652995

UCA1

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.

PURPOSE: Long non-coding RNA (LncRNA) urothelial carcinoma-associated 1 (UCA1) is reported to be dysregulated in hepatocellular carcinoma (HCC) progression. However, the functions of UCA1 in HCC still need further study. The aim is to detect the role of UCA1 involving in HCC cells proliferation and invasion, and epithelial-mesenchymal transition (EMT). METHODS: The quantitative real-time PCR was used to detect the UCA1 and miR-203 expression levels in 60 cases' HCC tissues and adjacent normal tissues. Western blotting analysis was performed to detect the EMT markers E-cadherin, Vimentin and transcription factor Snail1, Snail2 expression. Luciferase reporter assay, RNA immunoprecipitation (RIP) and pull-down assays were used to evaluate whether miR-203 was a target of UCA1. RESULTS: Our results showed that UCA1 was markedly upregulated in HCC tissues and higher UCA1 expression in HCC was positively associated with tumor size, vascular invasion and American Joint Committee on cancer (AJCC) stage (P < 0.05). Furthermore, gain-of-function and loss-of-function analysis showed that UCA1 knockdown inhibited HCC cells proliferation and invasion in vitro and xenograft tumour growth in vivo. Moreover, UCA1 overexpression promoted cell epithelial-mesenchymal transition (EMT) in HCC via effectively sponging to miR-203 and thereby activating the expression of transcription factor Snail2. CONCLUSIONS: Our results identified that UCA1/miR-203/Snail2 pathway might involve in HCC progression. Inhibition of UCA1 acted as a promising therapeutic target for HCC patients.

Transforming growth factor-beta (TGF-beta) has received much attention as a major inducer of epithelial-mesenchymal transition (EMT) during cancer progression, mainly by activating a set of pleiotropic transcription factors including SNAI2/Slug. However, the involvement of long non-coding RNAs (lncRNAs) in TGF-beta-induced Slug activation and EMT remains largely unknown. Methods: In this study, we used microarray analysis to compare lncRNA expression profiles between TGF-beta treated and untreated breast cancer cells. Then, the clinical significance of lncRNAs in breast cancer was investigated by qPCR and Kaplan-Meier survival analysis. The molecular mechanisms and EMT-promoting effects in vitro were analyzed by confocal laser microscopy, Western blotting, chromosome conformation capture (3C), chromatin isolation by RNA purification (ChIRP), ChIP, luciferase reporter assay and transwell migration assay. Lastly, the pro-metastatic effects in vivo were evaluated by bioluminescent imaging and hematoxylin and eosin (H&E) staining. Results: We observed that TGF-beta induced genome-wide changes in lncRNA levels in breast cancer cells, among which AC026904.1 and UCA1 were highly expressed in metastatic breast cancer and closely associated with poor prognosis. Mechanistic study revealed that AC026904.1 and UCA1 were upregulated by non-canonical and canonical TGF-beta pathways, respectively. Further analysis showed that AC026904.1 functions as an enhancer RNA in the nucleus, whereas UCA1 exerts a competitive endogenous RNA (ceRNA) activity in the cytoplasm. In addition, the biological functions of these two lncRNAs converged on the activation and maintenance of Slug, constituting a one-two punch in promoting EMT and tumor metastasis. Conclusion: These findings uncover for the first time that AC026904.1 and UCA1 could cooperatively upregulate Slug expression at both transcriptional and post-transcriptional levels, exerting critical roles in TGF-beta-induced EMT. The present work provides new evidence that lncRNAs function as key regulators of EMT and hold great promise to be used as novel biomarkers and therapeutic targets for metastatic breast cancer.

Melanoma is an aggressive skin carcinoma with poor prognosis. Increasing studies have been carried out to investigate effective therapeutic targets for melanoma treatment. This study focuses on the LncRNA UCA1 and its downstream regulated factors. In our present study, UCA1 expression was discovered to be up-regulated while miR-185-5p expression was down-regulated in melanoma tissues and cell lines. We found that miR-185-5p could directly bind to UCA1 at the miRNA recognition site, and there existed a negative relationship between UCA1 and miR-185-5p. Additionally, knockdown of UCA1 was found to suppress cell invasion through inhibiting EMT in melanoma. However, miR-185-5p inhibitor transfection counteracted the inhibitory effect of UCA1 shRNA on cell invasion and EMT, suggesting that UCA1 shRNA suppressed invasion through inhibiting EMT via up-regulating miR-185-5p expression in melanoma. In addition, depletion of UCA1 decreased the expression of beta-catenin and c-myc, indicating that UCA1 shRNA suppressed Wnt/beta-catenin signaling pathway. Moreover, activation of Wnt/beta-catenin signaling pathway by Licl treatment could abolish the effects of UCA1 shRNA on melanoma cells mobility and EMT. Finally, in vivo experiments revealed that knockdown of UCA1 inhibited tumor growth and invasion via targeting miR-185-5p through Wnt/beta-catenin signaling pathway. In conclusion, our study indicated that the UCA1/miR-185-5p/Wnt/beta-catenin axis might provide a new potential therapeutic strategy for melanoma treatment.CI - Copyright (c) 2018 Elsevier B.V. All rights reserved.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a marked potential for invasion and metastasis. Emerging evidence has suggested that dysregulation of long non-coding RNAs (lncRNAs) is associated with the development of multiple types of cancer. However, the function of lncRNAs in PDAC is poorly known. In the present study, a microarray assay was used to screen for differently expressed lncRNAs in PDAC and it was identified that cancer upregulated drug resistance (CUDR) was upregulated in PDAC. CUDR increased PDAC cell proliferation, migration and invasion, inhibited apoptosis, and promoted drug resistance; it also regulated the PDAC cell epithelial-mesenchymal transition. The CUDR-induced PDAC malignant phenotypes is via the protein kinase B and extracellular-signal-regulated kinase signaling pathways. Downregulation of CUDR may be a novel therapeutic strategy to prevent PDAC development and drug resistance in the future.