Non-coding RNA Urothelial Cancer Associated 1 Research Articles

The role of long non-coding RNA UCA1 and MALAT1 in bladder cancer patients

BackgroundBladder cancer (BC) is considered the most prevalent tumor of the urinary tract, and incidence rates are rising globally. Long noncoding RNAs (lncRNAs) can serve as biomarkers to help the diagnosis and anticipation of recurrence in cancer patients as they are implicated in carcinogenesis and tumor progression. This study targeted to investigate the expression of lncRNA as urothelial cancer associated 1 (UCA1) as well as metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the diagnosis of BC. Subjects and methodsThe study included 70 BC patients, 70 benign urinary tract diseases and 70 controls. The UCA1 and MALAT1 expressions were studied utilizing quantitative real-time polymerase chain reaction. ResultsThe UCA1 and MALAT1 expression were significantly increased in patients with BC than patients with chronic cystitis and controls (p < 0.001). The sensitivity and specificity for the diagnosis of BC for UCA1(87.14%, 97.14% respectively) and MALAT1 (92.86%, 90% respectively). Multivariate logistic regression analysis showed that UCA1 and MALAT1 were risk factors for the development of BC where the odds ratio (OR) for UCA1 was 1.262 (CI 1.004–1.587) and MALAT1 was 2.201(CI 1.036–4.676). ConclusionUCA1 and MALAT1 could be potential diagnostic biomarkers with good specificity and sensitivity in bladder cancer.

Comment on 'Long noncoding RNA UCA1 promotes glutamine-driven anaplerosis of bladder cancer by interacting with hnRNP I/L to upregulate GPT2 expression' by Chen et al.'”

Bladder cancer is prevalent cancer worldwide with poor outcomes for patients with high-grade disease. Emerging evidence shows that alteration of metabolic status drives tumorigenesis in bladder cancer. As long noncoding RNA urothelial cancer associated 1 (UCA1) is known to play an essential role in cancer metabolisms, such as glycolysis and glutaminolysis. Chen et al. report the novel function of UCA1 in glutamine metabolism through interacting with heterogeneous nuclear ribonucleoproteins (hnRNPs) I and L (hnRNP I/L). This study reveals that UCA1 promotes glutamic pyruvate transaminase 2 (GPT2) expression at the transcription level in mechanistic studies. Inhibition of either UCA1, hnRNPI/L, or GPT2 significantly reduces bladder cancer tumor growth in the mice model. This work explores a new mechanism for glutamine metabolism and the novel therapeutic target of the UCA1-hnRNPI/L-GPT2 axis across malignancies.

Long noncoding RNA UCA1 promotes glutamine-driven anaplerosis of bladder cancer by interacting with hnRNP I/L to upregulate GPT2 expression

Long noncoding RNA urothelial cancer associated 1 (UCA1), initially identified in bladder cancer, is associated with multiple cellular processes, including metabolic reprogramming. However, its characteristics in the anaplerosis context of bladder cancer (BLCA) remain elusive. We identified UCA1 as a binding partner of heterogeneous nuclear ribonucleoproteins (hnRNPs) I and L, RNA-binding proteins (RBPs) with no previously known role in metabolic reprogramming. UCA1 and hnRNP I/L profoundly affected glycolysis, TCA cycle, glutaminolysis, and proliferation of BLCA. Importantly, UCA1 specifically bound to and facilitated the combination of hnRNP I/L to the promoter of glutamic pyruvate transaminase 2 (GPT2), an enzyme transferring glutamate to α-ketoglutarate, resulting in upregulated expression of GPT2 and enhanced glutamine-derived carbons in the TCA cycle. We also systematically confirmed the influence of UCA1 and hnRNP I/L on metabolism and proliferation via glutamine-driven anaplerosis in BLCA. Our study revealed the critical role of UCA1-mediated mechanisms involved in glutamine-driven anaplerosis and provided novel evidence that lncRNA regulates metabolic reprogramming in tumor cells.

Long non-coding RNA UCA1 mediates proliferation and metastasis of laryngeal squamous cell carcinoma cells via regulating miR-185-5p/HOXA13 axis.

LncRNA urothelial cancer associated 1 (UCA1) is involved in the development of laryngeal squamous cell carcinoma (LSCC), however, its specific mechanism is not fully clear. Quantitative reverse transcription-PCR (RT-qPCR) was conducted to determine the expressions of lncRNA-UCA1, miR-185-5p and homeobox A13 (HOXA13) in LSCC tissues and cell lines. Cell Counting Kit-8 assay, colony formation assay, wound healing assay, Transwell and flow cytometry, DIANA-LncBase V2, as well as Starbase, Targetscan, and Dual-Luciferase reporter gene system were conducted to detect and confirm the crosstalk networks among lncRNA-UCA1, miR-185-5p, and HOXA13. The levels of UCA1 and HOXA13 were significantly higher and the expression of miR-185-5p was reduced in LSCC tissues and cell lines. Moreover, miR-185-5p was predicted as a target gene for lncRNA UCA1, while HOXA13 was the target gene for miR-185-5p. UCA1 siRNA inhibited the proliferation and invasion of LSCC cells, moreover, the proliferation and invasion of LSCC cells were suppressed by miR-185-5p mimics but were enhanced by miR-185-5p inhibitor. UCA1 siRNA and overexpressed HOXA13 reversed the promotive effects of miR-185-5p inhibitor and inhibitory effects of miR-185-5p mimics on cell proliferation and metastasis, respectively. The current findings reveal the important role of lncRNA UCA1/miR-185-5p/HOXA13 regulatory network in LSCC cells, and potentially provide new insights into the pathogenesis of LSCC.

Long noncoding RNA UCA1 regulates CCR7 expression to promote tongue squamous cell carcinoma progression by sponging miR-138-5p.

Tongue squamous cell carcinoma (TSCC) is a malignant tumor. Long noncoding RNAs (lncRNAs) have been proved to be involved in the regulation of the progression of various cancers. However, the mechanism of lncRNA urothelial cancer-associated 1 (UCA1) in the progression of TSCC remains unclear. The expression levels of UCA1, microRNA-138-5p (miR-138-5p), and CC chemokine receptor 7 (CCR7) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, migration, and invasion were detected using colony formation assay and transwell assay, respectively. Western blot (WB) analysis was used to test the levels of proliferation and metastasis-related proteins and CCR7 protein. Moreover, the extracellular acidification rate (ECAR) of cells was measured by the Seahorse XF Extracellular Flux Analyzer, and the adenosine triphosphate (ATP) level, glucose uptake, and lactate produce of cells were tested by their corresponding assay kits. Further, the dual-luciferase reporter assay was used to confirm the interaction between miR-138-5p and UCA1 or CCR7. In addition, the effect of UCA1 on TSCC tumor growth in vivo was evaluated by animal experiments. We found that UCA1 and CCR7 were upregulated, while miR-138-5p was downregulated in TSCC tissues. Silenced UCA1 restrained the proliferation, migration, invasion, and glycolysis metabolism of TSCC cells. Similarly, knockdown of CCR7 also could suppress the progression of TSCC. Besides, UCA1 overexpression promoted TSCC progression, while this promotion effect could be reversed by CCR7 silencing. miR-138-5p could be sponged by UCA1 and could target CCR7. Additionally, miR-138-5p overexpression could reverse the promotion effect of overexpressed UCA1 on TSCC progression. Furthermore, the UCA1 knockdown reduced TSCC tumor growth in vivo. In conclusion, lncRNA UCA1 might function as an oncogene in TSCC through regulating the miR-138-5p/CCR7 axis, providing a new biomarker for TSCC treatment.

Abstract A30: Super-enhancer-associated long noncoding RNA UCA1 interacts directly with AMOT to inhibit Hippo signaling pathway in epithelial ovarian cancer

Abstract Long noncoding RNAs (lncRNAs) have emerged as critical regulators of tumorigenesis and yet their mechanistic role remains challenging to characterize. Here, we present LncRNA Interpreter, a strategy integrating functional proteomics with interacting proteins to characterize lncRNAs. Its robustness is exemplified by lncRNA Urothelial Cancer Associated 1 (UCA1), a driver of ovarian cancer development. Reverse phase protein array (RPPA) analysis indicates that UCA1 inhibits Hippo signaling pathway and in vivo RNA antisense purification (iRAP) of UCA1 interacting proteins identified angiomotin (AMOT), a known YAP regulator, as direct binding partner. Loss-of-function experiments show that AMOT mediates Hippo signaling pathway inhibition by UCA1. UCA1 enhances the AMOT-YAP interaction to prevent YAP phosphorylation and facilitate its nuclear translocation. Together, our LncRNA Interpreter pipeline identified UCA1 as an lncRNA regulator of the Hippo signaling pathway and highlighted the UCA1-AMOT-YAP signaling axis in ovarian cancer development. LncRNA Interpreter can readily be applied to other lncRNAs implicated in complex diseases. Citation Format: Xianzhi Lin, Tassja J. Spindler, Marcos A de Souza Fonseca, Rosario I. Corona, Ji-Heui Seo, Felipe S Dezem, Lewyn Li, Janet M. Lee, Henry W. Long, Thomas A. Sellers, Beth Y. Karlan, Houtan Noushmehr, Matthew L. Freedman, Simon A. Gayther, Kate Lawrenson. Super-enhancer-associated long noncoding RNA UCA1 interacts directly with AMOT to inhibit Hippo signaling pathway in epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A30.

Long non-coding RNA UCA1 promotes malignant phenotypes of renal cancer cells by modulating the miR-182-5p/DLL4 axis as a ceRNA

BackgroundAccumulating literatures have indicated that long non-coding RNAs (lncRNAs) are potential biomarkers that play key roles in tumor development and progression. Urothelial cancer associated 1 (UCA1) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancers. However, the molecular mechanism of UCA1 in renal cancer is still needed to further explore.MethodsThe relative expression level of UCA1 was determined by Real-Time qPCR in a total of 88 patients with urothelial renal cancer and in different renal cancer cell lines. Loss-of-function experiments were performed to investigate the biological roles of UCA1 and miR-182-5p on renal cancer cell proliferation, migration, apoptosis and tumorigenicity. Comprehensive transcriptional analysis, dual-luciferase reporter assay and western blot etc. were performed to explore the molecular mechanisms underlying the functions of UCA1.ResultsIn this study, we found that UCA1 was significantly up-regulated in renal cancer. Moreover, increased UCA1 expression was positively correlated with differentiation and advanced TNM stage. Further experiments demonstrated that knockdown of UCA1 inhibited malignant phenotypes and Notch signal path of renal cancer cells, and miR-182-5p was reverse function as UCA1. UCA1 functioned as a miRNA sponge to positively regulate the expression of Delta-like ligand 4(DLL4) through sponging miR-182-5p and subsequently promoted malignant phenotypes of renal cancer cells, thus UCA1 playing an oncogenic role and miR-182-5p as an antioncogenic one in renal cancer pathogenesis.ConclusionUCA1-miR-182-5p-DLL4 axis is involved in proliferation and progression of renal cancer. Thus, this study demonstrated that UCA1 plays a critical regulatory role in renal cancer cell and UCA1 may serve as a potential diagnostic biomarker and therapeutic target of renal cancer.

Prognostic and clinicopathological significance of long non-coding RNA UCA1 in colorectal cancer: Results from a meta-analysis.

Objective:Urothelial cancer-associated 1 (UCA1), an oncogenic long non-coding RNA, was aberrantly upregulated in colorectal cancer (CRC). This study aimed to further explore the clinical value of UCA1 in CRC.Methods:Eligible studies were retrieved by searching Pubmed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, and Wanfang databases. Pooled hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were applied to assess the prognostic role and clinical significance of UCA1.Results:A total of 7 eligible studies with 775 cancer patients were recruited in the meta-analysis. The results showed that UCA1 overexpression was significantly correlated with poor overall survival in patients with CRC (HR = 2.25, 95% CI: 1.77–2.87, P < .001). There was also a significantly negative association between high UCA1 levels and tumor differentiation (OR = 2.84, 95% CI: 1.87–4.31, P < .001), lymph node metastasis (OR = 3.48, 95% CI: 2.24–5.41, P < .001), distant metastasis (OR = 2.67, 95% CI: 1.32–5.38, P = .006), tumor node metastasis stage (OR = 3.01, 95% CI: 2.16–4.18, P < .001), tumor invasion depth (OR = 2.18, 95% CI: 1.03–4.61, P = .04), and tumor size (OR = 2.27, 95% CI: 1.56–3.32, P < .001).Conclusions:Our study revealed that UCA1 overexpression was associated with poor prognosis and more advanced clinicopathological features, suggesting that UCA1 may serve as an indicator for unfavorable outcome of patients with CRC.

UPF1 inhibits the hepatocellular carcinoma progression by targeting long non-coding RNA UCA1

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. However, the molecular mechanism underlying HCC carcinogenesis remains to be further elucidated. Up-frameshift protein 1 (UPF1) is a RNA/DNA-dependent ATPase and ATP-dependent RNA helicase. Here, we explored the expression and function of UPF1 in HCC. In this study, we demonstrated that UPF1 expression was significantly reduced in hepatocellular carcinoma (HCC) tissues compared with the adjacent normal tissues. And further functional assays revealed that knockdown of UPF1 promoted HCC cells growth and invasion. Furthermore, we found that UPF1 could bind to long non-coding RNA urothelial cancer associated 1 (UCA1) and was negatively correlated with UCA1. UCA1 expression also affected HCC growth and invasion. Knockdown of UCA1 ameliorated the effect of UPF1 knock down on HCC growth and invasion. Knockdown of UPF1 enhances glycolysis in HCC. Taken together, our results provided new insights for finding novel therapeutic targets for hepatocellular carcinoma progression.

Long non-coding RNA UCA1 desensitizes breast cancer cells to trastuzumab by impeding miR-18a repression of Yes-associated protein 1

Breast cancer resistance to the monoclonal erbB2/HER2 antibody trastuzumab (or herceptin) has become a significant obstacle in clinical targeted therapy of HER2-positive breast cancer. Previous research demonstrated that such drug resistance may be related to dysregulation of miRNA expression. Here, we found that knockdown of the long non-coding RNA, urothelial cancer associated 1 (UCA1), can promote the sensitivity of human breast cancer cells to trastuzumab. Mechanistically, UCA1 knockdown upregulated miR-18a and promoted miR-18a repression of Yes-associated protein 1 (YAP1). A luciferase reporter assay confirmed the association of miR-18a with wild-type UCA1 but not with UCA1 mutated at the predicted miR-18a-binding site. The direct targeting of YAP1 by miR-18a was verified by the observation that miR-18a mimic suppressed luciferase expression from a construct containing the YAP1 3′ untranslated region. Meanwhile, reciprocal repression of UCA1 and miR-18a were found to be Argonaute 2-dependent. Knockdown of YAP1 recapitulated the effect of UCA1 silencing by reducing the viability of trastuzumab-treated breast cancer cells, whereas inhibition of miR-18a abrogated UCA1 knockdown-induced improvement of trastuzumab sensitivity in breast cancer cells. These findings demonstrate that the UCA1/miR-18a/YAP1 axis plays an important role in regulating the sensitivity of breast cancer cells to trastuzumab, which has implications for the development of novel approaches to improving breast cancer responses to targeted therapy.

Prognostic and clinicopathological role of long non-coding RNA UCA1 in various carcinomas.

Urothelial cancer associated 1 (UCA1) as an oncogenic long non-coding RNA (LncRNA) was aberrantly upregulated in various solid tumors. Numerous studies have demonstrated overexpression of UCA1 is an unfavorable prognostic indicator in cancer patients. This study aimed to further explore the prognosis role and clinical significance of UCA1 in cancer. Eligible studies were recruited by a systematic search in PubMed, Embase, Cochrane Library and Web of Science databases. A total of 19/16 studies with 1587/1291 cancer patients were included to evaluate the association between UCA1 expression and overall survival (OS) and clinicopathological factors of malignancies by computing hazard ratio (HR), odds ratios (OR) and confidence interval (CI). The meta-analysis indicated overexpression of UCA1 was significantly correlated with unexpected OS in patients with cancer (pooled HR = 1.85, 95% CI 1.62–2.10, p < 0.001). There was also a significantly negative association between high level of UCA1 and poor grade cancer (pooled OR = 2.74, 95% CI 2.04–3.70, p < 0.001) and positive lymphatic metastasis (pooled OR = 2.43, 95% CI 1.72–3.41, p < 0.001). In conclusion, our study suggested that UCA1 was correlated with more advanced clinicopathological features and poor prognosis as a novel predictive biomarker of patients with various tumors.

Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR-196a-5p in bladder cancer cells

Chemoresistance constitutes the major failing of clinical therapy for bladder cancer. However, the molecular mechanisms involved in the chemoresistance of bladder cancer are unclear. Long non-coding RNAs (lncRNAs) have been implicated in chemotherapeutic drug resistance. Urothelial Cancer Associated 1 (UCA1), an lncRNA, is reportedly upregulated in human bladder carcinoma and promotes cancer cell proliferation, migration, invasion, and drug resistance. In the present study, knockdown of UCA1 decreased chemosensitivity to cisplatin/gemcitabine by suppressing cell proliferation and inducing apoptosis, while overexpression of UCA1 increased chemosensitivity in bladder cancer cells. Moreover, UCA1 activated transcription factor CREB which led to miR-196a-5p expression by binding with its promoter. miR-196a-5p induction is involved in UCA1 inhibition of apoptosis induced by cisplatin/gemcitabine via targeting p27Kip1. These results provide a novel UCA1-CREB-miR-196a-5p paradigm to explain in part how UCA1 functions in cisplatin/gemcitabine resistance, and suggest that UCA1 may be a potential therapeutic target for chemotherapy in bladder cancer.

Long non-coding RNA UCA1 promotes the tumorigenesis in pancreatic cancer.

The contribution of long non-coding RNAs (lncRNAs) to tumorigenesis and metastasis of pancreatic cancer (PC) remains largely unknown. Urothelial cancer-associated 1 (UCA1), which is an originally identified lncRNA in bladder cancer, has be proved to play a pivotal role in bladder cancer progression and embryonic development. In this study, we detected the mRNA expression of UCA1 in 128 PC patients by qRT-PCR, and found that UCA1 expression was significantly, up-regulated in tumor tissues than that in matched adjacent non-tumor tissues (p<0.05). Clinicopathological analysis demonstrated that UCA1 expression in PC significantly correlated with malignant potential factors such as tumor size (p=0.021), depth of invasion (p=0.033), CA19-9 level (p=0.034) and tumor stage (p=0.013). Cox proportional hazards regression analysis also confirmed that high UCA1 expression was an independent prognostic biomarker of PC (p=0.046), which led to an obviously shorter 5-year overall survival (OS) compared to those patients with low UCA1 expressions (p=0.018). Furthermore, we effectively down-regulated UCA1 mRNA expression by transfecting RNA interfere fragments into SW-1990 cells, and our results in vitro indicated that down-regulation of UCA1 could effectively inhibit the cell proliferative activities, induce apoptotic rate and cause cell cycle arrest in PC cells (p<0.05). Meanwhile, UCA1 expression negative-correlated with p27 in PC tissues (r2=0.46, p<0.01), and knockdown of p27 partly abrogated the cell proliferative activities caused by UCA1 (p<0.05). Our results raised the possibility of using UCA1 as a potential prognostic biomarker and therapy target of PC, and down-regulation of UCA1 might be considered to be a novel molecular treatment strategy for patients with PC.

Long non-coding RNA UCA1 induces non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway in EGFR-mutant non-small cell lung cancer.

The aim of this study was to explore the role of long non-coding RNA UCA1 (urothelial cancer-associated 1) in acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). In our study, UCA1 expression was significantly increased in lung cancer cells and patients with acquired resistance to EGFR-TKIs. Over-expression of UCA1 was significantly associated with a shorter progression-free survival (PFS) [13.0 vs. 8.5 months, P < 0.01] in tumors with respond to EGFR-TKIs. The significant relationship was not observed in patients with T790M mutation (10.5 vs. 12.0 months, P = 0.778), but in patients with non-T790M (19.0 vs. 9.0 months, P = 0.023). UCA1 knockdown restored gefitinib sensitivity in acquired resistant cells with non-T790M and inhibited the activation of the AKT/mTOR pathway and epithelial-mesenchymal transition (EMT). The mTOR inhibitor was effective in UCA1-expressing cell PC9/R. Inhibiting mTOR could change the expression of UCA1, although there was no significant difference. In conclusion, the influence of over-expression of UCA1 on PFS for patients with acquired resistance to EGFR-TKIs was from the subgroup with non-T790M mutation. UCA1 may induce non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway and EMT.

Increased expression of the long non-coding RNA UCA1 in tongue squamous cell carcinomas: a possible correlation with cancer metastasis

The aim of this study was to examine the expression of several cancer-related long non-coding RNAs (lncRNAs) in patients with tongue squamous cell carcinoma (TSCC) and to explore its clinical significance. A total of 94 TSCC tissue specimens and matched adjacent normal tissue specimens were collected from patients undergoing surgery for TSCC. Differences in the expression of cancer-related lncRNAs were examined via quantitative reverse transcriptase polymerase chain reaction. WST-1 assay and transwell migration assay were carried out to estimate the proliferation and migration abilities of TSCC cells with different expression levels of urothelial cancer-associated 1 (UCA1) lncRNA. The expression levels of lncRNA UCA1 were significantly elevated in TSCC tissues (P < .0001) and were statistically correlated with lymph node metastasis (P = .0371). Over-expression of UCA1 lncRNA could promote metastatic but not proliferation ability of TSCC cells. Expression of UCA1 lncRNA was enhanced in TSCCs and may play a role in tumor metastasis.