Journal of Cancer Research and Clinical Oncology

, Volume 142, Issue 7, pp 1407–1419 | Cite as

Urothelial cancer associated 1: a long noncoding RNA with a crucial role in cancer

Review – Cancer Research

Abstract

Background

Urothelial cancer associated 1 (UCA1) is a long noncoding RNA (lncRNA) which has gained more attention in recent years due to its aberrant expression in embryogenesis and a broad range of cancer tissues and cells. Importantly, multiple studies have shown that UCA1 plays oncogenic roles in tumor growth and metastasis, and it may act as a potential biomarker and therapeutic target for human cancers. However, the molecular mechanism of UCA1 in cancer initiation, progression and metastasis remains incompletely understood. Thus, gaining a better understanding of the functional mechanism of UCA1 in cancer onset and progression is of the utmost significance for evaluating the potential application of UCA1.

Results and discussion

In this review, we discuss UCA1 expression profiling, isoform, expression regulation, biological role and mechanism for UCA1 tumor-promoting effect. We further discuss the potential clinical application of UCA1 as a promising diagnostic biomarker or therapeutic target for human cancers.

Conclusion

UCA1 functions as an oncogenic lncRNA in several malignancies, and it might become a potential biomarker or therapeutic target for human cancers.

Keywords

Long noncoding RNA UCA1 Cancer Metastasis Chemoresistance 

Introduction

Long noncoding RNAs (lncRNAs) are considered as a group of RNA which do not encode for proteins, and the lengths of these molecules are more than 200 nucleotides (Mercer et al. 2009; Derrien et al. 2012). They interact with DNA, RNA or proteins as molecular sponges, scaffolds and activators to play important regulatory roles in a variety of biological processes ranging from gene regulation, cellular differentiation to human diseases, especially in cancers (Wang and Chang 2011; Klattenhoff et al. 2013; Mercer and Mattick 2013). Recent observations have illustrated that a large number of deregulated lncRNAs are involved in human cancers and their function as oncogenes and tumor suppressors in cancer onset and progression (Li et al. 2009; Gutschner and Diederichs 2012; Shen et al. 2015). Based on the biological functions of lncRNAs in cancers, lncRNAs can be classified into two broad categories: (1) oncogenic lncRNAs, such as metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) or (2) tumor suppressor lncRNAs, such as maternally expressed gene 3 (MEG3) (Tsang et al. 2010; Zhou et al. 2012; Luo et al. 2013; Gutschner et al. 2013). Suppression of oncogenic lncRNAs or re-expression of tumor suppressor lncRNAs could inhibit tumor growth and metastasis in vitro and in vivo, indicating the potential application of lncRNAs-mediated cancer therapy (Nana-Sinkam and Croce 2011; Tsai et al. 2011; Qi and Du 2013).

In 2006, urothelial cancer associated 1 (UCA1) was initially discovered, and reverse transcription polymerase chain reaction (RT-PCR) assay confirmed that UCA1 was highly expressed in bladder cancer tissues compared with adjacent normal tissues (Wang et al. 2006). A later study of our group identified UCA1 by isolating from two bladder cancer cell lines BLS-211 and BLZ-211 via subtractive suppression hybridization (SSH). Ectopic expression of UCA1 in BLS-211 cells demonstrated that UCA1 acts as an oncogenic lncRNA to promote bladder cancer progression (Wang et al. 2008). Although UCA1 has been discovered only a decade, several recent studies have focused on the oncogenic role of UCA1 in a variety of cancers, including bladder cancer, breast cancer, colorectal cancer, esophageal squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, melanoma, ovarian cancer and tongue squamous cell carcinoma (Wang et al. 2006, 2008, 2015a, b; Huang et al. 2014; Han et al. 2014; Zheng et al. 2015; Li et al. 2014a; Tian et al. 2014; Fang et al. 2014). So the aim of this review is to highlight the recent advances on the expression of UCA1 in various malignancies, the biological role of UCA1 in cancer development and the potential clinical application of UCA1 in cancer diagnosis and therapy.

Expression profiling of UCA1

The expression profiling of UCA1 at different stages of embryogenesis was determined by RT-PCR. UCA1 is highly expressed at 5–10 weeks of gestation. After 28 weeks of gestation, UCA1 is upregulated in bladder, heart and uterus, but low expressed in cervix, kidney, liver, lung, intestine, skin, spleen and stomach. In adult tissues, UCA1 is significantly downregulated in most tissues, except heart and spleen tissues (Wang et al. 2006, 2008). In cancer tissues, UCA1 is upregulated in bladder cancer tissues compared with adjacent normal tissues (Wang et al. 2006, 2008). Moreover, UCA1 is also overexpressed in other cancer tissues compared with adjacent normal tissues, including breast cancer, cervical cancer, colorectal cancer, esophageal squamous cell carcinoma, hepatocellular carcinoma, gastric cancer, lung cancer, melanoma, ovarian cancer, thyroid cancer and tongue squamous cell carcinoma (Wang et al. 2006, 2008, 2015a, b; Huang et al. 2014; Han et al. 2014; Zheng et al. 2015; Li et al. 2014a; Tian et al. 2014; Fang et al. 2014). Through analysis of UCA1 expression profiling in human tissues, we conclude that UCA1 may be tightly associated with embryogenesis, cancer development and progression.

Structure and isoforms of UCA1

UCA1 gene contains three exons and two introns, which is located on human chromosome 19p13.12 positive strand (Fig. 1a). Importantly, UCA1 sequence contains multiple stop condons and it does not contain any conserved long open reading frames (ORFs). In vitro translation assay found that the full-length cDNA of UCA1 (1.4 kb) does not produce protein products (Wang et al. 2006, 2008). Taken together, these studies illustrate that UCA1 is a bona fide lncRNA. There are three isoforms of UCA1 including 1.4, 2.2 and 2.7 kb that can be spliced and polyadenylated. There are two 1.4 kb isoforms of UCA1 in the GenBank nucleotide sequence database with individual accession number DQ343132.1 (1411 bp) and EU334869.1 (1442 bp) (Fig. 1b).
Fig. 1

Schematic representation of the UCA1 gene and the different isoforms of UCA1. a The UCA1 gene consists of three exons (yellow boxes) and two introns (blue boxes). b DQ343132.1 and EU334869.1 are the 1.4 kb isoforms of UCA1, and GU357550.1 and GP468879.1 are the 2.2 kb isoforms of UCA1. Red numbers represent the common regions of these UCA1 isoforms

Another 2.2 kb isoform of UCA1, also known as cancer upregulated drug resistant (CUDR, GenBank Accession no. GP468879.1), is highly expressed in several cancer tissues including colon, cervix, lung and doxorubicin-resistant squamous carcinoma cells. Overexpression of CUDR can promote chemoresistance and cellular transformation (Tsang et al. 2007). UCA1a (GenBank Accession no. GU357550.1) is another 2.2 kb isoform of UCA1 discovered by our group, in which cDNA sequence has 99 % identity with CUDR (33–2245 bp) and contains a 1265 bp common region with UCA1 (GenBank Accession no. EU334869.1) cDNA sequence (150–1414 bp) (Fig. 1b) (Wang et al. 2012). Similar to the expression pattern and biological function of UCA1, UCA1a is highly expressed in embryo tissues and bladder cancer tissues. Overexpression of UCA1a can promote bladder cancer cell proliferation, migration and invasion. Moreover, overexpression of UCA1a also inhibits apoptosis induced by cisplatin and promotes tumor growth in vivo. These studies indicate that both UCA1a and UCA1 could play the similar roles in bladder cancer progression.

Currently, most studies are mainly focused on the expression regulation and functional significance of 1.4 kb isoform of UCA1, because it is the most abundant isoform of UCA1 in various cancers, such as bladder cancer, breast cancer and hepatocellular carcinoma (Wang et al. 2006, 2008, 2015a; Huang et al. 2014). Of note, there is still a lack of information on the sequence and biological role of 2.7 kb isoform of UCA1 in cancers, and future studies should explore the transcriptional regulatory mechanisms responsible for the differentially expressed three isoforms of UCA1 in cancers.

Transcriptional regulation of UCA1

The transcriptional regulation of lncRNAs is similar to that of protein-encoding genes (Guttman et al. 2009; Yang et al. 2013b). A number of studies on the transcriptional regulation of lncRNAs indicate that transcription factors or transcriptional complexes regulate the expression of lncRNAs mainly by binding with their promoters (Huarte et al. 2010; Wang et al. 2010; Liu et al. 2013a). Recently, a growing body of evidence shows that the UCA1 expression can be regulated by transcription factor, transcriptional complex, hypoxia-inducible transcription factor and microRNA. A schematic depicting a complicated regulatory network of transcription factors for UCA1 expression in tumor microenvironment is shown in Fig. 2.
Fig. 2

The complicated regulatory network of lncRNA–UCA1 expression in tumor microenvironment. Under normoxic conditions, several transcription factors (Ets-2 and C/EBPα) or complexes (TAZ/YAP/TEAD/SMAD) promote cancer progression by regulating UCA1 expression. Furthermore, miR-1 can also modulate UCA1 expression by interacting with UCA1. Under hypoxic conditions, transcription factor HIF-1α effectively activates UCA1 transcription by binding with two HREs in UCA1 promoter, and UCA1 expression also favors the proliferation, migration, invasion and apoptosis resistance of cancer cells

Transcription factor

The transcription start site of UCA1 gene is located at 15939757 position of chromosome 19, which is designated as +1 bp. UCA1 core promoter region is situated from −400 to −150 bp at 5′ end upstream of the UCA1 gene, which is capable of initiating its transcription (Wu et al. 2013). Several bioinformatical software programs found that there are a large number of putative transcription factor binding sites in UCA1 core promoter. Transcription factor Ets-2 has been shown to upregulate UCA1 expression in bladder cancer cells, which binds to UCA1 core promoter and enhances UCA1 promoter activity and its expression. Moreover, Ets-2 can inhibit bladder cancer cell apoptosis by upregulating the expression of UCA1. Similar to Ets-2, transcription factor CCAAT/enhancer-binding protein α (C/EBPα) is another regulator that can also bind with UCA1 core promoter. When the expression of UCA1 is upregulated by C/EBPα, it contributes to increased bladder cancer cell viability and reduced cell apoptosis (Xue et al. 2014b). These evidences suggest that both Ets-2 and C/EBPα interact with UCA1 core promoter, leading to the upregulation of UCA1 in bladder cancer. However, the interaction between Ets-2 and C/EBPα toward the activation of UCA1 in cancers has not been investigated thus far.

Transcriptional complex

Apart from the transcription factors, a recent study found that a transcriptional complex composed of the effectors of Hippo pathway (TAZ/YAP/TEAD) and transforming growth factor-β (TGF-β) pathway (SMAD2/3) is enriched at the promoter of UCA1 in breast cancer cells after TGF-β treatment (Beyer et al. 2013; Hiemer et al. 2014). Transcriptional coactivator with PDZ-binding motif (TAZ)/yes-associated protein (YAP), TEA domain family member (TEAD) and TGF-β synergistically induce the expression of UCA1 in breast cancer cells. Moreover, knockdown of UCA1 suppresses the migration and large mammosphere colonies formation of breast cancer cells after TGF-β treatment. By contrast, the coactivator of activating protein-1 and estrogen receptors (CAPERα)/T-box 3 (TBX3) transcriptional complex represses UCA1 expression in primary cultured human foreskin fibroblasts (HFFs). Thus, the dissociation of CAPERα/TBX3 complex from UCA1 promoter leads to elevated UCA1 expression and induced senescence in HFFs that are stimulated by oncogenic Ras gene (Kumar et al. 2014). These findings argue against the oncogenic role of UCA1 in cancers and provide direct evidence that UCA1 functions as a tumor suppressor in some circumstances.

Hypoxia-inducible transcription factor

The most remarkable hallmark of various solid tumors is hypoxia that can activate hypoxia-inducible factor 1 (HIF-1α) to facilitate the expression of numerous protein-encoding genes (Ruan et al. 2009; Gilkes et al. 2014). In addition to protein-encoding genes, multiple lncRNAs can also be modulated by hypoxia (Matouk et al. 2010; Yang et al. 2013a; Michalik et al. 2014). Recently, our data indicate that UCA1 is upregulated by hypoxic microenvironment of bladder cancer. HIF-1α binds to the hypoxia response elements (HREs) of UCA1 promoter to enhance UCA1 expression in a hypoxia-dependent manner. As commonly observed in a broad range of human cancer cells, HIF-1α is found to be broadly activated under hypoxic tumor microenvironments. Thus, the interaction between HIF-1α and UCA1 under hypoxic conditions may not be limited to bladder cancer. Actually, in epithelial ovarian cancer cells, HIF-1α can also bind to HRE of UCA1 promoter to upregulate UCA1 expression under hypoxic conditions (Xue et al. 2014a). Taken together, these studies suggest that the expression of UCA1 in distinct tumor microenvironments is precisely controlled by diverse transcription factors, which comprise a complicated regulatory network (Fig. 2).

MicroRNAs

MicroRNAs (miRNAs) have been shown to target lncRNAs through interacting with the putative miRNAs binding sites on lncRNAs sequences (Liu et al. 2013a; Zhang et al. 2013b; Han et al. 2013). A recent study demonstrated that UCA1 is a direct target of miR-1, and the third exon of UCA1 contains the miR-1 binding element. Depletion of miR-1 contributes to UCA1 overexpression, while overexpression of miR-1 downregulates UCA1 expression in bladder cancer cells. Furthermore, miR-1 negatively regulates UCA1 expression in an Ago2-slicer-dependent manner, and miR-1 plays tumor suppressive roles to decrease bladder cancer cell proliferation, inhibit cell motility and promote cell apoptosis by downregulating UCA1 (Wang et al. 2014a). Remarkably, emerging evidence suggests that lncRNAs serve as a molecular sponge or competing endogenous RNA (ceRNA) to sponge miRNA, thereby altering the expression of miRNA target (Salmena et al. 2011; Tay et al. 2014; Giza et al. 2014). However, it is currently unknown whether UCA1 could repress miR-1 expression or activity, thereby forming a reciprocal repression regulatory loop, and the functions of UCA1 as a ceRNA for miR-1 or other miRNAs are still expected to be confirmed in subsequent research.

Functional role and molecular mechanism of UCA1 in malignancy

Currently, the aberrant expression of UCA1 in various types of cancer has been identified. Intensive research efforts are underway to better understand the roles of UCA1 in malignancy. As shown in Table 1 and Fig. 3, we summarize a large number of factors and pathways involved in cancer development and progression which regulate UCA1 expression or interact with UCA1.
Table 1

List of the regulators controlling UCA1 expression or interacting with UCA1

Regulators

Functions

Binding sites

References

Ets-2

Upregulate UCA1 expression

−378 to −357 bp

Wu et al. (2013)

C/EBPα

Upregulate UCA1 expression

−239 to −230 bp

Xue et al. (2014b)

TAZ/YAP/TEAD

Upregulate UCA1 expression

−528 to −369 bp

Hiemer et al. (2014)

HIF-1α

Upregulate UCA1 expression

−53 to −49 bp

−1515 to −1511 bp

Xue et al. (2014a)

CAPERα/TBX3

Downregulate UCA1 expression

Kumar et al. (2014)

miR-1

Downregulate UCA1 expression

635 nt

Wang et al. (2014a)

CREB

Regulation of bladder cancer cell cycle

Yang et al. (2012)

AKT/Bax/Bcl-2

Regulation of bladder cancer cell apoptosis

Wu et al. (2013)

hnRNP I

Regulate the tumor suppressor p27 to promote breast tumor growth

1–740 nt

Huang et al. (2014)

Wnt/Wnt6

Promote cisplatin resistance

Fan et al. (2014)

hnRNP A1

Stabilize the tumor suppressor p16 mRNA to control primary cell proliferation, fate and senescence

Kumar et al. (2014)

mTOR

Regulate HK2 to promote aerobic glycolysis

Li et al. (2014b)

BRG1

Interrupt the interaction between BRG1 and p21 to promote bladder cancer cell proliferation

Wang et al. (2014b)

SRPK1

Activate SRPK1 to promote ovarian cancer cell proliferation, migration, invasion and chemoresistance

Wang et al. (2015b)

miR-216b/FGFR1/ERK

Reduce miR-216b and activate FGFR1/ERK pathway to promote hepatocellular carcinoma cell growth and metastasis

Wang et al. (2015a)

Fig. 3

The molecular mechanism of lncRNA–UCA1-mediated cancer progression and metastasis. UCA1 promotes cancer cell proliferation by indirectly or directly interacting with BRG1, hnRNP I, CREB or miR-216b. UCA1 increases drug resistance via SPRK1, Wnt6 and Wnt signaling pathway. Ets-2 and C/EBPα regulate UCA1 expression, and the upregulation of UCA1 inhibits cell apoptosis via AKT-Bax-Bcl-2 signaling pathway. UCA1 promotes glycolysis by upregulating HK2 through mTOR pathway. TGF-β and HIF-1α signaling pathways regulate UCA1 expression, and the upregulation of UCA1 supports cancer metastasis by miR-216b-FGFR1-ERK signaling pathway

Proliferation

The role and mechanism of UCA1 in cell proliferation have been explored in bladder cancer, breast cancer and hepatocellular carcinoma (Yang et al. 2012; Wang et al. 2014b, 2015a; Huang et al. 2014). UCA1 promotes cell cycle progression and cell proliferation of bladder cancer cells by increasing cAMP response element-binding protein (CREB) expression and activity through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)-dependent signaling pathways (Yang et al. 2012). A recent study found that UCA1 interacts with chromatin remodeling factor (BRG1) that upregulates cell cycle inhibitor p21 by binding with its promoter. Furthermore, UCA1 expression promotes bladder cancer cell proliferation by interrupting the interaction between BRG1 and p21 and inhibiting chromatin remodeling activity of BRG1 (Wang et al. 2014b). In breast cancer cells, UCA1 increases cell proliferation through interaction with heterogeneous nuclear ribonucleoprotein I (hnRNP I), leading to the suppression of p27 protein expression (Huang et al. 2014). In addition, it has been reported that UCA1 promotes hepatocellular carcinoma cell proliferation and suppresses G0/G1 cell cycle arrest by inhibiting miR-216b and activating fibroblast growth factor receptor 1 (FGFR1)/extracellular signal-regulated kinase (ERK) pathway (Wang et al. 2015a). By contrast, in primary human cells, UCA1 decreases cell proliferation through sequestering hnRNP A1 to stabilize p16INK mRNA (Kumar et al. 2014) (Fig. 3).

Apoptosis

Overexpression of UCA1a in bladder cancer cells downregulates tumor necrosis factor receptor superfamily member (Fas) and ataxia telangiectasia mutated (ATM) that are the regulatory factors of cell apoptosis pathway (Wang et al. 2012). Moreover, Ets-2 activates UCA1 expression and induces bladder cancer cell apoptosis by suppressing AKT pathway (Wu et al. 2013). Importantly, depletion of UCA1 induces hypoxic bladder cancer cell apoptosis by upregulated proapoptotic Bax and downregulated antiapoptotic Bcl-2, which are downstream effectors of AKT (Maddika et al. 2007). These findings suggest that UCA1a might control bladder cancer cell apoptosis by regulating Fas and ATM, and UCA1 regulates bladder cancer cell apoptosis at least in part via AKT-Bax-Bcl-2 pathway (Fig. 3).

Invasion and metastasis

In vitro assay overexpression of UCA1 increases the migration and invasion of many cancer cells. Under hypoxia conditions, HIF-1α induces UCA1 expression in bladder cancer cells, thereby promoting bladder cancer cell migration and invasion (Xue et al. 2014a). Similarly, TGF-β signaling pathway can also induce UCA1 expression in breast cancer cells and contributes to the transformation of breast cancer cells into more malignant phenotypes (Hiemer et al. 2014). Specifically, a recent study indicates that UCA1 promotes hepatocellular carcinoma cell migration and invasion by functioning as an important ceRNA for miR-216b to regulate its target gene FGFR1 (Wang et al. 2015a). To elucidate the molecular mechanism of UCA1 in cancer metastasis will be important, and the elucidation of this mechanism will ultimately provide a potential treatment strategy for cancer metastasis (Fig. 3).

Metabolism

Warburg effect is an important hallmark of cancer cells that consume larger amounts of glucose and produce more lactate than normal cells under normoxia conditions, thus facilitating cancer cell survival and proliferation (Warburg 1956; Vander et al. 2009; Ganapathy-Kanniappan and Geschwind 2013). LncRNAs have been found to act as key regulatory factors of Warburg effect (Yang et al. 2014; Kornfeld and Bruning 2014; Ellis et al. 2014). Among these lncRNAs, UCA1 dramatically enhances aerobic glycolysis in bladder cancer cells by regulating hexokinase 2 (HK2) that is the first rate-limiting enzyme of glycolysis (Fang et al. 2012; Li et al. 2014b). UCA1 contributes to the upregulation of HK2 in bladder cancer cells by two pathways: (1) UCA1 activates mammalian target of rapamycin (mTOR) and its downstream effector signal transducer and activator of transcription 3 (STAT3) that activates HK2 expression at transcription level; (2) mTOR activation by UCA1 also downregulates miR-143 that suppresses HK2 expression at the posttranscriptional level (Fig. 3).

Chemoresistance

Drug resistance is a major obstacle to the effective treatment of cancer patients (Broxterman et al. 2009; Dasari and Tchounwou 2014). Recent studies have shown that UCA1 has been implicated in cisplatin resistance of bladder cancer cells, and UCA1 expression induces cisplatin resistance via upregulating Wnt6 expression and activating Wnt signaling pathway (Wang et al. 2008; Fan et al. 2014). Moreover, the regulatory role of UCA1 in ovarian cancer cell chemoresistance is associated with the expression of serine/arginine-rich protein-specific kinase 1 (SRPK1) that has been identified as a cisplatin-sensitive protein (Wang et al. 2015b). In addition to UCA1, other isoforms of UCA1 and CUDR are also related to drug resistance. In particular, CUDR is isolated from the doxorubicin-resistant squamous carcinoma cells. Overexpression of CUDR induces doxorubicin resistance at least through caspase 3-dependent apoptosis (Wang et al. 2012; Tsang et al. 2007) (Fig. 3).

Deregulation of UCA1 in cancers

UCA1 has been first discovered in bladder cancer, and recent studies have confirmed that a broad range of human cancers are always accompanied with UCA1 aberrant expression. Furthermore, UCA1 expression is associated with clinical parameters and regulates cancer cell proliferation, apoptosis, migration and invasion. Table 2 summarizes the expression patterns and biological roles of UCA1 in different types of cancers.
Table 2

UCA1 involved in various cancers

Cancer types

Expression

Specimens

Methods

Biological function

Application

References

Bladder cancer

Upregulated in cancer tissues

94 cancer samples

RT-PCR

Biomarker

Wang et al. (2006)

20 cancer samples

RT-PCR

Promotes cell proliferation, migration, invasion and chemoresistance

Biomarker therapeutic target

Wang et al. (2008)

117 cancer samples

RT-PCR

Biomarker

Srivastava et al. (2014)

Breast cancer

Upregulated in cancer tissues

62 cancer samples

CISH

Promotes cell and tumor growth

Biomarker

Huang et al. (2014)

Colorectal cancer

Upregulated in cancer tissues and cells

80 paired samples

RT-PCR

Promotes cell proliferation Inhibits apoptosis

Biomarker therapeutic target

Han et al. (2014)

Esophageal squamous cell carcinoma

Upregulated in cancer tissues and cells

90 paired samples

RT-PCR

Promotes cell proliferation, invasion and migration

Biomarker therapeutic target

Li et al. (2014a)

Gastric cancer

Upregulated in cancer tissues and cells

112 paired samples

RT-PCR

Biomarker therapeutic target

Zheng et al. (2015)

Hepatocellular carcinoma

Upregulated in cancer tissues and cells

98 paired samples

RT-PCR

Promotes cell proliferation, invasion and migration

Biomarker therapeutic target

Wang et al. (2015a)

Melanoma

Upregulated in cancer tissues

63 paired samples

RT-PCR

Promotes cell migration

Biomarker

Tian et al. (2014)

Ovarian cancer

Upregulated in cancer tissues

24 cancer samples

RT-PCR

Promotes cell proliferation, invasion and migration

Therapeutic target

Wang et al. (2015b)

Tongue squamous cell carcinoma

Upregulated in cancer tissues

94 paired samples

RT-PCR

Promotes cell migration

Biomarker

Fang et al. (2014)

RT-PCR reverse transcription polymerase chain reaction; CISH chromogenic in situ hybridization

UCA1 in bladder cancer

The deregulation of UCA1 in bladder cancer was first reported by Wang et al. (2006). They found that the positive expression rate of UCA1 in bladder cancer tissues was as high as 85.1 %. Using RT-PCR, they also demonstrated that UCA1 is a highly specific (91.8 %) and very sensitive (80.9 %) biomarker for bladder cancer diagnosis. Additionally, the expression of UCA1 in bladder cancer tissues is associated with the clinical stage and histologic grade of bladder cancer. The higher expression of UCA1 is significantly correlated with high-grade (G2–G3) bladder cancer, but there is no correlation between UCA1 expression and bladder cancer patient’s age, sex and smoking habit (Srivastava et al. 2014). Hence, these findings suggest that UCA1 may be a potential biomarker for bladder cancer diagnosis.

Studies of the biological role of UCA1 in bladder cancer revealed that UCA1 could promote bladder cancer growth in vitro and in vivo. In bladder cancer BLS-211 cells, overexpression of UCA1 contributes to increased cell proliferation, motility, invasion and cisplatin resistance, and tumor growth is significantly enhanced in nude mice injected with UCA1-overexpressed bladder cancer cells (Wang et al. 2008). Furthermore, overexpression of UCA1 in T24 cells treated with cisplatin could increase cell viability. In contrast, deletion of UCA1 in T24 cells treated with cisplatin could decrease cell viability (Fan et al. 2014). Interestingly, overexpression of UCA1 significantly increases the rates of glucose consumption and lactate production in bladder cancer UMUC-2 cells (Li et al. 2014b).

UCA1 in breast cancer

UCA1 is upregulated in breast cancer tissues compared with the normal breast tissues. Overexpression of UCA1 in breast cancer MCF-7 cells increases the S phase population and decreases G1 phase population, while depletion of UCA1 by short interfering RNA (siRNA) can increase the G1 phase population and decrease the S phase population. Moreover, overexpression of UCA1 increases breast cancer cell proliferation, while depletion of UCA1 suppresses breast cancer cell proliferation and significantly reduces tumor growth in nude mice injected with UCA1 siRNA breast cancer cells. Overall, UCA1 promotes breast cancer growth in vitro and in vivo (Huang et al. 2014).

UCA1 in colorectal cancer

UCA1 is highly expressed in colorectal cancer tissues compared with adjacent normal tissues, and its expression is also significantly higher in colorectal cancer cells than in normal intestinal mucous cells. Furthermore, the expression of UCA1 in colorectal cancer is associated with tumor size, type of histopathology, tumor depth and prognosis of colon cancer patients. In in vitro assays, overexpression of UCA1 in colorectal cancer LoVo cell line promotes cell proliferation and cell cycle progression and inhibits apoptosis, and knockdown of UCA1 inhibits colorectal cancer SW480 cell proliferation and cell cycle progression and promotes apoptosis (Han et al. 2014).

UCA1 in esophageal squamous cell carcinoma

Study of UCA1 in esophageal squamous cell carcinoma (ESCC) revealed that UCA1 is highly expressed in ESCC tissues compared with the adjacent nontumor tissues, and its expression is also significantly higher in esophageal cancer cell lines compared with the immortalized esophageal epithelial cell line NE1. Furthermore, the high expression of UCA1 in ESCC is correlated with advanced clinical stage and poor prognosis. In vitro assays, knockdown of UCA1 decreases esophageal squamous cell carcinoma cell proliferation, migration and invasion (Li et al. 2014a).

UCA1 in gastric cancer

Studies of UCA1 expression profiling found that it is upregulated in gastric cancer tissues compared with adjacent normal tissues (Wang et al. 2006, 2008). Moreover, in order to evaluate the expression patterns of lncRNAs in gastric cancer, a study identified several lncRNAs including UCA1 that aberrantly expressed in gastric cancer by analyzing human exon arrays data from the gene expression omnibus (Cao et al. 2013). Similarly, a recent study demonstrated that UCA1 expression is markedly increased in gastric cancer tissues and cells compared with that in normal tissues and cells, and the high expression of UCA1 in gastric cancer is correlated with worse differentiation, tumor size, invasion depth, TNM stage and poor prognosis (Zheng et al. 2015).

UCA1 in hepatocellular carcinoma

The relationship between UCA1 and hepatocellular carcinoma (HCC) progression was recently discovered. UCA1 is aberrantly upregulated in HCC tissues compared with adjacent nontumorous tissues, and clinicopathological analysis revealed that the upregulation of UCA1 in HCC tissues is associated with advanced TNM stage and cancer metastasis. Importantly, UCA1 is identified as an independent prognostic factor to predict survival of patients with HCC. In addition, depletion of UCA1 in HCC cells inhibits cell proliferation, migration and invasion, and tumor growth is significantly decreased in athymic mice injected with UCA1-depleted HCC cells (Wang et al. 2015a).

UCA1 in melanoma

UCA1 displays significantly higher expression in melanoma tissues compared with adjacent normal tissues. Furthermore, UCA1 also exhibits higher expression in later stage (stage 3 and 4) melanoma tissues than that in early stages (stage 1 and 2). Knockdown of UCA1 in melanoma A-375 cells could sharply diminish the migratory ability of A-375 cells. In contrast, overexpression of UCA1 in A-375 cells could moderately increase cell migration. However, the altered expression of UCA1 did not significantly affect the cell proliferation of A-375 cells (Tian et al. 2014).

UCA1 in ovarian cancer

The expression pattern and biological function of UCA1 in ovarian cancer have recently been reported. The differentially expressed lncRNAs in ovarian cancer cells with different metastatic potentials were analyzed by microarray assay, and these results showed that seven lncRNAs are aberrantly expressed in ovarian cancer cells with different metastatic potentials. Among them, UCA1 is upregulated in the SKOV3.ip1 cells with high metastatic potential compared with in the SKOV3 cells (Liu et al. 2013b). Recent findings demonstrated that the expression of UCA1 is elevated in ovarian cancer tissues compared with normal tissues. Overexpression of UCA1 in ovarian cancer SKOV3 cells could enhance cell migration, invasion and cisplatin resistance (Wang et al. 2015b).

UCA1 in tongue squamous cell carcinoma

Study of tongue squamous cell carcinoma-associated lncRNAs revealed that the expression of UCA1 is dramatically upregulated in tongue squamous cell carcinoma (TSCC) tissues than that in adjacent normal mucosal tissues. Furthermore, UCA1 is highly expressed in TSCC tissues with lymph node metastasis than that in primary tumor tissues. Additionally, overexpression of UCA1 enhances the migration ability of tongue squamous cell carcinoma TCa8113 cells, but has little influence on cell proliferation (Fang et al. 2014).

Clinical applications of UCA1

UCA1 as a promising biomarker for cancer diagnosis

Due to the specific expression and critical role of lncRNAs in cancer initiation and development, lncRNAs can be used as promising biomarkers to diagnose and monitor human cancers. A major advantage of lncRNAs as cancer biomarkers is that they can be easily detected and noninvasively obtained from body fluids, such as serum or urine (Qi and Du 2013). The most striking example of lncRNAs as cancer biomarkers is lncRNA prostate cancer antigen 3 (PCA3), a Food and Drug Administration-approved urine biomarker for prostate cancer (Lee et al. 2011). The expression of lncRNA–PCA3 is significantly upregulated in prostate cancer tissues compared with benign prostate tissues (Hessels et al. 2003). Moreover, lncRNA–PCA3 in urine has been demonstrated as a more specific and sensitive biomarker of prostate cancer when compared to the widely used serum prostate-specific antigen (Stephan et al. 2014). Similar to lncRNA–PCA3 as a circulating cancer biomarker, UCA1 has been found to be highly expressed in bladder cancer tissues compared with adjacent normal tissues. Interestingly, lncRNA–UCA1 can also be detected in the circulation system including blood and urine samples of bladder cancer patients (Zhang et al. 2013a). Detection of UCA1 in urine samples by RT-PCR-based method was compared with the standard cytology approach in a recent study, and the results exhibited that RT-PCR-based UCA1 expression detection in urine samples may be an effective and noninvasive assay with high sensitivity (100 %) and specificity (67 %) for the diagnosis of bladder cancer (Rorive et al. 2009). Additionally, UCA1 is upregulated in blood samples of advanced bladder cancer patients after cisplatin-based combination chemotherapy, suggesting that UCA1 as a predictive biomarker may monitor the treatment outcome of chemotherapy for bladder cancer (Fan et al. 2014). Taken together, these limited clinical data suggest that circulating UCA1 is a promising biomarker for bladder cancer diagnosis and therapeutic monitoring. However, in other types of cancers, such as breast cancer, colorectal cancer and gastric cancer, the diagnostic value of UCA1 has not been studied sufficiently in body fluid samples. Hence, the diagnostic value of circulating UCA1 in different types of cancers is still required to assess in large-scale clinical studies.

UCA1 as a potential therapeutic target for cancer therapy

Recently, the potential application of lncRNAs as cancer therapeutic targets has attracted increasing interest, and some lncRNA-based therapy clinical trials have been undertaken. For example, lncRNA–H19 is specifically expressed in tumor tissues, but absent in normal tissues. Hence, targeting cancer-specific H19 expression would selectively kill cancer cells without harming normal cells (Matouk et al. 2013). H19 promoter has been cloned in the BC-819 plasmid to regulate the expression of diphtheria toxin, and this plasmid can cause tumor cell growth arrest without affecting normal cells (Smaldone and Davies 2010). Accordingly, the phase I/II clinical trials are being conducted in patients with bladder cancer, pancreatic cancer and ovarian cancer (Smaldone and Davies 2010; Mizrahi et al. 2010; Hanna et al. 2012). Similar to lncRNA–H19, most studies have demonstrated that lncRNA-UCA1 is also specifically expressed in many types of cancer tissues, but not expressed in normal tissues (Wang et al. 2006, 2015a, b; Huang et al. 2014; Han et al. 2014; Zheng et al. 2015; Li et al. 2014a; Tian et al. 2014; Fang et al. 2014). To date, the specific expression of UCA1 in cancers has not been exploited effectively for cancer therapy. Thus, future investigations are required to exploit the therapeutic potential of cancer-specific UCA1 expression in clinical application.

Multiple in vitro and in vivo studies have shown that several lncRNAs play oncogenic roles to promote tumor growth and metastasis. In this scenario, silencing of oncogenic lncRNAs expression at the genomic DNA level or at the RNA level could provide another straightforward therapeutic approach for cancers (Gutschner et al. 2011; Qi and Du 2013). According to recent studies, UCA1 plays oncogenic roles in many types of cancers, and depletion of UCA1 at the RNA level by short interfering RNAs (siRNA) or short hairpin RNA (shRNA) in many types of cancer cells such as bladder cancer, breast cancer and hepatocellular carcinoma could suppress tumor growth in vitro and in vivo (Wang et al. 2008; Huang et al. 2014; Wang et al. 2015a). Furthermore, targeting UCA1 genomic locus is another approach to inhibiting UCA1 expression in cancers. Tsui-Ting Ho and colleagues report that the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system as a novel genome editing tool can be used to target lncRNA–UCA1. This study also demonstrated that UCA1 is effectively silenced in human colon cancer HCT-116 cells by CRISPR/Cas9 system (Ho et al. 2014). Taken together, studies on the specific expression and functional role of UCA1 in cancers indicate that it has great therapeutic potential in clinical practice. However, there is a long way to go before UCA1 could be used in clinical practice. To date, the efficacy and safety of UCA1-based cancer therapy have not been investigated in preclinical and clinical trials. Future studies on UCA1 should aim to further define the clinical utility of UCA1-based cancer therapy in clinical trials.

Conclusion

In conclusion, recent advances have confirmed that UCA1 is frequently overexpressed in many tumors to play oncogenic roles in cancer development and progression. Nevertheless, several questions concerning the regulation and biological function of UCA1 remain unanswered. Ongoing and future researches should focus on the transcriptional and epigenetic regulatory mechanisms of UCA1 expression in cancers and the molecules and signal pathways regulated by UCA1 in tumor growth and metastasis. To sum up, addressing these questions will be essential to completely understand the functional roles of UCA1 in caners and to further explore the potential applications of UCA1 as a biomarker and/or therapeutic target for human cancers.

Notes

Acknowledgments

The authors apologize to all colleagues whose important work could not be cited owing to space restrictions. This work was supported by the National Natural Science Foundation of China (Grant Nos. 81372151, 81572735 and 81502529) and the First Affiliated Hospital Foundation of Xi’an Jiaotong University of China (2014YK9).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Center for Translational MedicineThe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anPeople’s Republic of China
  2. 2.Clinical LaboratoryThe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anPeople’s Republic of China

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