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      m6A RNA methylation regulators can contribute to malignant progression and impact the prognosis of bladder cancer

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          Abstract

          N6-methyladenosine (m6A) is the most common form of messenger RNA (mRNA) modification. An increasing number of studies have proven that m6A RNA methylation regulators are overexpressed in many cancers and participate in the development of cancer through the dynamic regulation of m6A RNA methylation regulators. However, the prognostic role of m6A RNA methylation regulators in bladder cancer (BC) is poorly understood. In the present study, we downloaded the mRNA expression data from The Cancer Genome Atlas (TCGA) database and the corresponding clinical and prognostic information. The relationship between m6A RNA methylation regulators and clinicopathological variables of BC patients was assessed by the Kolmogorov–Smirnov test. The expression of the m6A RNA methylation regulators was differentially associated with different clinicopathological variables of BC patients. The least absolute shrinkage and selection operator (LASSO) Cox regression model was then applied to identify three m6A RNA methylation regulators. The risk signature was constructed as follows: 0.164FTO − (0.081YTHDC1+0.032WTAP). Based on the risk signature, the risk score of each patient was calculated, and the patients were divided into a high-risk group and a low-risk group. The overall survival (OS) rate of the high-risk group was significantly lower than that of the low-risk group. The risk signature was not only an independent prognostic marker for BC patients but also a predictor of clinicopathological variables. In conclusion, m6A RNA methylation regulators can participate in the malignant progression of BC, and a risk signature with three selected m6A RNA methylation regulators may be a promising prognostic biomarker to guide personalized treatment for BC patients.

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          Most cited references23

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          METTL3 facilitates tumor progression via an m 6 A-IGF2BP2-dependent mechanism in colorectal carcinoma

          Background Colorectal carcinoma (CRC) is one of the most common malignant tumors, and its main cause of death is tumor metastasis. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism for gene expression and methyltransferase-like 3 (METTL3) participates in tumor progression in several cancer types. However, its role in CRC remains unexplored. Methods Western blot, quantitative real-time PCR (RT-qPCR) and immunohistochemical (IHC) were used to detect METTL3 expression in cell lines and patient tissues. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL3. The biological functions of METTL3 were investigated in vitro and in vivo. RNA pull-down and RNA immunoprecipitation assays were conducted to explore the specific binding of target genes. RNA stability assay was used to detect the half-lives of the downstream genes of METTL3. Results Using TCGA database, higher METTL3 expression was found in CRC metastatic tissues and was associated with a poor prognosis. MeRIP-seq revealed that SRY (sex determining region Y)-box 2 (SOX2) was the downstream gene of METTL3. METTL3 knockdown in CRC cells drastically inhibited cell self-renewal, stem cell frequency and migration in vitro and suppressed CRC tumorigenesis and metastasis in both cell-based models and PDX models. Mechanistically, methylated SOX2 transcripts, specifically the coding sequence (CDS) regions, were subsequently recognized by the specific m6A “reader”, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), to prevent SOX2 mRNA degradation. Further, SOX2 expression positively correlated with METTL3 and IGF2BP2 in CRC tissues. The combined IHC panel, including “writer”, “reader”, and “target”, exhibited a better prognostic value for CRC patients than any of these components individually. Conclusions Overall, our study revealed that METTL3, acting as an oncogene, maintained SOX2 expression through an m6A-IGF2BP2-dependent mechanism in CRC cells, and indicated a potential biomarker panel for prognostic prediction in CRC. Electronic supplementary material The online version of this article (10.1186/s12943-019-1038-7) contains supplementary material, which is available to authorized users.
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            Cytoplasmic m6A reader YTHDF3 promotes mRNA translation

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              Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/ASTRO/SUO Guideline

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                Author and article information

                Contributors
                Journal
                Biosci Rep
                Biosci. Rep
                bsr
                Bioscience Reports
                Portland Press Ltd.
                0144-8463
                1573-4935
                20 December 2019
                20 December 2019
                : 39
                : 12
                : BSR20192892
                Affiliations
                Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, China
                Author notes
                Correspondence: Shufang Zhang ( zsf66189665@ 123456126.com )
                Author information
                http://orcid.org/0000-0003-4894-4951
                http://orcid.org/0000-0002-1398-0998
                Article
                BSR20192892
                10.1042/BSR20192892
                6923333
                31808521
                0e7701f8-aa9b-4863-8d99-b0ce3cadf047
                © 2019 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 23 August 2019
                : 24 November 2019
                : 05 December 2019
                : 06 December 2019
                Page count
                Pages: 10
                Categories
                Bioinformatics
                Cancer
                Diagnostics & Biomarkers
                Gene Expression & Regulation
                Research Articles

                Life sciences
                bladder cancer,m6a,n6-methyladenosine,prognosis
                Life sciences
                bladder cancer, m6a, n6-methyladenosine, prognosis

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