2018).
[64] J. Teng, X. Ai, Z. Jia, K. Wang, Y. Guan, Y. Guo, Long non-coding RNA ARAP1-AS1 promotes the progression of bladder cancer by regulating miR-4735-3p/NOTCH2 axis, Cancer Biol. Ther.
(2018) 1-10.
[65] C. Chen, W. He, J. Huang, B. Wang, H. Li, Q. Cai, F. Su, J. Bi, H. Liu, B. Zhang, N. Jiang, G. Zhong, Y. Zhao, W. Dong, T. Lin, LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment, Nat Commun 9(1) (2018) 3826. [66] J. Zhuang, Q. Lu, B. Shen, X. Huang, L. Shen, X. Zheng, R. Huang, J. Yan, H. Guo, TGFbeta1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT, Sci. Rep. 5 (2015) 11924. [67] D. Liu, Y. Li, G. Luo, X. Xiao, D. Tao, X. Wu, M. Wang, C. Huang, L. Wang, F. Zeng, LncRNA SPRY4-IT1 sponges miR-101-3p to promote proliferation and metastasis of bladder cancer cells through upregulating EZH2, Cancer Lett. 388 (2017) 281-291. [68] M. Luo, Z. Li, W. Wang, Y. Zeng, Z. Liu, J. Qiu, Upregulated H19 contributes to bladder cancer cell proliferation by regulating ID2 expression, The FEBS journal 280(7) (2013) 1709-16. [69] Z. Zheng, D. Zhu, F. Zhao, J. Han, H. Chen, Y. Cai, W. Xie, Upregulated GAPLINC predicts a poor prognosis in bladder cancer patients and promotes tumor proliferation and invasion, Oncol. Lett. 15(5) (2018) 6770-6776. [70] S.Q. Feng, X.Y. Zhang, H.T. Fan, Q.J. Sun, M. Zhang, Up-regulation of LncRNA MEG3 inhibits cell migration and invasion and enhances cisplatin chemosensitivity in bladder cancer cells, Neoplasma 65(6) (2018) 925-932. [71] M. Xue, H. Pang, X. Li, H. Li, J. Pan, W. Chen, Long non-coding RNA urothelial cancer-associated 1 promotes bladder cancer cell migration and invasion by way of the hsa-miR-145-ZEB1/2-FSCN1 pathway, Cancer Sci. 107(1) (2016) 18-27. [72] M. Lv, Z. Zhong, M. Huang, Q. Tian, R. Jiang, J. Chen, lncRNA H19 regulates epithelial-mesenchymal transition and metastasis of bladder cancer by miR-29b-3p as competing endogenous RNA, Biochim Biophys Acta Mol Cell Res 1864(10) (2017) 1887-1899. [73] C. Li, Y. Cui, L.F. Liu, W.B. Ren, Q.Q. Li, X. Zhou, Y.L. Li, Y. Li, X.Y. Bai, X.B. Zu, High Expression of Long Noncoding RNA MALAT1 Indicates a Poor Prognosis and Promotes Clinical Progression and Metastasis in Bladder Cancer, Clin. Genitourin. Cancer 15(5) (2017) 570-576. [74] H. Xie, X. Liao, Z. Chen, Y. Fang, A. He, Y. Zhong, Q. Gao, H. Xiao, J. Li, W. Huang, Y. Liu, LncRNA MALAT1 Inhibits Apoptosis and Promotes Invasion by Antagonizing miR-125b in Bladder Cancer Cells, J. Cancer 8(18) (2017) 3803-3811. [75] Z. Li, S. Hong, Z. Liu, LncRNA LINC00641 predicts prognosis and inhibits bladder cancer progression through miR-197-3p/KLF10/PTEN/PI3K/AKT cascade, Biochem. Biophys. Res. Commun. 503(3) (2018) 1825-1829. [76] R. Zheng, M. Du, X. Wang, W. Xu, J. Liang, W. Wang, Q. Lv, C. Qin, H. Chu, M. Wang, L. Yuan, J. Qian, Z. Zhang, Exosome-transmitted long non-coding RNA PTENP1 suppresses bladder cancer progression, Mol. Cancer 17(1) (2018) 143. [77] Z. Qin, Y. Wang, J. Tang, L. Zhang, R. Li, J. Xue, P. Han, W. Wang, C. Qin, Q. Xing, J. Yang, W. Zhang, High LINC01605 expression predicts poor prognosis and promotes tumor progression via up-regulation of MMP9 in bladder cancer, Biosci. Rep. 38(5) (2018). [78] H. Yang, G. Li, B. Cheng, R. Jiang, ZFAS1 functions as an oncogenic long non-coding RNA in bladder cancer, Biosci. Rep. 38(3) (2018). [79] C. Wang, W. Tao, S. Ni, Q. Chen, Upregulation of lncRNA snoRNA host gene 6 regulates NUAK family SnF1-like kinase-1 expression by competitively binding microRNA-125b and interacting with Snail1/2 in bladder cancer, J. Cell. Biochem. 120(1) (2019) 357-367. [80] D. Brunen, S.M. Willems, U. Kellner, R. Midgley, I. Simon, R. Bernards, TGF-beta: an emerging player
in drug resistance, Cell cycle (Georgetown, Tex.) 12(18) (2013) 2960-8. [81] A. Moustakas, C.H. Heldin, Mechanisms of TGFbeta-Induced Epithelial-Mesenchymal Transition, Journal of clinical medicine 5(7) (2016). [82] X. Zhai, W. Xu, Long Noncoding RNA ATB Promotes Proliferation, Migration, and Invasion in Bladder Cancer by Suppressing MicroRNA-126, Oncol. Res. 26(7) (2018) 1063-1072. [83] Y. Fan, B. Shen, M. Tan, X. Mu, Y. Qin, F. Zhang, Y. Liu, TGF-beta-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12, Clin. Cancer Res. 20(6) (2014) 1531-41. [84] T. Valenta, G. Hausmann, K. Basler, The many faces and functions of beta-catenin, EMBO J. 31(12) (2012) 2714-36. [85] Y. Li, W.P. Hively, H.E. Varmus, Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer, Oncogene 19(8) (2000) 1002-9. [86] L. Ying, Q. Chen, Y. Wang, Z. Zhou, Y. Huang, F. Qiu, Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition, Mol Biosyst 8(9) (2012) 228994. [87] J. Wang, W. Ma, Y. Liu, Long non-coding RNA HULC promotes bladder cancer cells proliferation but inhibits apoptosis via regulation of ZIC2 and PI3K/AKT signaling pathway, Cancer Biomark. 20(4) (2017) 425-434. [88] X.Y. Lv, L. Ma, J.F. Chen, R. Yu, Y. Li, Z.J. Yan, Y. Cheng, Q. Ma, Knockdown of DUXAP10 inhibits proliferation and promotes apoptosis in bladder cancer cells via PI3K/Akt/mTOR signaling pathway, Int. J. Oncol. 52(1) (2018) 288-294. [89] M.S. Lee, M.H. Jeong, H.W. Lee, H.J. Han, A. Ko, S.M. Hewitt, J.H. Kim, K.H. Chun, J.Y. Chung, C. Lee, H. Cho, J. Song, PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis, Nat Commun 6 (2015) 7769. [90] H. Chi, R. Yang, X. Zheng, L. Zhang, R. Jiang, J. Chen, LncRNA RP11-79H23.3 Functions as a Competing Endogenous RNA to Regulate PTEN Expression through Sponging hsa-miR-107 in the Development of Bladder Cancer, Int J Mol Sci 19(9) (2018). [91] T. Liang, Y. Wang, Y. Wang, Y. Wang, Long noncoding RNA PEG10 facilitates bladder cancer cells proliferation, migration, and invasion via repressing microRNA-29b, J. Cell. Physiol. 234(11) (2019) 19740-19749. [92] R. Gao, N. Zhang, J. Yang, Y. Zhu, Z. Zhang, J. Wang, X. Xu, Z. Li, X. Liu, Z. Li, J. Li, C. Kong, J. Bi, Long non-coding RNA ZEB1-AS1 regulates miR-200b/FSCN1 signaling and enhances migration and invasion induced by TGF-beta1 in bladder cancer cells, J. Exp. Clin. Cancer Res. 38(1) (2019) 111. [93] Z. Tian, S. Cao, C. Li, M. Xu, H. Wei, H. Yang, Q. Sun, Q. Ren, L. Zhang, LncRNA PVT1 regulates growth, migration, and invasion of bladder cancer by miR-31/ CDK1, J. Cell. Physiol. 234(4) (2019) 4799-4811. [94] X. Rui, L. Wang, H. Pan, T. Gu, S. Shao, J. Leng, LncRNA GAS6-AS2 promotes bladder cancer proliferation and metastasis via GAS6-AS2/miR-298/CDK9 axis, J. Cell. Mol. Med.
(2018).
[95] J. Wang, K. Yang, W. Yuan, Z. Gao, Determination of Serum Exosomal H19 as a Noninvasive Biomarker for Bladder Cancer Diagnosis and Prognosis, Med. Sci. Monit. 24 (2018) 9307-9316. [96] Y. Zhan, L. Du, L. Wang, X. Jiang, S. Zhang, J. Li, K. Yan, W. Duan, Y. Zhao, L. Wang, Y. Wang, C. Wang, Expression signatures of exosomal long non-coding RNAs in urine serve as novel non-invasive biomarkers for diagnosis and recurrence prediction of bladder cancer, Mol. Cancer 17(1) (2018) 142. [97] F. Sanchez-Vega, M. Mina, J. Armenia, W.K. Chatila, A. Luna, K.C. La, S. Dimitriadoy, D.L. Liu, H.S. Kantheti, S. Saghafinia, D. Chakravarty, F. Daian, Q. Gao, M.H. Bailey, W.W. Liang, S.M. Foltz, I. Shmulevich, L. Ding, Z. Heins, A. Ochoa, B. Gross, J. Gao, H. Zhang, R. Kundra, C. Kandoth, I. Bahceci, L. Dervishi, U.
Dogrusoz, W. Zhou, H. Shen, P.W. Laird, G.P. Way, C.S. Greene, H. Liang, Y. Xiao, C. Wang, A. Iavarone, A.H. Berger, T.G. Bivona, A.J. Lazar, G.D. Hammer, T. Giordano, L.N. Kwong, G. McArthur, C. Huang, A.D. Tward, M.J. Frederick, F. McCormick, M. Meyerson, E.M. Van Allen, A.D. Cherniack, G. Ciriello, C. Sander, N. Schultz, Oncogenic Signaling Pathways in The Cancer Genome Atlas, Cell 173(2) (2018) 321-337.e10. [98] S. Maeda, H. Tomiyasu, M. Tsuboi, A. Inoue, G. Ishihara, T. Uchikai, J.K. Chambers, K. Uchida, T. Yonezawa, N. Matsuki, Comprehensive gene expression analysis of canine invasive urothelial bladder carcinoma by RNA-Seq, BMC Cancer 18(1) (2018) 472. [99] S.W. Young, M. Stenzel, J.L. Yang, Nanoparticle-siRNA: A potential cancer therapy?, Crit. Rev. Oncol. Hematol. 98 (2016) 159-69. [100] R. Kole, A.R. Krainer, S. Altman, RNA therapeutics: beyond RNA interference and antisense oligonucleotides, Nat Rev Drug Discov 11(2) (2012) 125-40. [101] H. Ling, M. Fabbri, G.A. Calin, MicroRNAs and other non-coding RNAs as targets for anticancer drug development, Nat Rev Drug Discov 12(11) (2013) 847-65. [102] O. Slaby, R. Laga, O. Sedlacek, Therapeutic targeting of non-coding RNAs in cancer, Biochem. J. 474(24) (2017) 4219-4251. [103] L. Chen, E.E. Dzakah, G. Shan, Targetable long non-coding RNAs in cancer treatments, Cancer Lett. 418 (2018) 119-124. [104] J.M. Lee, T.J. Yoon, Y.S. Cho, Recent developments in nanoparticle-based siRNA delivery for cancer therapy, Biomed Res Int 2013 (2013) 782041. [105] T. Coelho, D. Adams, A. Silva, P. Lozeron, P.N. Hawkins, T. Mant, J. Perez, J. Chiesa, S. Warrington, E. Tranter, M. Munisamy, R. Falzone, J. Harrop, J. Cehelsky, B.R. Bettencourt, M. Geissler, J.S. Butler, A. Sehgal, R.E. Meyers, Q. Chen, T. Borland, R.M. Hutabarat, V.A. Clausen, R. Alvarez, K. Fitzgerald, C. Gamba-Vitalo, S.V. Nochur, A.K. Vaishnaw, D.W. Sah, J.A. Gollob, O.B. Suhr, Safety and efficacy of RNAi therapy for transthyretin amyloidosis, N. Engl. J. Med. 369(9) (2013) 819-29. [106] V. Tripathi, Z. Shen, A. Chakraborty, S. Giri, S.M. Freier, X. Wu, Y. Zhang, M. Gorospe, S.G. Prasanth, A. Lal, K.V. Prasanth, Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB, PLoS genetics 9(3) (2013) e1003368. [107] L. Li, H. Chen, Y. Gao, Y.W. Wang, G.Q. Zhang, S.H. Pan, L. Ji, R. Kong, G. Wang, Y.H. Jia, X.W. Bai, B. Sun, Long Noncoding RNA MALAT1 Promotes Aggressive Pancreatic Cancer Proliferation and Metastasis via the Stimulation of Autophagy, Mol. Cancer Ther. 15(9) (2016) 2232-43. [108] G. Arun, S. Diermeier, M. Akerman, K.C. Chang, J.E. Wilkinson, S. Hearn, Y. Kim, A.R. MacLeod, A.R. Krainer, L. Norton, E. Brogi, M. Egeblad, D.L. Spector, Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss, Genes & development 30(1) (2016) 34-51. [109] A. Mizrahi, A. Czerniak, T. Levy, S. Amiur, J. Gallula, I. Matouk, R. Abu-lail, V. Sorin, T. Birman, N. de Groot, A. Hochberg, P. Ohana, Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences, J. Transl. Med. 7 (2009) 69. [110] D. Amit, A. Hochberg, Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences, J. Transl. Med. 8 (2010) 134. [111] A.A. Sidi, P. Ohana, S. Benjamin, M. Shalev, J.H. Ransom, D. Lamm, A. Hochberg, I. Leibovitch, Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette-Guerin, The Journal of urology 180(6) (2008) 2379-83. [112] O. Lavie, D. Edelman, T. Levy, A. Fishman, A. Hubert, Y. Segev, E. Raveh, M. Gilon, A. Hochberg, A
phase 1/2a, dose-escalation, safety, pharmacokinetic, and preliminary efficacy study of intraperitoneal administration of BC-819 (H19-DTA) in subjects with recurrent ovarian/peritoneal cancer, Arch. Gynecol. Obstet. 295(3) (2017) 751-761.
Fig.1 Role of EMT in bladder cancer progression and metastasis. When EMT process was activated, epithelial cells loss cell–cell adhesion, gaining enhanced ability of moving and invading. Then tumor cells break through the four layers of the bladder and invade surrounding tissues in turn. It may continue to invade distant tissue, just like bone and lung, through the blood vessels or lymphatics.
Figure.2 The potential signaling networks of EMT regulated by lncRNAs in metastasis. LncRNAs SNHG16, LSINCT5, HULC, DUXCAP10, TUG1, ZEB2NAT and MALAT1were participated in the EMT process. These lncRNAs take part in the TGF-β signaling pathway, Wnt/β signaling pathway, and PI3K/Akt signaling pathway. Abbreviations EMT: epithelial-to-mesenchymal transition; SNHG16: Small Nucleolar RNA Host Gene 16; LSINCT5: Long Stress Induced Non-Coding Transcripts 5; HULC: Highly upregulated in liver cancer; DUXCAP10:, TUG1: Taurine upregulated gene 1; ZEB2NAT: zinc finger E-box binding homeobox 2 antisense RNA 1;MALAT1: Metastasis associated lung adenocarcinoma transcript 1.
1. The overall survival (OS) declined dramatically as the bladder cancer progressed, especially urothelial cells changes from noninvasive to invasive. 2. Long non-coding RNAs (lncRNAs) has been proved to play a more important part in regulating biological processes and cellular pathways. 3. LncRNAs might be used as the potential noninvasive biomarkers, diagnostic methods and prospective therapies in the near future.
Table(s)
Table 1 LncRNAs involved in EMT and the progression of bladder cancer Study year LncRNA
Study
Sample
Expressio Correlatio Other clinical n changes n with characteristic Prognosis
2019 LNMAT2
Chen
266 pairs
up
positive
-
poor
2019 GAS6‐AS2Rui
TCGA database up
positive
clinical stage poor
2019 PVT1
Tian
35 pairs
up
-
-
-
2019 PEG10
Liang
-
up
-
histological grade, histological grade histological grade,
-
2019 ZEB1-AS1 Gao
60 BC ,23 normal tissues positive
2018 LNMAT1
266 pairs
Chen
up
positive
poor poor
2018 LINC01605Qin
TCGA database up
-
2018 MALAT1
56 pairs
up
positive
2018 GAPLINC Zheng
80 pairs
up
-
2018 ZFAS1
Wang
172 pairs up
-
2018 ZFAS1
Yang
102 BC ,20 up normal tissues positive
2018 LSINCT5
Zhu
108 pairs
up
-
poor clinical stage, muscularis no correlation tumour size, clinical stage poor
2018 H19
Luo
48 pairs
up
positive
clinical stage poor
2018 LINC00641Li
39 pairs
down
negative
-
poor
2018 ATB
Zhai
-
up
-
-
2018 CASC2a
Li
112 pairs
down
negative
histological grade,
2018 XIST
Xu
-
up
positive
-
-
2018 ARAP1-AS1Teng
88 pairs
up
positive
-
poor
2018 PTENP1
Zheng
50 BC，60 down normal tissues, 20 pairs clinical grade，advanced stage positive -
2018 NBAT1
Liu
76 pairs
down
positive
histological grade -
2018 SNHG6
Wang
24 pairs
up
-
-
-
2018 XIST
Hu
-
up
-
-
-
positive
histological grade poorand TNM stage
Jiao
clinical stage poor histological grade poor
2018 TP73-AS1 Tuo
128 pairs down
2018 AWPPH
20 Ta-T1 BC up , 20 T2-T4 - BC, 20 normal clinicaltissues stage
Zhu
2018 CALML3-AS1 Wang
55 pairs
up
2018 MEG3
21 pairs
down
positive
-
2018 RP11-79H23.3 Chi
30 pairs
down
negative
clinical stage
2018 SNHG16
26 pairs
up
-
-
Feng
Feng
poor
-
clinical stage poor
S0009-8981(20)30017-6 https://doi.org/10.1016/j.cca.2020.01.008 CCA 15988
To appear in:
Clinica Chimica Acta
Received Date: Revised Date: Accepted Date:
13 October 2019 7 January 2020 8 January 2020
Please cite this article as: Y. Cao, T. Tian, W. Li, H. Xu, C. Zhan, X. Wu, C. Wang, X. Wu, W. Wu, S. Zheng, K. Xie, Long non-coding RNA in bladder cancer, Clinica Chimica Acta (2020), doi: https://doi.org/10.1016/j.cca. 2020.01.008
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© 2020 Published by Elsevier B.V.
Long non-coding RNA in bladder cancer
Yuepeng Cao1，2†, Tian Tian3 †, Weijian Li4, Hanzi Xu5，Chuanfei Zhan1, Xuhong Wu1, Chao Wang1, Xiaoli Wu2, Wanke Wu2, Shuyun Zheng1* , Kaipeng Xie2* 1
Department of Critical Care Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of
Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China 2
Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing
Medical University, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing, China. 3
Department of Child Health Care, The First Affiliated Hospital of Nanjing Medical
University, Nanjing, China 4
Department of Urology, Drum Tower Hospital, Medical School of Nanjing
University, Institute of Urology, Nanjing University, Nanjing, China 5
Department of Radiotherapy, jiangsu Cancer Hospital, Jiangsu Institute of Cancer
Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
Correspondence Kaipeng Xie, Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing, China. E-mail: [email protected]. Shuyun Zheng, Shuyun Zheng1* Department of Critical Care Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China Email: [email protected] † These authors contributed equally to this work.
Abstract
Bladder cancer (BC) is the ninth most common malignant disease and ranks fourteenth in cancer mortality worldwide. Moreover, among cancers, the incidence and mortality of BC in males increased to the 6th and 9th place, respectively. The overall survival (OS) declines dramatically as the cancer progresses, especially when urothelial cells transition from noninvasive to invasive. It is well known that epithelial cells can acquire invasive properties and a propensity to metastasize through the epithelialto-mesenchymal transition (EMT) process in tumourigenesis and progression. However, the potential molecular mechanisms and key pathways are still unclear. As the sequencing technology advances, long non-coding RNAs (lncRNAs) have been proven to play an important role in regulating biological processes and cellular pathways. Here, we reviewed important lncRNAs, such as H19, UCA1 and MALAT1, that participate in the malignant phenotype of BC and regulate EMT signalling networks in the invasion-metastasis cascade during BC development. We further discuss MALAT1, PCAT-1 and SPRY4-IT1, and also urine and blood exosomal H19 and PTENP as potential noninvasive biomarkers. Moreover, antisense oligonucleotides (ASOs) and a double-stranded DNA plasmid (BC-819) have been designed for use in preclinical cancer models and clinical trials in patients. Therefore, the results of investigations have gradually prompted the utility of lncRNAs. Keywords: Long noncoding RNA; Metastasis; Bladder cancer; EMT
Introduction Bladder cancer (BC) is one of the most frequently diagnosed cancers worldwide, with nearly 430 000 new patients each year [1]. Based on the histological origin, approximately 90% of bladder cancers are urothelial carcinoma [2]. However, unlike other epithelial cancers with a single linear progression, bladder cancer is divided into two subgroups, non-muscleinvasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) [3]. The two are not different just in the depth infiltration but have distinctly different characteristics and outcomes [4]. NMIBC is characterized by a high rate of local recurrence [5, 6]. While NMIBC can be treated by endoscopic resection, 20% of NMIBC patients will progress to muscle-invasive bladder cancer within 5 years [7, 8]. MIBC cases are more likely to have lymphatic and lung metastasis [9]. Moreover, despite undergoing radical surgery, the 5-year survival of MIBC is lower than 50% [10]. Therefore, it is important to identify the molecular features behind progression and early metastasis. In the last decade, research institutions, especially The Cancer Genome Atlas (TCGA), have generated comprehensive panoramic maps of bladder cancer [11]. It is known that more than 90% of the human genome is transcribed, while only 1-2% encodes proteins. The majority of RNA transcripts do not encode proteins and are called noncoding RNAs [12]. LncRNAs are a class of noncoding RNA transcripts that are longer than
200 nucleotides [13]. Although they do not encode proteins, lncRNAs have been suggested to play regulatory roles in biological processes, especially in oncogenesis and progression [14-16]. H19, located on chromosome 1lpl 5.5, was the first not translated gene found in bladder cancer more than two decades ago [17, 18]. At that time, the authors only found a correlation between H19 expression and bladder cancer recurrence, while its biological role in bladder cancer remained unclear [19]. With the development of technology, more lncRNAs have been detected that are differentially expressed in bladder cancer [20, 21]. UCA1 (urothelial carcinoma associated 1) is another landmark lncRNA [22, 23]. Clinical data showed that UCA1 was specific and sensitive in the diagnosis of bladder cancer [21]. Until the first decade of the 21st century, there were few functional studies on lncRNAs in bladder cancer. In recent decades, biological research of lncRNAs in bladder cancer has grown explosively [24-28]. Compared to that in paired adjacent tissues, the expression of BLACAT2, SNHG6, and HOTAIR was increased, while the expression of CASC2a, XIST and NBAT1 was decreased in bladder cancer [29-34]. Taking clinical features into account, LSINCT5, CALML3-AS1 and ZFAS1 were positively correlated with the advanced clinical stage and lymph node distal metastasis [35-37]. The increased expression levels of CALML3-AS1, H19 and SNHG5 were associated with poor prognosis [36, 38, 39]. Moreover, lncRNAs have also been identified to play important
roles in the formation and progression of cancers. For example, increased BLACAT2, SNHG16, and HOTAIR expression promoted cell invasion, migration and metastasis [29, 31, 40] , while decreased CASC2a, XIST and NBAT1 expression was negatively correlated with invasion, migration and metastasis of bladder cancer cells [32, 34, 41]. However, the mechanisms of lncRNAs in the progression and metastasis of bladder cancer remain unknown. Lymphatic metastasis is a significant sign of poor prognosis in bladder cancer [42, 43]. Despite treating MIBC cases with radical cystectomy and pelvic lymph node dissection, more than 50% of patients will eventually develop distant metastasis [44]. Once the cancer becomes metastatic, the 5-year overall survival suddenly drops to 6% [9]. Metastasis is also known as the invasion-metastasis cascade, which consists of sequential and interrelated steps, whereby malignant cells disseminate from the primary tumour to distant organs [45]. One accepted explanation for the invasion and dissemination aspects of metastasis in cancer is EMT. EMT is a specific biological conversion process that contains a series of biochemical changes, such as disrupted intercellular junctions, loss of apical–basal polarity, reorganization of the cytoskeleton, and increased cell motility [46]. Thus, through undergoing the EMT process, epithelial cells acquire increased motility and develop an aggressive phenotype that favours invasion and metastasis [47]. Recently, a growing number of lncRNAs have been found to play regulatory roles in tumour
invasion/metastasis processes through EMT-based mechanisms in bladder cancers [48-52]. A comprehensive genomic analysis of NMIBC and MIBC cases demonstrated large differences in biological processes, including molecular processes, epithelial mesenchymal transition, and outcome [53, 54]. This review summarizes some of the EMT-related lncRNAs involved in bladder cancer and their potential applications in cancer therapy (Table 1). Biological functions of lncRNAs in bladder cancer LncRNAs can be classified into different categories based on their genomic localization, subcellular localization, and function. According to their location in the genome, lncRNAs are classified into five types: sense, antisense, bidirectional, intergenic and intronic lncRNAs. For example, H19, UCA1 and MALAT1 are intergenic lncRNAs [55-57]; BLACAT1, SPRY4-IT1 and lncRNA-LET are intronic lncRNAs [58-60]; and SNHG16 and GAS5 are antisense lncRNAs [40, 61], although a transcript of GAS5 may also be a bidirectional lncRNA [62]. Moreover, according to their subcellular location, lncRNAs are classified as nuclear lncRNAs and cytoplasmic lncRNAs. Both ISH and subcellular fractionation assays suggested that BLACAT2 and LBCS localized in the nuclei of bladder cancer cells [29, 63]. In contrast, ARAP1-AS1 and LSINCT5 were enriched in the cytoplasm of BC cells [35, 64]. Moreover, according to their functions, lncRNAs are classified as signalling, decoy, guide, and
scaffold lncRNAs. For example, LNMAT1 promoted lymphatic metastasis of bladder cancer by recruiting hnRNPL to the CCL2 promoter, which activated CCL2 expression [65]. DBCCR1-003 could bind to DNMT1 and prevent DNMT1-mediated methylation of DBCCR1 in BC. Then, overexpression of DBCCR1-003 led to a significant inhibition of bladder cancer cell growth and apoptosis [66]. SPRY4-IT1 promoted proliferation and metastasis of bladder cancer cells by upregulating EZH2 by sponging miR-101-3p [67]. In addition, regardless of their classifications, lncRNAs can exert their functions at the level of transcription, post-translation and epigenetic regulation. As a regulatory gene, lncRNA can exert a great influence on biological processes, including affecting apoptosis, the cell cycle, cell development and diff erentiation. For instance, Luo et al demonstrated that upregulated H19 increased bladder cancer cell proliferation[68]. GAPLINC was significantly increased in bladder cancer tissues compared with normal tissues. GAPLINC silencing promoted cell cycle arrest at G1 phase and inhibited migration and invasion ability [69]. Similarly, knockdown of SNHG16 also resulted in cell cycle arrest at G1 phase and promoted bladder cancer cell apoptosis [40]. Overexpressed BLACAT2 induced intratumoral/peritumoral lymphangiogenesis and promoted bladder cancer cell invasiveness by binding with WDR5 [29]. Additionally, upregulation of MEG3 not only inhibited cell invasion and
migration but also improved the cisplatin chemosensitivity of bladder cancer cells [70]. Role of lncRNAs in regulating invasion and metastasis in bladder cancer The death rate of bladder cancer patients with lymph node metastasis is markedly increased from 18.6% to 77.6% within 5 years compared to that of patients without lymph node metastasis. Moreover, bladder cancer patients with extranodal lymph node metastasis have an even worse prognosis. Metastasis involves a complex multistep process in cancer progression, whereby cancer cells acquire invasive properties and disseminate to other sites (Figure 1). In the cancer progression process, lncRNAs have been revealed to play crucial regulatory roles in promotion and inhibition. Herein, we discuss lncRNAs with the two opposite effects. 1. LncRNAs promote invasion and metastasis in bladder cancer The lncRNA UCA1 was the first discovered oncogenic lncRNA in bladder cancer [21]. It has been fully demonstrated that upregulation of UCA1 is associated with enhanced invasion and migration [71]. LncRNA H19 is also a well-known imprinted gene and is expressed in many cancers, including bladder cancer. Luo et al suggested that H19 expression levels are significantly upregulated in the most metastasized bladder cancer tissues and invasive cell lines. They also found that H19 increases bladder cancer metastasis by enhancing EZH2 expression and downregulating E-
cadherin [38]. Lv et al. also found that H19 and DNMT3B exhibited higher co-expression in bladder cancer tissues and cells. Moreover, H19 directly binds to miR-29b-3p (miR-29b) and inhibits the expression of its target DNMT3B to exert malignant transformation effects [72]. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression was associated with high tumour stage, advanced histological grade and positive lymph node metastasis [73]. One possible mechanism demonstrates that MALAT1-mediated bladder cancer progression is partly associated with specific suppression of miR-125b and activates target genes through the “MALAT1-miR-125b-Bcl-2/MMP-13” axis [74]. Furthermore, TP73-AS1, SNHG6, BLACAT2 and PVT1 are significantly upregulated in LN-metastatic bladder cancer and play oncogenic roles in bladder cancer progression. 2. LncRNAs inhibit invasion and metastasis in bladder cancer The number of studies on lncRNAs that suppress bladder cancer metastasis is slowly increasing. In general, the expression levels of lncRNAs GAS5, CASC2 CASC2a and LOWEG were negatively correlated with lymph node metastasis and clinical stage. LINC00641 is a novel lncRNA that inhibits bladder cancer cell proliferation, invasion and migration. The authors demonstrated that LINC00641 exerted its inhibitory effects through the miR-197-3p/KLF10/PTEN/PI3K/AKT axis [75]. PTENP1 was located in exosomes from plasma and was significantly reduced in BC
tissues. When BC cells were exposed to exosomal PTENP1, their malignant ability of invasion and migration was reduced through increased cell apoptosis. Exosome–transmitted PTENP1 suppresses the expression of PTEN by binding to microRNA-17 [76]. Similarly, overexpression of GAS5 reduced cell viability and induced cell apoptosis in the bladder by inhibiting EZH2 transcription in bladder cancer cells [62]. However, some lncRNAs, such as XIST and NBAT1, also have opposing effects in bladder cancer progression. Roles of lncRNAs in the regulation of EMT signalling networks in the invasion-metastasis cascade A large numbers of lncRNAs have been suggested to participate in the EMT process [77-79]. Thus, we summarized the signalling pathways of lncRNAs associated with EMT in bladder cancer progression (Figure 2). 1. TGF-β signalling pathway It is well-known that TGF-β signalling is a major signalling pathway in malignant progression [80]. When TGF-β signalling is activated, the expression of EMT-TFs and their downstream factors, including Snail, Slug and Twist, are upregulated. LncRNA-ATB was the first lncRNA found to be activated by TGF-β [81]. LncRNA-ATB promoted cell proliferation, invasion and migration by acting as a sponge of miR-126 [82]. HOTAIR expression level was found to be higher in BC tissues and cell lines [83]. Knockdown of HOTAIR reduced the expression of EMT genes,
including MMP1, SNAI1, TWIST1, ZEB1 and ZO1 in BC cell lines [31]. Furthermore, the authors found that MALAT1 is a vital mediator of TGFβ–induced EMT, involving the TGF-β/malat1/suz12 pathway. Zhuang et al found that cancer-associated fibroblasts secreted TGFβ1, which induced EMT and invasion of BC cells. Then, they revealed that TGFβ1 induced EMT through the TGFβ1-ZEB2NAT-ZEB2 axis [66]. 2. Wnt/β-catenin signalling pathway When the canonical signal of Wnt is activated, the degradation of β-catenin is inhibited, and the expression of EMT-TF genes is triggered after βcatenin enters the nucleus, thereby reducing the expression of E-cadherin [84]. E-cadherin is a critical molecule for epithelial cell-to-cell adhesion and loss of E-cadherin expression is a hallmark of EMT [85]. Many lncRNAs have been identified that participate in regulating the Wnt/βcatenin signalling pathway. The upregulated H19 promotes BC metastasis by associating with zeste homologue 2 (EZH2) and inhibiting E-cadherin expression [38]. Downregulated MALAT-1 levels were associated with reduced ZEB1, ZEB2 and Slug expression. TOPFlash and FOPFlash proved that MALAT-1 promotes BC cell migration by activating Wnt/βcatenin signalling [86]. SNHG16 contributes to the progression of bladder cancer by regulating the miR‐ 98/STAT3/Wnt/β‐ catenin axis [30]. 3. PI3K/Akt signalling pathway Among the pathways regulated by lncRNAs in EMT, the PI3K/Akt
signalling pathway is indispensable. Wang et al suggested that HULC could mediate BC cell proliferation and apoptosis by enhancing the expression of ZIC2 through activation of the PI3K/AKT pathway [87]. LINC00641, a novel tumour suppressor, could inhibit BC cell proliferation, migration and invasion. Mechanistically, LINC00641 could bind with miR-197-3p to enhance KLF10 expression, leading to suppression of the PTEN/PI3K/AKT pathway [75]. Knockdown of DUXAP10 in T24 and 5637 cells had an antitumour effect by interfering with the PI3K/AKT/mTOR signalling pathway [88]. PTEN is a negative regulator of the PI3K/Akt signalling pathway [89]. LncRNA-RP11-79H23.3 increased PTEN expression by sponging hsa-miR-107. Decreased RP1179H23.3 contributed to the progression of BC by activating the PI3K/Akt signalling pathway [90]. 4. Other pathways In addition, lncRNAs can regulate other pathways, including the hypoxia/HIF-1α pathway, NOTCH pathway, JNK pathway and p53 pathway [91-93]. LncRNA-ARAP1-AS1 activates the NOTCH signalling pathway in BC cells by sponging miR-4735-3p [64]. XIST can promote migration and induce EMT by reducing the expression of p53 through binding to TET1 [33]. LncRNAs function as potential biomarkers and gene therapy targets in bladder cancer
1. Potential biomarkers of EMT With the development of sequencing technologies, dysregulation of lncRNA expression has been detected more accurately during every step of the malignant process. Their abundance and stable distribution in tissues, blood and urine make lncRNAs ideal biomarkers. As EMT is a potential process during metastasis, lncRNAs that participate in EMT are valuable for predicting metastasis. For example, GAS6‐ AS2 was shown to be upregulated in BC tissues, and its increased levels were positively correlated with cancer stages [94]. Similarly, serum exosomal H19 and plasma exosomal PTENP1 were suggested as noninvasive biomarkers for BC diagnosis and prognosis [76, 95]. Specifically, the specificity and sensitivity of PTENP1 to predict bladder cancer were 84.2% and 65.4%, respectively. Additionally, for bladder cancer, urine is a natural and suitable sample. RT-PCR of urine sediments indicated that UCA1 was a very sensitive (91.8%, 78 of 85) and specific (80.9%, 76 of 94) unique marker for bladder cancer [21]. MALAT1, PCAT-1 and SPRY4-IT1 in urine exosomes can also serve as potential biomarkers for diagnosis and predict the recurrence of bladder cancer [96]. 2. Potential therapeutic strategies The Cancer Genome Atlas (TCGA) conducted comprehensive integrative molecular analyses of 9,125 tumours from 33 cancer types and charted the major common pathways, including Notch, PI-3-kinase/Akt, RTK-RAS,
TGF signalling, p53 and Wnt/β-catenin [97]. Although the tumour subtypes and original organs are different, some important similar genomic changes have been discovered. The integrated analysis also uncovered three most frequently dysregulated pathways in bladder cancer: p53/cell cycle regulation (89%), RTK/RAS/PI3K signalling (71%), and chromatin remodelling pathways in 52% of cases [98]. Interestingly, these signalling pathways are mostly related to the pathways regulated by lncRNAs, such as HOTAIR, XIST and H19. Given their structure and regulatory function in transcription, lncRNAs may have potential therapeutic applications. At present, some technologies, including antisense oligonucleotides (ASOs), siRNAs and small molecules, have been used to target lncRNAs to inhibit cancer progression and metastasis [99-102]. The most straightforward therapeutic strategy is targeting the RNA sequence directly [103]. The siRNA strategy can lead to intense downregulation of the targeted lncRNA and has recently gained momentum as a treatment modality [104, 105]. However, RNAi cannot be employed to knock down nuclear localized lncRNAs, and in those cases antisense oligonucleotides (ASOs) are a more suitable strategy MALAT1 is localized in many nuclear cancer cells, including bladder, cervical and pancreatic cancer [106, 107]. MALAT-1 ASOs have shown efficacy in a preclinical cancer model [108]. Moreover, BC-819 (DTA-H19) is a double-stranded DNA plasmid that was used to target H19 in bladder cancer cells [109]. The research demonstrates that
bladder cancer can be successfully treated via intravesical instillation of H19-DTA-P4-DTA [110]. The efficacy and toxicity of BC-819 instillations have been tested in a phase 2 clinical trial on 47 patients with recurrent bladder cancer. Patients expressing H19 received a 6-week induction course of BC-819. In all patients, the median time to recurrence was 11.3 months, and the recurrence time was 22.1 months when analysed by response status at 3 months. These results demonstrate that BC-819 could be used as a potential agent for cancers that express H19 [111, 112]. Conclusions In general, great attention has been paid to the role of lncRNAs in the diagnosis, treatment and prognosis of diseases by sequencing techniques. An increasing number of studies on cancers have indicated that lncRNAs may primarily contribute to cancer via their aberrant expression and may be associated with tumour development, progression and tumour metastasis, which can increase cancer-related deaths. In this review, we concentrated on the role of lncRNAs in bladder cancer. We introduced the biological functions of lncRNAs in bladder cancer and how lncRNAs may regulate invasion and metastasis in bladder cancer. In addition, we discussed the roles of lncRNAs in the regulation of EMT signalling networks in the invasion-metastasis cascade and indicated their potential as biomarkers and gene therapy targets in bladder cancer. Abbreviations:
ALML3-AS1: Human calmodulin-like protein3- antisense RNA 1; ARAP1-AS1:
ARAP1
antisense
RNA
1;
ASOs:
Antisense
oligonucleotides; BC: Bladder cancer; BC-819: DTA-H19,which contains diphtheria toxin controlled under the H19 promoter; BLACAT1: Bladder cancer associated transcript 1; BLACAT2: Bladder cancer-associated transcript 2; CALML3-AS1: Calmodulin-like-protein3- antisense RNA 1; CASC2: Cancer susceptibility candidate2; CASC2a: Cancer susceptibility candidate2a; CCL2: Chemokine (C-C motif) ligand 2; DBCCR1-003: Deleted in bladder cancer chromosome region 1; DNA: Deoxyribonucleic acid; DNMT1: DNA methyltransferase 1; DNMT3B: Deoxyribonucleic acid methyltransferases3B; EMT-TF: Epithelial-to-mesenchymal transition inducing transcription factors (EMT-TFs); EZH2: Zeste homolog 2; FOPFlash : The negative control of wnt signaling reporter; GAPLINC: Gastric adenocarcinoma predictive long intergenic noncoding RNA ; GAS5: Growth arrestspecific 5; H19: Long non-coding RNA H19; HOTAIR: HOX transcript antisense intergenic RNA; HOTAIR: HOX Transcript Antisense RNA; HULC: Highly upregulated in liver cancer; LBCS: Low expressed in Bladder Cancer Stem cell; LINC00641: Long intergenic non-coding RNA 641; LncRNAs: Long non-coding RNAs; LncRNA-LET: Long noncoding RNA (lncRNA) low expression in tumor (LET); LSINCT5: Long Stress Induced Non-Coding Transcripts
5;MALAT1: Metastasisassociated lung adenocarcinoma transcript 1; MIBC: Muscle-invasive bladder cancer; MMP1: Matrix metalloproteinase 1; mTOR：Mechanistic target of rapamycin; NBAT1: Neuroblastomaassociated transcript 1; NMIBC：Non-muscle-invasive bladder cancer; OS: overall survival; EMT: epithelial-to-mesenchymal transition; PCAT-1 and SPRY4-IT1: SPRY4 intronic transcript 1; PCAT-1: Prostate cancerassociated transcript 1 ; PI3K/Akt: Phosphatidylinositol 3-kinase-protein kinase B ; PTENP: Phosphatase and tensin homolog deleted on chromosome ten ; PTENP1: Phosphatase and tensin homolog pseudogene 1; PVT1: Plasmacytoma variant translocation 1; RTK-RAS: Receptor tyrosine kinases ; RT-PCR: real-time Polymerase Chain Reaction；siRNA: Small interfering RNA; SNAI1: Zinc finger Snail 1; SNHG16: Small Nucleolar RNA Host Gene 16; SNHG5: Small Nucleolar RNA Host Gene 5; SNHG6: SnoRNA host gene 6; SPRY4-IT1: Sprouty4-Intron 1; T24 and 5637: Bladder cancer cell lines (T24 、 5637); TCGA: The Cancer Genome Atlas; TGF-β: Transforming growth factor-β; TOPFlash: Wnt signaling reporter ; TP73-AS1: P73 antisense RNA 1: TWIST1: Twist basic helix-loop-helix transcription factor 1; WDR5: WD repeat domain 5;urothelial carcinoma associated 1; XIST: X-inactive specific transcript; XIST: X-inactivespecific transcript; ZEB1: Zinc finger E-box binding homeobox 1; ZIC2: Zinc family member 2; ZO1: Zona occludens protein-1; ZFAS1: Zinc
finger antisense 1; Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials Not applicable Competing interests The authors declare that they have no competing interests Funding This research was supported by the National Natural Science Fund of China (81772712, 81702569, 81801413), the Natural Science Foundation of Jiangsu Province (BK20170151)，Nanjing Medical Science and Technique Development Foundation (JQX18009). Authors’ contributions YP C, TT and WJ L wrote the manuscript. HZ X, CF Z, XH W, C W, XL W and WK W provided critical revision.SY Z and KP X Modified the manuscript at last. All authors read and agreed to the final manuscript. Acknowledgements None to declare.
References [1] A.M. Kamat, N.M. Hahn, J.A. Efstathiou, S.P. Lerner, P.-U. Malmström, W. Choi, C.C. Guo, Y. Lotan, W. Kassouf, Bladder cancer, The Lancet 388(10061) (2016) 2796-2810. [2] M.G.K. Cumberbatch, I. Jubber, P.C. Black, F. Esperto, J.D. Figueroa, A.M. Kamat, L. Kiemeney, Y. Lotan, K. Pang, D.T. Silverman, A. Znaor, J.W.F. Catto, Epidemiology of Bladder Cancer: A Systematic Review and Contemporary Update of Risk Factors in 2018, Eur. Urol.
(2018).
[3] R.H. Martinez Rodriguez, O. Buisan Rueda, L. Ibarz, Bladder cancer: Present and future, Med. Clin. (Barc.) 149(10) (2017) 449-455. [4] K. Inamura, Bladder Cancer: New Insights into Its Molecular Pathology, Cancers (Basel) 10(4) (2018). [5] V.T. Packiam, S.C. Johnson, G.D. Steinberg, Non-muscle-invasive bladder cancer: Intravesical treatments beyond Bacille Calmette-Guerin, Cancer 123(3) (2017) 390-400. [6] V. Soukup, O. Capoun, D. Cohen, V. Hernandez, M. Babjuk, M. Burger, E. Comperat, P. Gontero, T. Lam, S. MacLennan, A.H. Mostafid, J. Palou, B.W.G. van Rhijn, M. Roupret, S.F. Shariat, R. Sylvester, Y. Yuan, R. Zigeuner, Prognostic Performance and Reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in Non-muscle-invasive Bladder Cancer: A European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel Systematic Review, Eur. Urol. 72(5) (2017) 801-813. [7] M. Babjuk, Bladder Cancer in the Elderly, Eur. Urol. 73(1) (2018) 51-52. [8] S.L. Woldu, A. Bagrodia, Y. Lotan, Guideline of guidelines: non-muscle-invasive bladder cancer, BJU Int. 119(3) (2017) 371-380. [9] S.A. Funt, J.E. Rosenberg, Systemic, perioperative management of muscle-invasive bladder cancer and future horizons, Nat. Rev. Clin. Oncol. 14(4) (2017) 221-234. [10] M. Abufaraj, G. Dalbagni, S. Daneshmand, S. Horenblas, A.M. Kamat, R. Kanzaki, A.R. Zlotta, S.F. Shariat, The Role of Surgery in Metastatic Bladder Cancer: A Systematic Review, Eur. Urol. 73(4) (2018) 543-557. [11] N. Cancer Genome Atlas Research, J.N. Weinstein, E.A. Collisson, G.B. Mills, K.R. Shaw, B.A. Ozenberger, K. Ellrott, I. Shmulevich, C. Sander, J.M. Stuart, The Cancer Genome Atlas Pan-Cancer analysis project, Nat. Genet. 45(10) (2013) 1113-20. [12] An integrated encyclopedia of DNA elements in the human genome, Nature 489(7414) (2012) 5774. [13] J.S. Mattick, J.L. Rinn, Discovery and annotation of long noncoding RNAs, Nature structural & molecular biology 22(1) (2015) 5-7. [14] L. Yang, H. Wang, Q. Shen, L. Feng, H. Jin, Long non-coding RNAs involved in autophagy regulation, Cell Death Dis. 8(10) (2017) e3073. [15] Q. Huang, J. Yan, R. Agami, Long non-coding RNAs in metastasis, Cancer Metastasis Rev. 37(1) (2018) 75-81. [16] Y. Xie, W. Dang, S. Zhang, W. Yue, L. Yang, X. Zhai, Q. Yan, J. Lu, The role of exosomal noncoding RNAs in cancer, Mol. Cancer 18(1) (2019) 37. [17] B. Tycko, Genomic imprinting: mechanism and role in human pathology, Am. J. Pathol. 144(3) (1994) 431-43. [18] M. Elkin, A. Shevelev, E. Schulze, M. Tykocinsky, M. Cooper, I. Ariel, D. Pode, E. Kopf, N. de Groot, A. Hochberg, The expression of the imprinted H19 and IGF-2 genes in human bladder carcinoma, FEBS Lett. 374(1) (1995) 57-61.
[19] I. Ariel, O. Lustig, T. Schneider, G. Pizov, M. Sappir, N. De-Groot, A. Hochberg, The imprinted H19 gene as a tumor marker in bladder carcinoma, Urology 45(2) (1995) 335-8. [20] M.J. Cooper, M. Fischer, D. Komitowski, A. Shevelev, E. Schulze, I. Ariel, M.L. Tykocinski, S. Miron, J. Ilan, N. de Groot, A. Hochberg, Developmentally imprinted genes as markers for bladder tumor progression, The Journal of urology 155(6) (1996) 2120-7. [21] X.S. Wang, Z. Zhang, H.C. Wang, J.L. Cai, Q.W. Xu, M.Q. Li, Y.C. Chen, X.P. Qian, T.J. Lu, L.Z. Yu, Y. Zhang, D.Q. Xin, Y.Q. Na, W.F. Chen, Rapid identification of UCA1 as a very sensitive and specific unique marker for human bladder carcinoma, Clin. Cancer Res. 12(16) (2006) 4851-8. [22] J. Luo, J. Chen, H. Li, Y. Yang, H. Yun, S. Yang, X. Mao, LncRNA UCA1 promotes the invasion and EMT of bladder cancer cells by regulating the miR-143/HMGB1 pathway, Oncol. Lett. 14(5) (2017) 5556-5562. [23] Y. Wang, W. Chen, C. Yang, W. Wu, S. Wu, X. Qin, X. Li, Long non-coding RNA UCA1a(CUDR) promotes proliferation and tumorigenesis of bladder cancer, Int. J. Oncol. 41(1) (2012) 276-84. [24] L.J. Li, J.L. Zhu, W.S. Bao, D.K. Chen, W.W. Huang, Z.L. Weng, Long noncoding RNA GHET1 promotes the development of bladder cancer, Int. J. Clin. Exp. Pathol. 7(10) (2014) 7196-205. [25] J. Tan, K. Qiu, M. Li, Y. Liang, Double-negative feedback loop between long non-coding RNA TUG1 and miR-145 promotes epithelial to mesenchymal transition and radioresistance in human bladder cancer cells, FEBS Lett. 589(20 Pt B) (2015) 3175-81. [26] T. Ye, W. Ding, N. Wang, H. Huang, Y. Pan, A. Wei, Long noncoding RNA linc00346 promotes the malignant phenotypes of bladder cancer, Biochem. Biophys. Res. Commun. 491(1) (2017) 79-84. [27] D. Yu, C. Zhang, J. Gui, RNA-binding protein HuR promotes bladder cancer progression by competitively binding to the long noncoding HOTAIR with miR-1, Onco Targets Ther. 10 (2017) 26092619. [28] F. Zhu, X. Zhang, Q. Yu, G. Han, F. Diao, C. Wu, Y. Zhang, LncRNA AWPPH inhibits SMAD4 via EZH2 to regulate bladder cancer progression, J. Cell. Biochem. 119(6) (2018) 4496-4505. [29] W. He, G. Zhong, N. Jiang, B. Wang, X. Fan, C. Chen, X. Chen, J. Huang, T. Lin, Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis, The Journal of clinical investigation 128(2) (2018) 861-875. [30] F. Feng, A. Chen, J. Huang, Q. Xia, Y. Chen, X. Jin, Long noncoding RNA SNHG16 contributes to the development of bladder cancer via regulating miR-98/STAT3/Wnt/beta-catenin pathway axis, J. Cell. Biochem. 119(11) (2018) 9408-9418. [31] C. Berrondo, J. Flax, V. Kucherov, A. Siebert, T. Osinski, A. Rosenberg, C. Fucile, S. Richheimer, C.J. Beckham, Expression of the Long Non-Coding RNA HOTAIR Correlates with Disease Progression in Bladder Cancer and Is Contained in Bladder Cancer Patient Urinary Exosomes, PloS one 11(1) (2016) e0147236. [32] Z. Li, K.-E. Wang, X.-L. Zhou, J. Zhou, C.-H. Ye, Long Non-Coding RNA Cancer Susceptibility Candidate 2a (CASC2a) Is a Marker of Early Recurrence After Radical Cystectomy in Patients with Urothelial Carcinoma of the Bladder, Med. Sci. Monit. 24 (2018) 438-447. [33] B. Hu, G. Shi, Q. Li, W. Li, H. Zhou, Long noncoding RNA XIST participates in bladder cancer by downregulating p53 via binding to TET1, J. Cell. Biochem.
(2018).
[34] Z. Liu, D. Xie, H. Zhang, Long noncoding RNA neuroblastoma-associated transcript 1 gene inhibits malignant cellular phenotypes of bladder cancer through miR-21/SOCS6 axis, Cell Death Dis. 9(10) (2018) 1042. [35] X. Zhu, Y. Li, S. Zhao, S. Zhao, LSINCT5 activates Wnt/beta-catenin signaling by interacting with NCYM to promote bladder cancer progression, Biochem. Biophys. Res. Commun. 502(3) (2018) 299-306.
[36] F. Wang, Y. Zu, W. Huang, H. Chen, H. Xie, Y. Yang, LncRNA CALML3-AS1 promotes tumorigenesis of bladder cancer via regulating ZBTB2 by suppression of microRNA-4316, Biochem. Biophys. Res. Commun. 504(1) (2018) 171-176. [37] J.S. Wang, Q.H. Liu, X.H. Cheng, W.Y. Zhang, Y.C. Jin, The long noncoding RNA ZFAS1 facilitates bladder cancer tumorigenesis by sponging miR-329, Biomed. Pharmacother. 103 (2018) 174-181. [38] M. Luo, Z. Li, W. Wang, Y. Zeng, Z. Liu, J. Qiu, Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression, Cancer Lett. 333(2) (2013) 213-21. [39] Z. Ma, S. Xue, B. Zeng, D. Qiu, lncRNA SNHG5 is associated with poor prognosis of bladder cancer and promotes bladder cancer cell proliferation through targeting p27, Oncol. Lett. 15(2) (2018) 19241930. [40] X. Cao, J. Xu, D. Yue, LncRNA-SNHG16 predicts poor prognosis and promotes tumor proliferation through epigenetically silencing p21 in bladder cancer, Cancer Gene Ther. 25(1-2) (2018) 10-17. [41] R. Xu, X. Zhu, F. Chen, C. Huang, K. Ai, H. Wu, L. Zhang, X. Zhao, LncRNA XIST/miR-200c regulates the stemness properties and tumourigenicity of human bladder cancer stem cell-like cells, Cancer cell international 18 (2018) 41. [42] A. Siefker-Radtke, B. Curti, Immunotherapy in metastatic urothelial carcinoma: focus on immune checkpoint inhibition, Nature reviews. Urology 15(2) (2018) 112-124. [43] C. Chen, Y. Luo, W. He, Y. Zhao, Y. Kong, H. Liu, G. Zhong, Y. Li, J. Li, J. Huang, R. Chen, T. Lin, Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer, The Journal of clinical investigation
(2019).
[44] F.A. Yafi, A.G. Aprikian, J.L. Chin, Y. Fradet, J. Izawa, E. Estey, A. Fairey, R. Rendon, I. Cagiannos, L. Lacombe, J.B. Lattouf, D. Bell, D. Drachenberg, W. Kassouf, Contemporary outcomes of 2287 patients with bladder cancer who were treated with radical cystectomy: a Canadian multicentre experience, BJU Int. 108(4) (2011) 539-45. [45] J.E. Talmadge, I.J. Fidler, AACR centennial series: the biology of cancer metastasis: historical perspective, Cancer research 70(14) (2010) 5649-69. [46] T.T. Liao, M.H. Yang, Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness, Mol. Oncol. 11(7) (2017) 792-804. [47] B. De Craene, G. Berx, Regulatory networks defining EMT during cancer initiation and progression, Nature reviews. Cancer 13(2) (2013) 97-110. [48] S. Grelet, L.A. Link, B. Howley, C. Obellianne, V. Palanisamy, V.K. Gangaraju, J.A. Diehl, P.H. Howe, A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression, Nat. Cell Biol. 19(9) (2017) 1105-1115. [49] R. Mitra, X. Chen, E.J. Greenawalt, U. Maulik, W. Jiang, Z. Zhao, C.M. Eischen, Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition, Nat Commun 8(1) (2017) 1604. [50] Z. Fu, C. Chen, Q. Zhou, Y. Wang, Y. Zhao, X. Zhao, W. Li, S. Zheng, H. Ye, L. Wang, Z. He, Q. Lin, Z. Li, R. Chen, LncRNA HOTTIP modulates cancer stem cell properties in human pancreatic cancer by regulating HOXA9, Cancer Lett. 410 (2017) 68-81. [51] X. Yan, D. Zhang, W. Wu, S. Wu, J. Qian, Y. Hao, F. Yan, P. Zhu, J. Wu, G. Huang, Y. Huang, J. Luo, X. Liu, B. Liu, X. Chen, Y. Du, R. Chen, Z. Fan, Mesenchymal Stem Cells Promote Hepatocarcinogenesis via lncRNA-MUF Interaction with ANXA2 and miR-34a, Cancer research 77(23) (2017) 6704-6716. [52] Z. Tuo, J. Zhang, W. Xue, LncRNA TP73-AS1 predicts the prognosis of bladder cancer patients and functions as a suppressor for bladder cancer by EMT pathway, Biochem. Biophys. Res. Commun. 499(4)
(2018) 875-881. [53] J. Hedegaard, P. Lamy, I. Nordentoft, F. Algaba, S. Hoyer, B.P. Ulhoi, S. Vang, T. Reinert, G.G. Hermann, K. Mogensen, M.B.H. Thomsen, M.M. Nielsen, M. Marquez, U. Segersten, M. Aine, M. Hoglund, K. Birkenkamp-Demtroder, N. Fristrup, M. Borre, A. Hartmann, R. Stohr, S. Wach, B. Keck, A.K. Seitz, R. Nawroth, T. Maurer, C. Tulic, T. Simic, K. Junker, M. Horstmann, N. Harving, A.C. Petersen, M.L. Calle, E.W. Steyerberg, W. Beukers, K.E.M. van Kessel, J.B. Jensen, J.S. Pedersen, P.U. Malmstrom, N. Malats, F.X. Real, E.C. Zwarthoff, T.F. Orntoft, L. Dyrskjot, Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma, Cancer Cell 30(1) (2016) 27-42. [54] A.G. Robertson, J. Kim, H. Al-Ahmadie, J. Bellmunt, G. Guo, A.D. Cherniack, T. Hinoue, P.W. Laird, K.A. Hoadley, R. Akbani, M.A.A. Castro, E.A. Gibb, R.S. Kanchi, D.A. Gordenin, S.A. Shukla, F. SanchezVega, D.E. Hansel, B.A. Czerniak, V.E. Reuter, X. Su, B. de Sa Carvalho, V.S. Chagas, K.L. Mungall, S. Sadeghi, C.S. Pedamallu, Y. Lu, L.J. Klimczak, J. Zhang, C. Choo, A.I. Ojesina, S. Bullman, K.M. Leraas, T.M. Lichtenberg, C.J. Wu, N. Schultz, G. Getz, M. Meyerson, G.B. Mills, D.J. McConkey, J.N. Weinstein, D.J. Kwiatkowski, S.P. Lerner, Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer, Cell 171(3) (2017) 540-556.e25. [55] I. Ariel, M. Sughayer, Y. Fellig, G. Pizov, S. Ayesh, D. Podeh, B.A. Libdeh, C. Levy, T. Birman, M.L. Tykocinski, N. de Groot, A. Hochberg, The imprinted H19 gene is a marker of early recurrence in human bladder carcinoma, Mol. Pathol. 53(6) (2000) 320-3. [56] M. Xue, W. Chen, A. Xiang, R. Wang, H. Chen, J. Pan, H. Pang, H. An, X. Wang, H. Hou, X. Li, Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNAUCA1, Mol. Cancer 16(1) (2017) 143. [57] D. Jiao, Z. Li, M. Zhu, Y. Wang, G. Wu, X. Han, LncRNA MALAT1 promotes tumor growth and metastasis by targeting miR-124/foxq1 in bladder transitional cell carcinoma (BTCC), Am. J. Cancer Res. 8(4) (2018) 748-760. [58] W. He, Q. Cai, F. Sun, G. Zhong, P. Wang, H. Liu, J. Luo, H. Yu, J. Huang, T. Lin, linc-UBC1 physically associates with polycomb repressive complex 2 (PRC2) and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer, Biochim. Biophys. Acta 1832(10) (2013) 1528-37. [59] X.L. Zhao, Z.H. Zhao, W.C. Xu, J.Q. Hou, X.Y. Du, Increased expression of SPRY4-IT1 predicts poor prognosis and promotes tumor growth and metastasis in bladder cancer, Int. J. Clin. Exp. Pathol. 8(2) (2015) 1954-60. [60] J. Zhuang, L. Shen, L. Yang, X. Huang, Q. Lu, Y. Cui, X. Zheng, X. Zhao, D. Zhang, R. Huang, H. Guo, J. Yan, TGFbeta1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer, Theranostics 7(12) (2017) 3053-3067. [61] M. Avgeris, A. Tsilimantou, P.K. Levis, T. Tokas, D.C. Sideris, K. Stravodimos, A. Ardavanis, A. Scorilas, Loss of GAS5 tumour suppressor lncRNA: an independent molecular cancer biomarker for short-term relapse and progression in bladder cancer patients, Br. J. Cancer 119(12) (2018) 1477-1486. [62] M. Wang, C. Guo, L. Wang, G. Luo, C. Huang, Y. Li, D. Liu, F. Zeng, G. Jiang, X. Xiao, Long noncoding RNA GAS5 promotes bladder cancer cells apoptosis through inhibiting EZH2 transcription, Cell Death Dis. 9(2) (2018) 238. [63] X. Chen, R. Xie, P. Gu, M. Huang, J. Han, W. Dong, W. Xie, B. Wang, W. He, G. Zhong, Z. Chen, J. Huang, T. Lin, Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2, Clin. Cancer Res.
(2018).
[64] J. Teng, X. Ai, Z. Jia, K. Wang, Y. Guan, Y. Guo, Long non-coding RNA ARAP1-AS1 promotes the progression of bladder cancer by regulating miR-4735-3p/NOTCH2 axis, Cancer Biol. Ther.
(2018) 1-10.
[65] C. Chen, W. He, J. Huang, B. Wang, H. Li, Q. Cai, F. Su, J. Bi, H. Liu, B. Zhang, N. Jiang, G. Zhong, Y. Zhao, W. Dong, T. Lin, LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment, Nat Commun 9(1) (2018) 3826. [66] J. Zhuang, Q. Lu, B. Shen, X. Huang, L. Shen, X. Zheng, R. Huang, J. Yan, H. Guo, TGFbeta1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT, Sci. Rep. 5 (2015) 11924. [67] D. Liu, Y. Li, G. Luo, X. Xiao, D. Tao, X. Wu, M. Wang, C. Huang, L. Wang, F. Zeng, LncRNA SPRY4-IT1 sponges miR-101-3p to promote proliferation and metastasis of bladder cancer cells through upregulating EZH2, Cancer Lett. 388 (2017) 281-291. [68] M. Luo, Z. Li, W. Wang, Y. Zeng, Z. Liu, J. Qiu, Upregulated H19 contributes to bladder cancer cell proliferation by regulating ID2 expression, The FEBS journal 280(7) (2013) 1709-16. [69] Z. Zheng, D. Zhu, F. Zhao, J. Han, H. Chen, Y. Cai, W. Xie, Upregulated GAPLINC predicts a poor prognosis in bladder cancer patients and promotes tumor proliferation and invasion, Oncol. Lett. 15(5) (2018) 6770-6776. [70] S.Q. Feng, X.Y. Zhang, H.T. Fan, Q.J. Sun, M. Zhang, Up-regulation of LncRNA MEG3 inhibits cell migration and invasion and enhances cisplatin chemosensitivity in bladder cancer cells, Neoplasma 65(6) (2018) 925-932. [71] M. Xue, H. Pang, X. Li, H. Li, J. Pan, W. Chen, Long non-coding RNA urothelial cancer-associated 1 promotes bladder cancer cell migration and invasion by way of the hsa-miR-145-ZEB1/2-FSCN1 pathway, Cancer Sci. 107(1) (2016) 18-27. [72] M. Lv, Z. Zhong, M. Huang, Q. Tian, R. Jiang, J. Chen, lncRNA H19 regulates epithelial-mesenchymal transition and metastasis of bladder cancer by miR-29b-3p as competing endogenous RNA, Biochim Biophys Acta Mol Cell Res 1864(10) (2017) 1887-1899. [73] C. Li, Y. Cui, L.F. Liu, W.B. Ren, Q.Q. Li, X. Zhou, Y.L. Li, Y. Li, X.Y. Bai, X.B. Zu, High Expression of Long Noncoding RNA MALAT1 Indicates a Poor Prognosis and Promotes Clinical Progression and Metastasis in Bladder Cancer, Clin. Genitourin. Cancer 15(5) (2017) 570-576. [74] H. Xie, X. Liao, Z. Chen, Y. Fang, A. He, Y. Zhong, Q. Gao, H. Xiao, J. Li, W. Huang, Y. Liu, LncRNA MALAT1 Inhibits Apoptosis and Promotes Invasion by Antagonizing miR-125b in Bladder Cancer Cells, J. Cancer 8(18) (2017) 3803-3811. [75] Z. Li, S. Hong, Z. Liu, LncRNA LINC00641 predicts prognosis and inhibits bladder cancer progression through miR-197-3p/KLF10/PTEN/PI3K/AKT cascade, Biochem. Biophys. Res. Commun. 503(3) (2018) 1825-1829. [76] R. Zheng, M. Du, X. Wang, W. Xu, J. Liang, W. Wang, Q. Lv, C. Qin, H. Chu, M. Wang, L. Yuan, J. Qian, Z. Zhang, Exosome-transmitted long non-coding RNA PTENP1 suppresses bladder cancer progression, Mol. Cancer 17(1) (2018) 143. [77] Z. Qin, Y. Wang, J. Tang, L. Zhang, R. Li, J. Xue, P. Han, W. Wang, C. Qin, Q. Xing, J. Yang, W. Zhang, High LINC01605 expression predicts poor prognosis and promotes tumor progression via up-regulation of MMP9 in bladder cancer, Biosci. Rep. 38(5) (2018). [78] H. Yang, G. Li, B. Cheng, R. Jiang, ZFAS1 functions as an oncogenic long non-coding RNA in bladder cancer, Biosci. Rep. 38(3) (2018). [79] C. Wang, W. Tao, S. Ni, Q. Chen, Upregulation of lncRNA snoRNA host gene 6 regulates NUAK family SnF1-like kinase-1 expression by competitively binding microRNA-125b and interacting with Snail1/2 in bladder cancer, J. Cell. Biochem. 120(1) (2019) 357-367. [80] D. Brunen, S.M. Willems, U. Kellner, R. Midgley, I. Simon, R. Bernards, TGF-beta: an emerging player
in drug resistance, Cell cycle (Georgetown, Tex.) 12(18) (2013) 2960-8. [81] A. Moustakas, C.H. Heldin, Mechanisms of TGFbeta-Induced Epithelial-Mesenchymal Transition, Journal of clinical medicine 5(7) (2016). [82] X. Zhai, W. Xu, Long Noncoding RNA ATB Promotes Proliferation, Migration, and Invasion in Bladder Cancer by Suppressing MicroRNA-126, Oncol. Res. 26(7) (2018) 1063-1072. [83] Y. Fan, B. Shen, M. Tan, X. Mu, Y. Qin, F. Zhang, Y. Liu, TGF-beta-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12, Clin. Cancer Res. 20(6) (2014) 1531-41. [84] T. Valenta, G. Hausmann, K. Basler, The many faces and functions of beta-catenin, EMBO J. 31(12) (2012) 2714-36. [85] Y. Li, W.P. Hively, H.E. Varmus, Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer, Oncogene 19(8) (2000) 1002-9. [86] L. Ying, Q. Chen, Y. Wang, Z. Zhou, Y. Huang, F. Qiu, Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition, Mol Biosyst 8(9) (2012) 228994. [87] J. Wang, W. Ma, Y. Liu, Long non-coding RNA HULC promotes bladder cancer cells proliferation but inhibits apoptosis via regulation of ZIC2 and PI3K/AKT signaling pathway, Cancer Biomark. 20(4) (2017) 425-434. [88] X.Y. Lv, L. Ma, J.F. Chen, R. Yu, Y. Li, Z.J. Yan, Y. Cheng, Q. Ma, Knockdown of DUXAP10 inhibits proliferation and promotes apoptosis in bladder cancer cells via PI3K/Akt/mTOR signaling pathway, Int. J. Oncol. 52(1) (2018) 288-294. [89] M.S. Lee, M.H. Jeong, H.W. Lee, H.J. Han, A. Ko, S.M. Hewitt, J.H. Kim, K.H. Chun, J.Y. Chung, C. Lee, H. Cho, J. Song, PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis, Nat Commun 6 (2015) 7769. [90] H. Chi, R. Yang, X. Zheng, L. Zhang, R. Jiang, J. Chen, LncRNA RP11-79H23.3 Functions as a Competing Endogenous RNA to Regulate PTEN Expression through Sponging hsa-miR-107 in the Development of Bladder Cancer, Int J Mol Sci 19(9) (2018). [91] T. Liang, Y. Wang, Y. Wang, Y. Wang, Long noncoding RNA PEG10 facilitates bladder cancer cells proliferation, migration, and invasion via repressing microRNA-29b, J. Cell. Physiol. 234(11) (2019) 19740-19749. [92] R. Gao, N. Zhang, J. Yang, Y. Zhu, Z. Zhang, J. Wang, X. Xu, Z. Li, X. Liu, Z. Li, J. Li, C. Kong, J. Bi, Long non-coding RNA ZEB1-AS1 regulates miR-200b/FSCN1 signaling and enhances migration and invasion induced by TGF-beta1 in bladder cancer cells, J. Exp. Clin. Cancer Res. 38(1) (2019) 111. [93] Z. Tian, S. Cao, C. Li, M. Xu, H. Wei, H. Yang, Q. Sun, Q. Ren, L. Zhang, LncRNA PVT1 regulates growth, migration, and invasion of bladder cancer by miR-31/ CDK1, J. Cell. Physiol. 234(4) (2019) 4799-4811. [94] X. Rui, L. Wang, H. Pan, T. Gu, S. Shao, J. Leng, LncRNA GAS6-AS2 promotes bladder cancer proliferation and metastasis via GAS6-AS2/miR-298/CDK9 axis, J. Cell. Mol. Med.
(2018).
[95] J. Wang, K. Yang, W. Yuan, Z. Gao, Determination of Serum Exosomal H19 as a Noninvasive Biomarker for Bladder Cancer Diagnosis and Prognosis, Med. Sci. Monit. 24 (2018) 9307-9316. [96] Y. Zhan, L. Du, L. Wang, X. Jiang, S. Zhang, J. Li, K. Yan, W. Duan, Y. Zhao, L. Wang, Y. Wang, C. Wang, Expression signatures of exosomal long non-coding RNAs in urine serve as novel non-invasive biomarkers for diagnosis and recurrence prediction of bladder cancer, Mol. Cancer 17(1) (2018) 142. [97] F. Sanchez-Vega, M. Mina, J. Armenia, W.K. Chatila, A. Luna, K.C. La, S. Dimitriadoy, D.L. Liu, H.S. Kantheti, S. Saghafinia, D. Chakravarty, F. Daian, Q. Gao, M.H. Bailey, W.W. Liang, S.M. Foltz, I. Shmulevich, L. Ding, Z. Heins, A. Ochoa, B. Gross, J. Gao, H. Zhang, R. Kundra, C. Kandoth, I. Bahceci, L. Dervishi, U.
Dogrusoz, W. Zhou, H. Shen, P.W. Laird, G.P. Way, C.S. Greene, H. Liang, Y. Xiao, C. Wang, A. Iavarone, A.H. Berger, T.G. Bivona, A.J. Lazar, G.D. Hammer, T. Giordano, L.N. Kwong, G. McArthur, C. Huang, A.D. Tward, M.J. Frederick, F. McCormick, M. Meyerson, E.M. Van Allen, A.D. Cherniack, G. Ciriello, C. Sander, N. Schultz, Oncogenic Signaling Pathways in The Cancer Genome Atlas, Cell 173(2) (2018) 321-337.e10. [98] S. Maeda, H. Tomiyasu, M. Tsuboi, A. Inoue, G. Ishihara, T. Uchikai, J.K. Chambers, K. Uchida, T. Yonezawa, N. Matsuki, Comprehensive gene expression analysis of canine invasive urothelial bladder carcinoma by RNA-Seq, BMC Cancer 18(1) (2018) 472. [99] S.W. Young, M. Stenzel, J.L. Yang, Nanoparticle-siRNA: A potential cancer therapy?, Crit. Rev. Oncol. Hematol. 98 (2016) 159-69. [100] R. Kole, A.R. Krainer, S. Altman, RNA therapeutics: beyond RNA interference and antisense oligonucleotides, Nat Rev Drug Discov 11(2) (2012) 125-40. [101] H. Ling, M. Fabbri, G.A. Calin, MicroRNAs and other non-coding RNAs as targets for anticancer drug development, Nat Rev Drug Discov 12(11) (2013) 847-65. [102] O. Slaby, R. Laga, O. Sedlacek, Therapeutic targeting of non-coding RNAs in cancer, Biochem. J. 474(24) (2017) 4219-4251. [103] L. Chen, E.E. Dzakah, G. Shan, Targetable long non-coding RNAs in cancer treatments, Cancer Lett. 418 (2018) 119-124. [104] J.M. Lee, T.J. Yoon, Y.S. Cho, Recent developments in nanoparticle-based siRNA delivery for cancer therapy, Biomed Res Int 2013 (2013) 782041. [105] T. Coelho, D. Adams, A. Silva, P. Lozeron, P.N. Hawkins, T. Mant, J. Perez, J. Chiesa, S. Warrington, E. Tranter, M. Munisamy, R. Falzone, J. Harrop, J. Cehelsky, B.R. Bettencourt, M. Geissler, J.S. Butler, A. Sehgal, R.E. Meyers, Q. Chen, T. Borland, R.M. Hutabarat, V.A. Clausen, R. Alvarez, K. Fitzgerald, C. Gamba-Vitalo, S.V. Nochur, A.K. Vaishnaw, D.W. Sah, J.A. Gollob, O.B. Suhr, Safety and efficacy of RNAi therapy for transthyretin amyloidosis, N. Engl. J. Med. 369(9) (2013) 819-29. [106] V. Tripathi, Z. Shen, A. Chakraborty, S. Giri, S.M. Freier, X. Wu, Y. Zhang, M. Gorospe, S.G. Prasanth, A. Lal, K.V. Prasanth, Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB, PLoS genetics 9(3) (2013) e1003368. [107] L. Li, H. Chen, Y. Gao, Y.W. Wang, G.Q. Zhang, S.H. Pan, L. Ji, R. Kong, G. Wang, Y.H. Jia, X.W. Bai, B. Sun, Long Noncoding RNA MALAT1 Promotes Aggressive Pancreatic Cancer Proliferation and Metastasis via the Stimulation of Autophagy, Mol. Cancer Ther. 15(9) (2016) 2232-43. [108] G. Arun, S. Diermeier, M. Akerman, K.C. Chang, J.E. Wilkinson, S. Hearn, Y. Kim, A.R. MacLeod, A.R. Krainer, L. Norton, E. Brogi, M. Egeblad, D.L. Spector, Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss, Genes & development 30(1) (2016) 34-51. [109] A. Mizrahi, A. Czerniak, T. Levy, S. Amiur, J. Gallula, I. Matouk, R. Abu-lail, V. Sorin, T. Birman, N. de Groot, A. Hochberg, P. Ohana, Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences, J. Transl. Med. 7 (2009) 69. [110] D. Amit, A. Hochberg, Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences, J. Transl. Med. 8 (2010) 134. [111] A.A. Sidi, P. Ohana, S. Benjamin, M. Shalev, J.H. Ransom, D. Lamm, A. Hochberg, I. Leibovitch, Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette-Guerin, The Journal of urology 180(6) (2008) 2379-83. [112] O. Lavie, D. Edelman, T. Levy, A. Fishman, A. Hubert, Y. Segev, E. Raveh, M. Gilon, A. Hochberg, A
phase 1/2a, dose-escalation, safety, pharmacokinetic, and preliminary efficacy study of intraperitoneal administration of BC-819 (H19-DTA) in subjects with recurrent ovarian/peritoneal cancer, Arch. Gynecol. Obstet. 295(3) (2017) 751-761.
Fig.1 Role of EMT in bladder cancer progression and metastasis. When EMT process was activated, epithelial cells loss cell–cell adhesion, gaining enhanced ability of moving and invading. Then tumor cells break through the four layers of the bladder and invade surrounding tissues in turn. It may continue to invade distant tissue, just like bone and lung, through the blood vessels or lymphatics.
Figure.2 The potential signaling networks of EMT regulated by lncRNAs in metastasis. LncRNAs SNHG16, LSINCT5, HULC, DUXCAP10, TUG1, ZEB2NAT and MALAT1were participated in the EMT process. These lncRNAs take part in the TGF-β signaling pathway, Wnt/β signaling pathway, and PI3K/Akt signaling pathway. Abbreviations EMT: epithelial-to-mesenchymal transition; SNHG16: Small Nucleolar RNA Host Gene 16; LSINCT5: Long Stress Induced Non-Coding Transcripts 5; HULC: Highly upregulated in liver cancer; DUXCAP10:, TUG1: Taurine upregulated gene 1; ZEB2NAT: zinc finger E-box binding homeobox 2 antisense RNA 1;MALAT1: Metastasis associated lung adenocarcinoma transcript 1.
1. The overall survival (OS) declined dramatically as the bladder cancer progressed, especially urothelial cells changes from noninvasive to invasive. 2. Long non-coding RNAs (lncRNAs) has been proved to play a more important part in regulating biological processes and cellular pathways. 3. LncRNAs might be used as the potential noninvasive biomarkers, diagnostic methods and prospective therapies in the near future.
Table(s)
Table 1 LncRNAs involved in EMT and the progression of bladder cancer Study year LncRNA
Study
Sample
Expressio Correlatio Other clinical n changes n with characteristic Prognosis
2019 LNMAT2
Chen
266 pairs
up
positive
-
poor
2019 GAS6‐AS2Rui
TCGA database up
positive
clinical stage poor
2019 PVT1
Tian
35 pairs
up
-
-
-
2019 PEG10
Liang
-
up
-
histological grade, histological grade histological grade,
-
2019 ZEB1-AS1 Gao
60 BC ,23 normal tissues positive
2018 LNMAT1
266 pairs
Chen
up
positive
poor poor
2018 LINC01605Qin
TCGA database up
-
2018 MALAT1
56 pairs
up
positive
2018 GAPLINC Zheng
80 pairs
up
-
2018 ZFAS1
Wang
172 pairs up
-
2018 ZFAS1
Yang
102 BC ,20 up normal tissues positive
2018 LSINCT5
Zhu
108 pairs
up
-
poor clinical stage, muscularis no correlation tumour size, clinical stage poor
2018 H19
Luo
48 pairs
up
positive
clinical stage poor
2018 LINC00641Li
39 pairs
down
negative
-
poor
2018 ATB
Zhai
-
up
-
-
2018 CASC2a
Li
112 pairs
down
negative
histological grade,
2018 XIST
Xu
-
up
positive
-
-
2018 ARAP1-AS1Teng
88 pairs
up
positive
-
poor
2018 PTENP1
Zheng
50 BC，60 down normal tissues, 20 pairs clinical grade，advanced stage positive -
2018 NBAT1
Liu
76 pairs
down
positive
histological grade -
2018 SNHG6
Wang
24 pairs
up
-
-
-
2018 XIST
Hu
-
up
-
-
-
positive
histological grade poorand TNM stage
Jiao
clinical stage poor histological grade poor
2018 TP73-AS1 Tuo
128 pairs down
2018 AWPPH
20 Ta-T1 BC up , 20 T2-T4 - BC, 20 normal clinicaltissues stage
Zhu
2018 CALML3-AS1 Wang
55 pairs
up
2018 MEG3
21 pairs
down
positive
-
2018 RP11-79H23.3 Chi
30 pairs
down
negative
clinical stage
2018 SNHG16
26 pairs
up
-
-
Feng
Feng
poor
-
clinical stage poor