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LncRNA TUG1 Promotes Cisplatin Resistance by Regulating CCND2 via Epigenetically Silencing miR-194-5p in Bladder Cancer.

ABSTRACT: Taurine-upregulated gene 1 (TUG1) has been involved in tumorigenesis of several human cancers, but its precise biological role in bladder cancer remains largely elusive. In this study, we found that TUG1 was upregulated in bladder cancer and the expression of TUG1 was positively and negatively correlated with CCND2 and miR-194-5p, respectively. MiR-194-5p expression was frequently decreased through promoter hypermethylation, while it was epigenetically increased following cisplatin and 5-aza-2'-deoxycytidine (5-Aza-DC) treatment. Furthermore, knockdown of TUG1 attenuated the expression of epigenetic regulator Enhancer of zeste homolog 2 (EZH2), and it alleviated the promoter hypermethylation of miR-194-5p and induced its expression. Increased miR-194-5p expression or decreased TUG1 expression significantly sensitized bladder cancer cells to cisplatin, inhibited the proliferation, and induced apoptosis. Besides, CCND2 was a direct target of miR-194-5p, while miR-194-5p was regulated by TUG1. CCND2 could partially restore the tumor-suppressive effects on cell proliferation and cisplatin resistance following TUG1 silencing. Additionally, TUG1 expression was correlated with clinical stage, lymphatic metastasis, and patient prognosis. In conclusion, TUG1 promotes bladder cancer cell growth and chemoresistance by regulating CCND2 via EZH2-associated silencing of miR-194-5p. Our study may be conducive to elucidating the molecular mechanism of and providing novel therapeutic target and biomarker for bladder cancer.

SUBMITTER: Yu G

PROVIDER: S-EPMC6439231 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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lncRNA TUG1 Promotes Cisplatin Resistance by Regulating CCND2 via Epigenetically Silencing miR-194-5p in Bladder Cancer.

Yu Gan G Zhou Hui H Yao Weimin W Meng Lirong L Lang Bin B

Molecular therapy. Nucleic acids 20190226

Taurine-upregulated gene 1 (TUG1) has been involved in tumorigenesis of several human cancers, but its precise biological role in bladder cancer remains largely elusive. In this study, we found that TUG1 was upregulated in bladder cancer and the expression of TUG1 was positively and negatively correlated with CCND2 and miR-194-5p, respectively. MiR-194-5p expression was frequently decreased through promoter hypermethylation, while it was epigenetically increased following cisplatin and 5-aza-2'- ...[more]

PMID: 30925453

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Project description:BackgroundNumerous studies proved that long non-coding RNA (lncRNA) is involved in the progression of multifarious diseases, especially in some carcinomas. As a potential tumor biomarker, plasmacytoma variant translocation 1 gene (PVT1) is involved in the development and progression of multifarious cancers. Nevertheless, the intrinsic and concrete molecular mechanism of PVT1 in bladder cancer still remained unclear, which is also the dilemma faced in many non-coding RNA studies.ResultsOur research revealed that PVT1 was significantly higher expression in bladder carcinoma specimens and cell lines. Further experiments indicated that knockdown or overexpression of PVT1 restrained or promoted the malignant phenotype and WNT/β-catenin signaling in bladder cancer cells. Meanwhile miR-194-5p was in contrast and miR-194-5p could partially reverse the function of PVT1 in malignant bladder tumor cells. As a microRNA sponge, PVT1 actively promotes the expression of b-cells lymphoma-2-associated transcription factor 1 (BCLAF1) to sponge miR-194-5p and subsequently increases malignant phenotypes of bladder cancer cells. Therefore, it performs a carcinogenic effect and miR-194-5p as the opposite function, and serves as an antioncogene in the bladder carcinomas pathogenesis.ConclusionPVT1-miR-194-5p-BCLAF1 axis is involved in the malignant progression and development of bladder carcinomas. Experiments revealed that PVT1 has a significant regulatory effect on bladder cancer (BC) and can be used as a clinical diagnostic marker and a therapeutic molecular marker for patients suffering from BC.MethodsIn urothelial bladder carcinoma specimens and cell lines, the relative expression levels of PVT1 and miR-194-5p were detected by quantitative reverse transcription PCR (RT-qPCR). Through experiments such as loss-function and over-expression, the biological effects of PVT1 and miR-194-5p on the proliferation, migration, apoptosis and tumorigenicity were explored in bladder cancer cells. Co-immunoprecipitation, proteomics experiments, dual luciferase reporter gene analysis, western blot and other methods were adopted to investigate the PVT1 potential mechanism in bladder carcinomas.

Dataset Information

LncRNA TUG1 Promotes Cisplatin Resistance by Regulating CCND2 via Epigenetically Silencing miR-194-5p in Bladder Cancer.

Publications

lncRNA TUG1 Promotes Cisplatin Resistance by Regulating CCND2 via Epigenetically Silencing miR-194-5p in Bladder Cancer.

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