Urothelial Carcinoma Associated 1 Overexpression Research Articles

Abstract 1291: Signaling pathways modulated by lncRNA UCA1 during anchorage-independent growth in colorectal cancer

Abstract Colorectal cancer (CRC) is the second deadliest cancer, and over 40-50% of patients develop metastasis during their fight against the disease. CRC survival rate drops from 90% to 14% when the condition is contained within the colon vs. when found at distant sites within the body. Metastasis is a multistep process and one of the critical steps for cancer cells to acquire anoikis resistance to survive after detachment from the primary sites and travel through the circulatory and lymphatic systems to distant target organs. Thus, understanding the molecular players involved in the anoikis process and metastasis could be vital for improving the survival of CRC patients. The aberrant expression of a long noncoding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been identified in CRC. However, its role in metastasis processes is not yet well defined. Our preliminary results in the anchorage-independent growth (anoikis model) demonstrate increased expression of lncRNA UCA1. Moreover, the overexpression of lncRNA UCA1 led to high expression of stemness markers SOX2 and Kaiso, along with increased survival of anchorage-independent cells, which indicates a potential mechanistic role of UCA1 in anoikis resistance. Thus, in this study, we propose elucidating the role(s) of UCA1 and its associated signaling pathways during anoikis resistance. We hypothesize that the overexpression of lncRNA UCA1 enhances CRC metastasis through anoikis resistance-associated signaling pathways. We will utilize Isogenic CRC cell lines SW480 (oncogenic) and SW620 (metastatic) to understand the mechanistic regulation of anoikis resistance. Lentiviral transduced stable overexpression (SW480+UCA1//GFP) and knockdown (SW620+CRISPRgUCA1) cell lines have been utilized for this study. After subjecting these cell lines (along with control) to anchorage-independent growth conditions, cell cycle, pro-survival, anti-apoptotic, stemness, and glucose metabolism factors will be analyzed through RT-PCR, Digital Droplet PCR (ddPCR), western blot, and FACS analyses. Utilizing the same model, we will examine lncRNA UCA1 linked anoikis resistance specific phosphorylation profiles of kinases, their protein substrates using the Proteome Profiler Phospho-Human Phospho-Kinase Array. Citation Format: Sophia Leslie, Kyle D. Doxtater, Samantha Lopez, Kristopher Ezell, Adithya Anilkumar, Amayrani Sanchez, Bilal Hafeez, Tamer Oraby, Meena Jaggi, Timothy Loy, Subhash Chauhan, Manish K. Tripathi. Signaling pathways modulated by lncRNA UCA1 during anchorage-independent growth in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1291.

Long noncoding RNA UCA1 promotes the expression and function of P-glycoprotein by sponging miR-16-5p in human placental BeWo cells.

Investigations on placental P-glycoprotein (P-gp) regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. The role of long noncoding RNA (lncRNA) on placental P-gp regulation is lacking. The present study was carried out to investigate the regulation and underlying mechanisms of lncRNA urothelial carcinoma associated 1 (UCA1) on P-gp in Bewo cells. lncRNA UCA1 inhibition or overexpression could decrease or increase ABCB1 mRNA expression, P-gp expression and its cellular efflux function, respectively. RNA-FISH revealed that lncRNA UCA1 was mainly located in the cytoplasm of Bewo cells. MicroRNA array was applied and 10 significant miRNAs was identified after lncRNA UCA1 inhibition. Databases of LncTarD, LncRNA2Target, and miRcode were further used to search potential target miRNAs of lncRNA UCA1 and miR-16-5p was screened out. Thereafter, we confirmed that miR-16-5p expression was significantly upregulated or reduced after lncRNA UCA1 knockdown or overexpression, respectively. Furthermore, we also proved that ABCB1 mRNA expression, P-gp expression and its cellular efflux function was enhanced or reduced after miR-16-5p inhibition or overexpression, respectively. The rescue experiment further indicated that miR-16-5p was involved in the positive regulation of lncRNA UCA1 on the expression and function of P-gp. Lastly, dual-luciferase reporter system, RNA-binding protein immunoprecipitation and RNA pull-down assays were performed to explore the relationships among lncRNA UCA1, miR-16-5p, and ABCB1. It was found that lncRNA UCA1(1103-1125) could directly interact with miR-16-5p and miR-16-5p could directly target ABCB1 coding DNA sequence region (882-907). In conclusion, LncRNA UCA1 could promote the expression and function of P-gp by sponging miR-16-5p in BeWo cells.

Mechanistic study of lncRNA UCA1 promoting growth and cisplatin resistance in lung adenocarcinoma

AimThis study aimed to explore the mechanism of LncRNA urothelial carcinoma-associated 1 (UCA1) promoting cisplatin resistance in lung adenocarcinoma (LUAD).MethodThe UCA1 expression level in LUAD cell lines was detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). We overexpressed UCA1 in A549 cells and downregulated UCA1 in A549/DDP cells by the lentivirus‑mediated technique. Subsequently, in vitro, and in vivo functional experiments were performed to investigate the functional roles of UCA1 in the growth and metastasis of LUAD cell lines. Furthermore, RNA pulldown, mass spectrometry, and RNA immunoprecipitation technique were performed to analyze various downstream target factors regulated by UCA1.ResultsThe results revealed a higher UCA1 expression level in A549/DDP cells and LUAD tissues than in A549 cells and adjacent cancer tissues. UCA1 expression was significantly associated with distant metastasis, clinical stage, and survival time of patients with LUAD. UCA1 overexpression significantly increased the proliferation, invasion, clone formation, and cisplatin resistance ability and enhanced the expression levels of proliferating cell nuclear antigen and excision repair cross-complementing gene 1 in A549 cells. However, these trends were mostly reversed after the knockdown of UCA1 in A549/DDP cells. Tumorigenic assays in nude mice showed that UCA1 knockdown significantly inhibited tumor growth and reduced cisplatin resistance. Enolase 1 was the RNA-binding protein (RBP) of UCA1.ConclusionBased on the results, we concluded that UCA1 promoted LUAD progression and cisplatin resistance and hence could be a potential diagnostic marker and therapeutic target in patients with LUAD.

UCA1 Overexpression Promotes Hypoxic Breast Cancer Cell Proliferation and Inhibits Apoptosis via HIF-1α Activation.

The noncoding RNA termed urothelial carcinoma-associated 1 (UCA1) is an oncogenic lncRNA involved in promoting the growth of several tumors through various pathways. The aim of this study was to explore the expression of UCA1 in hypoxic breast cancer and its impact on tumorigenesis in low levels of oxygen. Here, we show that UCA1 is upregulated in a number of hypoxic (1% O2) breast cancer cells. In addition, UCA1 expression is significantly overexpressed in breast cancer tissues compared to matched normal cells. UCA1 knockdown in hypoxia inhibits breast cancer proliferation and induces apoptosis. The knockdown of hypoxia-inducible transcription factor 1α (HIF-1α) but not HIF-2α significantly decreases the expression of UCA1 in hypoxia. Overall, these findings indicate that UCA1 is a hallmark of hypoxic breast cancer and its expression is positively regulated by HIF-1α.

Overexpression of long non-coding RNA urothelial carcinoma associated 1 causes paclitaxel (Taxol) resistance in colorectal cancer cells by promoting glycolysis

Some colorectal cancer patients show resistance to conventional chemotherapeutic agents including Taxol. This study investigated the roles of lncRNA urothelial carcinoma-associated 1 (UCA1) in the modulation of Taxol resistance in human colorectal cancer cells. According to our results, UCA1 was significantly upregulated in colon cancer cell lines/tissues. Construction of the UCA1 overexpression vector revealed that high UCA1 expression was responsible for Taxol resistance and that Taxol can induce UCA1 expression. Importantly, Taxol-resistant cells had a higher glycolysis rate and upregulated expression of the key glycolysis enzymes hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA) than Taxol-sensitive cells. Further research demonstrated that UCA1 could directly regulate glycolysis by regulating HK2 and LDHA expression, which contributes to Taxol resistance. UCA1 is a potential target to overcome chemoresistance in colorectal cancer. We report the modulation of UCA-1-regulated glycolysis as a novel anticancer strategy along with the novel role of UCA1 in Taxol resistance.

Upregulated Long Noncoding RNA UCA1 Enhances Warburg Effect via miR-203/HK2 Axis in Esophagal Cancer.

Reprogrammed glucose metabolism of enhanced aerobic glycolysis, also known as Warburg effect, which exerts a significant contributor to cancer progression, is regarded as a hallmark of cancer. The roles of long noncoding RNAs (lncRNA) in regulating cancer via metabolic reprogramming are mostly unknown, including esophagal cancer (EC). Here, we showed that how the lncRNA urothelial carcinoma associated 1 (UCA1) exerts pro-oncogene in regulating EC glucose metabolism. Firstly, we found that upregulated UCA1 expression enhances the malignant phenotypes of EC, including poor outcome, larger tumor size, positive lymphatic invasion, and advanced pathological stages. UCA1 silencing could suppress EC cell proliferation and metastasis. Following, bioinformatics analyses revealed that UCA1 regulated the HK2 expression through functioning as a competing endogenous RNA (ceRNA). Mechanistically, UCA1 overexpression could elevate the activation of HK2 oncogenes via inhibition of miR-203 activity, as evidenced by the positive correlation of UCA1 with HK2 and inverse correlation with miR-203 expression. Luciferase activity assay further verified the targeting relationship between UCA1, miR-203, and HK2. Upregulated UCA1 in EC cells significantly suppressed the degradation of HK2 by miR-203. Further research showed that upregulated UCA1 effectively increased the rate of glucose uptake, lactate output, and ECAR value, all of which can be attenuate by HK2 interference and 2-DG, whereas knockdown of UCA1 had the opposite effect. In sum, our findings suggest that the UCA1/miR-203/HK2 axis contributes to EC development by reprogramming tumor glucose metabolism, providing new insight into the management of EC patients.

Long Noncoding RNA UCA1 Facilitates Endometrial Cancer Development by Regulating KLF5 and RXFP1 Gene Expressions.

Objective: Long noncoding RNA urothelial carcinoma associated 1 (UCA1) was found to facilitate endometrial cancer cell metastasis, and high UCA1 expression predicted endometrial cancer development and patients' worsened outcomes. This research aimed to investigate the cancer promoting role and mechanism of UCA1 in endometrial cancer. Materials and Methods: Around 64 endometrioid adenocarcinoma patients' tissue specimens were analyzed by qRT-PCR. Primary endometrial cancer cell culture was established in vitro. UCA1 overexpression or knockdown was executed by adenoviral transduction. Cell proliferation, apoptosis, colony formation, transwell invasion, and epithelia-to-mesenchymal transition of primary endometrial cancer cells were assessed. Interactions among UCA1, microRNAs (miRNAs), and mRNAs were investigated by luciferase reporter assay and argonaute 2 (AGO2)-RNA immunoprecipitation. Nude mouse xenograft assay was used to explore the role of UCA1 in endometrial cancer in vivo. Results: UCA1 was significantly upregulated in endometrial cancer tissues compared to normal tissues. High expression of UCA1 associated with endometrial cancer progression and patients' decreased survival. Overexpressing UCA1 significantly increased the malignancy of primary endometrial cancer cells in vitro, while UCA1 knockdown showed opposite effect. Kruppel-like factor 5 (KLF5) and relaxin like family peptide receptor 1 (RXFP1) were found as two UCA1 co-expressing genes in endometrial cancer. UCA1 increased the malignancy of endometrial cells partially through KLF5, and it increased the relaxin 2-induced endometrial cancer cell metastasis through RXFP1. UCA1 reduced the si-RNA-induced silencing of KLF5 and RXFP1 genes in endometrial cancer cells. MiR-143-3p and miR-1-3p were found to interact with both UCA1 and KLF5 mRNA. In addition, knockdown of UCA1 suppressed tumor growth in endometrial cancer in vivo. Conclusion: UCA1 might facilitate endometrial cancer development by upregulating KLF5 and RXFP1 gene expression by sponging miR-143-3p and miR-1-3p.

Silencing of lncRNA UCA1 curbs proliferation and accelerates apoptosis by repressing SIRT1 signals by targeting miR-204 in pediatric AML.

The long noncoding RNA urothelial carcinoma-associated 1 (UCA1) has been reported to sustain the proliferation of acute myeloid leukemia (AML) cells through downregulating cell cycle regulators p27kip1 . Yet, the foundational mechanism of UCA1 in AML pathologies remains unclear. Herein, we found an escalation of UCA1 expression and suppression of miR-204 expression in pediatric AML patients and cells. UCA1 silencing suppressed cell proliferative abilities, promoted apoptotic rates, decreased Ki67, and increased cleaved caspase-3 in AML cells. Moreover, UCA1 sponged miR-204 and suppressed its expression. UCA1 overexpression inversed the miR-204 suppressed proliferation and promoted apoptosis. UCA1 also boosted the expression of SIRT1, a miR-204 target, via the sponging interaction. Furthermore, miR-204 inhibited inducible nitric oxide synthase and cyclooxygenase-2 expression, while UCA1 overexpression inversed the inhibitory effects in AML cells. Our findings concluded that UCA1 downregulation repressed cell proliferation and promoted apoptosis through inactivating SIRT1 signals by upregulating miR-204 in pediatric AML.

The long non-coding RNA, urothelial carcinoma associated 1, promotes cell growth, invasion, migration, and chemo-resistance in glioma through Wnt/β-catenin signaling pathway.

The long non-coding RNA, urothelial carcinoma associated 1 (UCA1) has been demonstrated to play important roles in various types of cancers. This study investigated the functional role of UCA1 in glioma and explored the underlying molecular mechanisms. UCA1 was found to be highly up-regulated in glioma cells, and knock-down of UCA1 inhibited cell growth, invasion and migration, and also induced apoptosis in glioma cells. On the other hand, overexpression of UCA1 promoted cell proliferation, cell invasion and migration in glioma cells. Knock-down of UCA1 suppressed the activity of Wnt/β-catenin signaling, and treatment with lithium chloride restored the inhibitory effect of UCA1 knock-down on cell invasion and migration. More importantly, the aberrant expression of UCA1 was associated with chemo-resistance to cisplatin and temozolomide in glioma cells via interacting with Wnt/β-catenin signaling. In vivo studies showed that overexpression of UCA1 promoted the in vivo tumor growth of U87 cells in the nude mice. Clinically, UCA1 was found to be up-regulated in glioma tissues and higher expression level of UCA1 was correlated with poor survival in patients with glioma. Taken together, our results showed that UCA1 had a functional role in the regulation of glioma cell growth, invasion and migration, and chemo-resistance possibly via Wnt/β-catenin signaling pathway.

Long Noncoding RNA UCA1 Overexpression Is Associated with Poor Prognosis in Digestive System Malignancies: A Meta-analysis.

Long noncoding RNA (lncRNA) urothelial carcinoma associated 1 (UCA1) has been reported to be highly expressed in many kinds of cancers. This meta-analysis summarized its potential prognostic value in digestive system malignancies. A meta-analysis was performed through a comprehensive search in PubMed, EMBASE, the Cochrane Library, Web of Science and Chinese National Knowledge Infrastructure (CNKI) for suitable articles on the prognostic impact of UCA1 in digestive system malignancies from inception to June 27, 2019. Pooled hazard ratios (HRs) with 95% confidence interval (95%CI) were calculated to summarize the effect. Sixteen studies were included in the study, with a total of 1504 patients. A significant association was observed between UCA1 abundance and poor overall survival (OS), and shorter disease-free survival (DFS) for patients with digestive system malignancies, with pooled HR of 2.07 (95%CI: 1.74-2.47), and of 2.50 (95%CI: 1.62-3.86). Subgroup analysis and sensitivity analysis suggested the reliability of our findings. It is suggested that UCA1 abundance may serve as a reliable predictive factor for poor prognosis in patients with digestive system malignancies.

Long non-coding RNA UCA1 relieves cardiomyocytes H9c2 injury aroused by oxygen-glucose deprivation via declining miR-122

Background Many lncRNAs have been recognized as critical regulatory factors in acute myocardial infarction (AMI). Herein, we further tested the influence of long non-coding RNA urothelial carcinoma associated 1 (UCA1) on cardiomyocytes injury in AMI, along with the role of microRNA-122 (miR-122) in this influence. Methods Cardiomyocytes H9c2 was subjected to oxygen-glucose deprivation (OGD) stimulation. Cell viability and apoptosis were assessed. The UCA1 and miR-122 expressions were measured by qRT-PCR. Plasmids and miRNAs transfection were utilized to elevate UCA1 and miR-122 expressions. Subsequently, the influences of UCA1 and/or miR-122 overexpression on OGD-aroused H9c2 cell viability inhibition and apoptosis were probed. The AKT/mTOR and JNK/p38MAPK pathways in cells were analyzed. Results OGD aroused H9c2 cell injury by suppressing cell viability and elevating cell apoptosis. Followed by OGD stimulation, the UCA1 expression was lowered in H9c2 cells. Overexpression of UCA1 weakened H9c2 cell injury aroused by OGD and declined miR-122 expression. Moreover, miR-122 attended to the influence of UCA1 overexpression on OGD-aroused H9c2 cell injury. Overexpression of UCA1 weakened OGD-aroused AKT/mTOR pathway inactivation and JNK/p38MAPK pathway activation by declining miR-122. Conclusion UCA1-relieved OGD-aroused H9c2 cell injury might be achieved via declining miR-122 and then promoting AKT/mTOR pathway and suppressing JNK/p38MAPK pathway.

Long non-coding RNA UCA1 promotes proliferation and invasion of intrahepatic cholangiocarcinoma cells through targeting microRNA-122.

Long non-coding RNA urothelial carcinoma-associated 1 (UCA1) has a role in various common types of human malignancy, including cholangiocarcinoma; however, the expression and function of UCA1 in intrahepatic cholangiocarcinoma (ICC) has remained elusive. In the present study, it was observed that UCA1 expression was significantly upregulated in ICC tissues and cell lines compared with that in the adjacent non-tumour tissues and a human intrahepatic biliary epithelial cell line, respectively. The increased expression of UCA1 was significantly associated with lymph node metastasis and clinical T-stage in ICC. Furthermore, the ICC patients with high expression of UCA1 had a shorter survival time when compared with that of patients with low UCA1 expression. Knockdown of UCA1 caused a significant decrease in ICC cell proliferation and invasion, while ectopic overexpression of UCA1 significantly promoted the proliferation and invasion of ICC cells. Furthermore, it was revealed that UCA1 directly binds to microRNA (miR)-122 to negatively regulate its expression in ICC cells. In addition, miR-122 mimics abrogated the promoting effects of UCA1 on ICC cell proliferation and invasion. In addition, an inverse correlation between miR-122 and UCA1 expression in ICC tissues was observed. In conclusion, the present study demonstrates that the lncRNA UCA1 promotes ICC cell proliferation and invasion at least in part by targeting miR-122, suggesting that the UCA1/miR-122 interaction may become a potential therapeutic target for the treatment of ICC.

Long non-coding RNA UCA1 promoted the growth of adrenocortical cancer cells via modulating the miR-298-CDK6 axis

Adrenocortical cancer (ACC) is an aggressive malignancy with no available effective treatments; therefore, exploring the molecular mechanisms involved in the initiation and progression of ACC is quite important. Here, we found that the long noncoding RNA urothelial carcinoma-associated 1 (UCA1) was highly expressed in ACC tissues and closely associated with the TNM stage and metastasis of ACC patients. Overexpression of UCA1 significantly promoted the proliferation and suppressed the apoptosis of ACC cells. Mechanism study showed that UCA1 acted as sponge of miR-298 and decreased the expression abundance of miR-298 in ACC cells. Further investigation identified that miR-298 bound the 3’-UTR of the cyclin-dependent kinase 6 (CDK6) and inhibited the expression of CDK6. Consistently, ectopic expressed UCA1 suppressed miR-298 and up-regulated the expression of CDK6, which promoted the cell cycle progression of ACC cells. Taken together, our results identified the potential oncogenic function of UCA1 in ACC by regulating the miR-298-CDK6 axis.

Overexpression of LncRNA-UCA1 Correlates with Lung Adenocarcinoma Progression and Poor Prognosis.

Long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been predicted to play a critical role in various biological processes including tumorigenesis. However, the clinical significance of UCA1 in lung adenocarcinoma (LUAD) is still not understood in detail. The aim of this study was to assess the clinical significance of the UCA1 expression levels in LUAD based on publicly available data and to evaluate its potential signaling pathways. The RNA-sequencing (RNA-seq) dataset and clinical information of all LUAD patients were downloaded from The Cancer Genome Atlas (TCGA). Kaplan-Meier plot and log-rank test were performed for survival analysis; Cox proportional hazards regression model were used to assess the relative factors. Furthermore, Starbase, Cbioportal, and Multi Experiment Matrix starbases were used to identify UCA1-related genes in LUAD. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of UCA1-related genes were performed using DAVID. The expression level of UCA1 in LUAD tissues (n = 468) was significantly increased compared with the adjacent non-tumor lung tissues (n = 52) (p < 0.0001). In addition, UCA1 level was significantly correlated with TNM stage and lymph node metastasis. Survival analysis showed that UCA1 over-expression was significantly associated with poor overall survival (OS) (p = 0.0098) and poor recurrence-free survival (RFS) (p = 0.0298) in LUAD patients. Multivariate analysis confirmed that high expression of lncRNA-UCA1 was an independent prognostic factor of poor OS (HR = 1.353, 95% CI: 1.005 - 1.822, p = 0.046). Finally, KEGG analysis for UCA1-related genes indicated that UCA1 might be enriched with the microRNAs in cancer, pathways in cancer, endocytosis, focal adhesion, and proteoglycans in cancer. This study showed that UCA1 may be involved in lung carcinogenesis, which could act as a biomarker of prognosis and therapeutic target in LUAD patients.

UCA1 overexpression is associated with less aggressive subtypes of bladder cancer.

Non-coding RNAs (ncRNAs) have been shown to serve important roles in carcinogenesis via complex mechanisms, including transcriptional and post-transcriptional regulation, and chromatin interactions. Urothelial carcinoma-associated 1 (UCA1), a long ncRNA, was recently shown to have tumorigenic properties in urothelial bladder cancer (UBC), as demonstrated by enhanced proliferation, migration, invasion and therapy resistance of UBC cell lines in vitro. These in vitro findings suggested that UCA1 is associated with aggressive tumor behavior and could have prognostic implications in UBC. The aims of the present study were to therefore to investigate the statistical associations between UCA1 RNA expression and UBC pathological features, patient prognosis and p53 and Ki-67 expression. Chromogenic in situ hybridization and immunohistochemistry were performed on UBC tissue microarrays to characterize UCA1 RNA, and p53 and Ki-67 expression in 208 UBC cases, including 145 non-muscle-invasive and 63 muscle-invasive cases. UCA1 was observed in the tumor cells of 166/208 (80%) UBC cases tested. No expression was noted in normal stromal and endothelium cells. Patients with UBC that overexpressed UCA1 (35%) had a significantly higher survival rate (P=0.006) compared with that in patients with UBC that did not overexpress UCA1. This prognostic factor was independent of tumor morphology, concomitant carcinoma in situ, tumor grade and tumor stage. In addition, the absence of UCA1 overexpression was significantly associated with a high Ki-67 proliferative index (P=0.008) and a p53 ‘mutated’ immunoprofile (strong nuclear expression or complete absence of staining; P=0.003). In conclusion, the present results identified UCA1 as potentially being a novel independent prognostic marker in UBC that was associated with a better patient prognosis and that could serve a pivotal role in bladder cancer carcinogenesis.

Knockdown of LncRNA-UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the microRNA-125a/hexokinase 2 pathway.

Dysregulation of lncRNAs is implicated in chemoresistance in varieties of tumor including acute myeloid leukemia (AML). LncRNA urothelial carcinoma-associated 1 (UCA1) was reported to play an oncogenic role in AML. However, whether UCA1 was involved in chemoresistance in pediatric AML remains unclear. UCA1 expression in AML patients after adriamycin (ADR)-based chemotherapy and ADR-resistant AML cells was examined by qRT-PCR. The effects of UCA1 on the cytotoxicity of ADR and glycolysis were evaluated by MTT assay and measuring the glucose consumption and lactate production in HL60 and HL60/ADR cells, repectively. The protein levels of hypoxia-inducible factor 1α (HIF-1α) and hexokinase 2 (HK2) were determined by Western blot. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm the relationships between UCA1, HK2, and miR-125a. We found that UCA1 expression was upregulated following ADR-based chemotherapy. Knockdown of UCA1 increased the cytotoxic effect of ADR and inhibited HIF-1α-dependent glycolysis in ADR-resistant AML cells. Additionally, UCA1 functioned as a ceRNA of miR-125a by directly binding to miR-125a. HK2, a target of miR-125a, was positively regulated by UCA1 in HL60 and HL60/ADR cells. More notably, UCA1 overexpression overturned miR-125-mediated inhibition on HIF-1α-dependent glycolysis in HL60 and HL60/ADR cells. Furthermore, 2-deoxy-glucose (2-DG) exposure inhibited HIF-1α-dependent glycolysis, and attenuated UCA1-induced increase of chemoresistance in HL60 and HL60/ADR cells. We conclude that knockdown of UCA1 plays a positive role in overcoming the chemoresistance of pediatric AML, through suppressing glycolysis by the miR-125a/HK2 pathway, contributing to a better understanding of the molecular mechanism of chemoresistance in AML.

Circulating UCA1 is highly expressed in patients with systemic lupus erythematosus and promotes the progression through the AKT pathway.

To investigate the role of Urothelial Carcinoma Associated 1 (UCA1) during the progression of systemic lupus erythematosus (SLE) and the underlying mechanism. UCA1 expression in peripheral blood of SLE patients, as well as the expression of protein kinase B (AKT) in the peripheral blood mononuclear cell (PBMC), was detected by qRT-PCR. Expression differences in UCA1 and AKT between different groups were compared by t-test or univariate analysis. Through correlation analysis, the correlation between UCA1, AKT and clinical indicators of patients was analyzed. After overexpression and knockout of UCA1, the effect on phenotypes of BaF3 cell was examined. Finally, we analyzed the correlation between AKT and UCA1, and the effect on AKT pathway after overexpression and knockout of UCA1. We found that plasma level of UCA1 and AKT was significantly enhanced in SLE patients. By analyzing the clinical data, a higher UCA1 level was observed in female patients than in males. In addition, UCA1 level in SLE patients with active stage and pathological lesions was higher than those in a stable stage without organ involvement. Correlation analysis showed that there was a positive correlation between UCA1 and C3, anti-ds-DNA, ESR and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Similarly, there was a positive correlation between AKT and C3, anti-ds-DNA, erythrocyte sedimentation rate (ESR) and SLEDAI, respectively. After overexpression and knockdown of UCA1, it was found that overexpression of UCA1 significantly enhanced cell proliferation, while the interference with UCA1 significantly inhibited cell proliferation. Western blot revealed increased expressions of PI3K and AKT after overexpressing UCA1, whereas knockdown of UCA1 led significantly decreased expressions of PI3K and AKT. UCA1 expression was significantly increased in SLE, which promoted the progression of SLE by activating AKT pathway.

Long non-coding RNA UCA1 indicates an unfavorable prognosis and promotes tumorigenesis via regulating AKT/GSK-3β signaling pathway in cholangiocarcinoma.

Long non-coding RNAs (lncRNAs) have been documented to play key roles in a wide range of pathophysiological processes, including cancer initiation and progression. Recently, the aberrant expression of urothelial carcinoma associated 1 (UCA1) was observed in many types of cancers. However, its clinical relevance and exact effects in cholangiocarcinoma (CCA) remains unknown. In the present study, we aimed to investigate the clinical significance of UCA1 and evaluate its prognostic value in patients with CCA. Besides, the functional roles of UCA1 were detected both in vitro and in vivo. Moreover, potential signaling pathways were explored to clarify the molecular mechanisms underlying CCA cell proliferation. The results indicated that UCA1 transcription is enhanced in both CCA tissue samples and cell lines, and this overexpression is associated with tumor stage (P = 0.007), lymph node invasion (P = 0.027), TNM stage (P = 0.004) and postoperative recurrence (P = 0.033) of CCA patients. Besides, UCA1 could function as an independent prognostic predictor for overall survival in patients with CCA (P = 0.014). For the part of functional assays, knockdown of UCA1 could attenuate CCA cell growth both in vitro and in vivo. Besides, UCA1 facilitates apoptosis via Bcl-2/caspase-3 pathway. In addition, UCA1 regulates migration and invasion potential of CCA cells by affecting EMT. Furthermore, AKT/GSK-3β axis was activated to upregulate CCND1 expression due to overexpression of UCA1 in CCA. To summary, UCA1 might be a potentially useful prognostic biomarker and therapeutic target for CCA.

Augmented expression levels of lncRNAs ecCEBPA and UCA1 in gastric cancer tissues and their clinical significance.

Objective(s):As the second cause of cancer death, gastric cancer (GC) is one of the eminent dilemmas all over the world, therefore investigating the molecular mechanisms involved in this cancer is pivotal. Unrestricted proliferation is one of the characteristics of cancerous cells, which is due to deficiency in cell regulatory systems. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of the epigenome. lncRNA extra coding CEBPA (ecCEBPA) is involved in DNA methylation. This lncRNA reduces CEBPA promoter methylation by interacting with DNA methyltransferase 1. lncRNA UCA1 (urothelial carcinoma-associated 1) elevates cell proliferation through the PI3K/Akt signaling pathway which has a critical role in cell growth and apoptosis. The aim of this study was to examine the expression of ecCEBPA and UCA1 genes in GC tissues as well as their clinical significance.Materials and Methods:Total RNA extraction, cDNA synthesis, and quantitative real-time PCR were performed for cells and 80 paired GC tissues. Furthermore, clinical relevance of UCA1 expression was investigated in TCGA cohort data.Results:Our results showed ecCEBPA and UCA1 over-expression in GC tissues. Furthermore, lncRNAs associations with clinicopathological features were demonstrated both in the current and TCGA cohort. Kaplan-Meier analysis indicated that patients with higher UCA1 expression had a worse overall survival in the case of pancreatic and lung adenocarcinomas but not other solid cancer types including GC.Conclusion:These data demonstrate UCA1 and ecCEBPA involvement in GC and suggest that these lncRNAs might be useful as diagnostic/ prognostic biomarkers in cancer.

LncRNA UCA1 in anti-cancer drug resistance.

The pivotal role of the long non-coding RNA (lncRNA) urothelial carcinoma associated 1 (UCA1) in anti-cancer drug resistance has been confirmed in many cancers. Overexpression of lncRNA UCA1 correlates with resistance to chemotherapeutics such as cisplatin, gemcitabine, 5-FU, tamoxifen, imatinib and EGFR-TKIs, whereas lncRNA UCA1 knockdown restores drug sensitivity. These studies highlight the potential of lncRNA UCA1 as a diagnostic and prognostic biomarker, and a therapeutic target in malignant tumors. In this review, we address the role of lncRNA UCA1 in anti-cancer drug resistance and discuss its potential in future clinical applications.