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Open accessJournal ArticleDOI: 10.3389/FCELL.2021.650023

m6A Regulators Is Differently Expressed and Correlated With Immune Response of Esophageal Cancer

04 Mar 2021-Frontiers in Cell and Developmental Biology (Frontiers Media SA)-Vol. 9, pp 650023-650023
Abstract: N6 methyladenosine (m6A) RNA methylation regulators play an important role in the development of tumors. However, their function in esophageal cancer (EC) has not been fully elucidated. Here, we analyzed the gene expression data of 24 major m6A RNA methylation regulators from 775 patients with EC from TCGA dataset. The present study showed the aberrations of m6A regulators in genome were correlated to prognosis in human ECs. Meanwhile, 17 m6A regulators showed increased expression in EC samples, including YTHDC1, IGF2BP2, FTO, METTL14, YTHDF3, RBM15, WTAP, HNRNPA2B1, HNRNPC, ALKBH5, YTHDF2, METTL16, IGF2BP3, VIRMA, RBM15B, YTHDF1, KIAA1429, HAKAI, and ZC3H13. Among them, we found HNRNPC, YTHDC2, WTAP, VIRMA, IGF2BP3, and HNRNPA2B1 were significantly correlated to worse outcomes and advanced stage in EC. Furthermore, we showed levels of m6A regulators is correlated with the expression of Immuno-regulators (Immunoinhibitors, Immunostimulators, and MHC molecules) and immune infiltration levels in EC. Bioinformatics further confirm m6A regulators were involved in regulating RNA splicing, RNA stability, and cell proliferation. Our study showed m6A regulators are promising targets and biomarkers for cancer immunotherapy in EC.

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Topics: HNRNPC (57%), N6-Methyladenosine (53%), RNA methylation (52%) ... show more
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7 results found


Open accessJournal ArticleDOI: 10.3390/BIOM11060908
18 Jun 2021-
Abstract: RNA methylation at the nitrogen sixth of adenosine (m6A, N6-methyladenosine) is the most abundant RNA modification which plays a crucial role in all RNA metabolic aspects. Recently, m6A modification has been assigned to mediate the biological processes of cancer cells, but their significance in HNSCC development is still poorly described. Thus, the main aim of this study was to globally quantify m6A modification by the mass spectrometry approach and determine the mRNA expression level of selected m6A RNA methyltransferase (METTL3), demethylase (FTO), and m6A readers (YTHDF2, YTHDC2) in 45 HNSCC patients and 4 cell lines (FaDu, Detroit 562, A-253 and SCC-15) using qPCR. In the results, we have not observed differences in the global amount of m6A modification and the mRNA level of the selected genes between the cancerous and paired-matched histopathologically unchanged tissues from 45 HNSCC patients. However, we have found a positive correlation between selected RNA methylation machinery genes expression and m6A abundance on total RNA and characterized the transcript level of those genes in the HNSCC cell lines. Moreover, the lack of global m6A differences between cancerous and histopathologically unchanged tissues suggests that m6A alterations in specific RNA sites may specifically influence HNSCC tumorigenesis.

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Topics: RNA methylation (67%), RNA (62%), Head and neck squamous-cell carcinoma (60%) ... show more

2 Citations


Open accessJournal ArticleDOI: 10.3389/FCELL.2021.736298
Lei Zhan, Junhui Zhang1, Junhui Zhang2, Suding Zhu2  +8 moreInstitutions (2)
Abstract: Immunotherapy is a novel clinical approach that has shown clinical efficacy in multiple cancers. However, only a fraction of patients respond well to immunotherapy. Immuno-oncological studies have identified the type of tumors that are sensitive to immunotherapy, the so-called hot tumors, while unresponsive tumors, known as "cold tumors," have the potential to turn into hot ones. Therefore, the mechanisms underlying cold tumor formation must be elucidated, and efforts should be made to turn cold tumors into hot tumors. N6-methyladenosine (m6A) RNA modification affects the maturation and function of immune cells by controlling mRNA immunogenicity and innate immune components in the tumor microenvironment (TME), suggesting its predominant role in the development of tumors and its potential use as a target to improve cancer immunotherapy. In this review, we first describe the TME, cold and hot tumors, and m6A RNA modification. Then, we focus on the role of m6A RNA modification in cold tumor formation and regulation. Finally, we discuss the potential clinical implications and immunotherapeutic approaches of m6A RNA modification in cancer patients. In conclusion, m6A RNA modification is involved in cold tumor formation by regulating immunity, tumor-cell-intrinsic pathways, soluble inhibitory mediators in the TME, increasing metabolic competition, and affecting the tumor mutational burden. Furthermore, m6A RNA modification regulators may potentially be used as diagnostic and prognostic biomarkers for different types of cancer. In addition, targeting m6A RNA modification may sensitize cancers to immunotherapy, making it a promising immunotherapeutic approach for turning cold tumors into hot ones.

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Open accessJournal ArticleDOI: 10.1186/S12935-021-02163-9
Jinfang Liu1, Zijian Zhou1, Ling Ma1, Chujun Li1  +5 moreInstitutions (1)
Abstract: Background Melanoma is an extremely aggressive type of skin cancer and experiencing a expeditiously rising mortality in a current year. Exploring new potential prognostic biomarkers and therapeutic targets of melanoma are urgently needed. The ambition of this research was to identify genetic markers and assess prognostic performance of N6-methyladenosine (m6A) regulators in melanoma. Methods Gene expression data and corresponding clinical informations of melanoma patients as well as sequence data of normal controls are collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. Quantitative real-time PCR (qRT-PCR) analysis was carried out to detect the RNA expression of IGF2BP3 in A375 cell line, melanoma tissues, and normal tissues. Western blot, cell proliferation, and migration assays were performed to assess the ability of IGF2BP3 in A375 cell line. Results Differently expressed m6A regulators between tumor samples and normal samples were analyzed. A three-gene prognostic signature including IGF2BP3, RBM15B, and METTL16 was constructed, and the risk score of this signature was identified to be an independent prognostic indicator for melanoma. In addition, IGF2BP3 was verified to promote melanoma cell proliferation and migration in vitro and associate with lymph node metastasis in clinical samples. Moreover, risk score and the expression of IGF2BP3 were positively associated with the infiltrating immune cells and these hub genes made excellent potential drug targets in melanoma. Conclusion We identified the genetic changes in m6A regulatory genes and constructed a three-gene risk signature with distinct prognostic value in melanoma. This research provided new insights into the epigenetic understanding of m6A regulators and novel therapeutic strategies in melanoma.

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Topics: Melanoma (56%), Skin cancer (52%)

Open accessJournal ArticleDOI: 10.1016/J.PHYMED.2021.153871
Xian Lin1, Xian Lin2, Cheng Tao, Ren Zhang3  +6 moreInstitutions (3)
30 Nov 2021-Phytomedicine
Abstract: Background Developing alternative targets and drugs for rheumatoid arthritis (RA) treatment is currently an urgent issue. The relationship between TGM2 and the abnormal immune microenvironment in synovium tissues, as well as the specific role of TGM2 in RA are yet to be elucidated. Sarsasapogenin (Sar) is a sapogenin extracted from the Chinese medical herb Anemarrhena asphodeloides Bunge. and served as a representative anti-inflammatory drug capable of ameliorating inflammatory responses in several human diseases. However, the therapeutic effect of Sar on RA remains unknown. Purpose This investigation aims to elucidate the role of TGM2 in RA and investigate whether Sar is a candidate drug to target TGM2 of fibroblast-like synoviocytes (FLS). Methods Bioinformatics analyses were applied for elucidating the role of N(6)-methyladenine (m6A) RNA methylation in RA and identifying the specific target regulated by m6A methylation in RA-FLS. Methylated RNA immunoprecipitation, CCK8 assay, Edu assay, flow cytometry, RT-qPCR and Western blot were utilized to investigate the function of Sar and TGM2 in RA-FLS. Results Bioinformatics analyses emphasized the importance of m6A RNA methylation in RA and identified an m6A methylation-mediated gene TGM2. Interestingly, both m6A RNA methylation and TGM2 expression in RA synovium tissues correlated with activated immuno-inflammatory phenotype and associated with clinical characteristics and therapy response of RA patients. TGM2 served as a promoter of RA-FLS proliferation by inducing DNA replication and cell cycle transition and inhibiting apoptosis through activating NF-κB signaling. Intriguingly, Sar could impair m6A methylation of TGM2 mRNA and downregulate TGM2 expression. Downregulated TGM2 contributed to the suppressive role of Sar in DNA replication and the stimulatory role of Sar in cell cycle arrest and apoptosis of RA-FLS. Mechanically, Sar inhibited the expression of key regulators in DNA replication, cell cycle, and apoptosis by impairing NF-κB signaling, thus abolishing FLS proliferation to ameliorate RA progression. Conclusions This cross-validated work based on three independent datasets is detailedly delineated using cell lines and clinical samples, recognizing that TGM2 can be an attractive target and Sar might be a novel anti-RA drug.

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Topics: RNA methylation (54%), Cell cycle (53%), Methylation (51%) ... show more

Open accessJournal ArticleDOI: 10.3748/WJG.V27.I36.6110
Abstract: Background Esophageal cancer (ESCA) is the sixth most common malignancy in the world, and its incidence is rapidly increasing. Recently, several microRNAs (miRNAs) and messenger RNA (mRNA) targets were evaluated as potential biomarkers and regulators of epigenetic mechanisms involved in early diagnosis. In addition, computed tomography (CT) radiomic studies on ESCA improved the early stage identification and the prediction of response to treatment. Radiogenomics provides clinically useful prognostic predictions by linking molecular characteristics such as gene mutations and gene expression patterns of malignant tumors with medical images and could provide more opportunities in the management of patients with ESCA. Aim To explore the combination of CT radiomic features and molecular targets associated with clinical outcomes for characterization of ESCA patients. Methods Of 15 patients with diagnosed ESCA were included in this study and their CT imaging and transcriptomic data were extracted from The Cancer Imaging Archive and gene expression data from The Cancer Genome Atlas, respectively. Cancer stage, history of significant alcohol consumption and body mass index (BMI) were considered as clinical outcomes. Radiomic analysis was performed on CT images acquired after injection of contrast medium. In total, 1302 radiomics features were extracted from three-dimensional regions of interest by using PyRadiomics. Feature selection was performed using a correlation filter based on Spearman's correlation (ρ) and Wilcoxon-rank sum test respect to clinical outcomes. Radiogenomic analysis involved ρ analysis between radiomic features associated with clinical outcomes and transcriptomic signatures consisting of eight N6-methyladenosine RNA methylation regulators and five up-regulated miRNA. The significance level was set at P Results Of 25, five and 29 radiomic features survived after feature selection, considering stage, alcohol history and BMI as clinical outcomes, respectively. Radiogenomic analysis with stage as clinical outcome revealed that six of the eight mRNA regulators and two of the five up-regulated miRNA were significantly correlated with ten and three of the 25 selected radiomic features, respectively (-0.61 Conclusion Our study revealed interesting relationships between the expression of eight N6-methyladenosine RNA regulators, as well as five up-regulated miRNAs, and CT radiomic features associated with clinical outcomes of ESCA patients.

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Topics: Radiogenomics (56%), Gene mutation (51%)

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44 results found


Open accessJournal ArticleDOI: 10.1093/NAR/GKX247
Zefang Tang1, Chenwei Li1, Boxi Kang1, Ge Gao1  +2 moreInstitutions (1)
Abstract: Tremendous amount of RNA sequencing data have been produced by large consortium projects such as TCGA and GTEx, creating new opportunities for data mining and deeper understanding of gene functions. While certain existing web servers are valuable and widely used, many expression analysis functions needed by experimental biologists are still not adequately addressed by these tools. We introduce GEPIA (Gene Expression Profiling Interactive Analysis), a web-based tool to deliver fast and customizable functionalities based on TCGA and GTEx data. GEPIA provides key interactive and customizable functions including differential expression analysis, profiling plotting, correlation analysis, patient survival analysis, similar gene detection and dimensionality reduction analysis. The comprehensive expression analyses with simple clicking through GEPIA greatly facilitate data mining in wide research areas, scientific discussion and the therapeutic discovery process. GEPIA fills in the gap between cancer genomics big data and the delivery of integrated information to end users, thus helping unleash the value of the current data resources. GEPIA is available at http://gepia.cancer-pku.cn/.

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3,491 Citations


Open accessJournal ArticleDOI: 10.1016/J.NEO.2017.05.002
01 Aug 2017-Neoplasia
Abstract: Genomics data from The Cancer Genome Atlas (TCGA) project has led to the comprehensive molecular characterization of multiple cancer types. The large sample numbers in TCGA offer an excellent opportunity to address questions associated with tumo heterogeneity. Exploration of the data by cancer researchers and clinicians is imperative to unearth novel therapeutic/diagnostic biomarkers. Various computational tools have been developed to aid researchers in carrying out specific TCGA data analyses; however there is need for resources to facilitate the study of gene expression variations and survival associations across tumors. Here, we report UALCAN, an easy to use, interactive web-portal to perform to in-depth analyses of TCGA gene expression data. UALCAN uses TCGA level 3 RNA-seq and clinical data from 31 cancer types. The portal's user-friendly features allow to perform: 1) analyze relative expression of a query gene(s) across tumor and normal samples, as well as in various tumor sub-groups based on individual cancer stages, tumor grade, race, body weight or other clinicopathologic features, 2) estimate the effect of gene expression level and clinicopathologic features on patient survival; and 3) identify the top over- and under-expressed (up and down-regulated) genes in individual cancer types. This resource serves as a platform for in silico validation of target genes and for identifying tumor sub-group specific candidate biomarkers. Thus, UALCAN web-portal could be extremely helpful in accelerating cancer research. UALCAN is publicly available at http://ualcan.path.uab.edu.

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1,802 Citations


Open accessJournal ArticleDOI: 10.1158/0008-5472.CAN-17-0307
Taiwen Li1, Taiwen Li2, Jingyu Fan3, Binbin Wang3  +6 moreInstitutions (3)
01 Nov 2017-Cancer Research
Abstract: Recent clinical successes of cancer immunotherapy necessitate the investigation of the interaction between malignant cells and the host immune system. However, elucidation of complex tumor-immune interactions presents major computational and experimental challenges. Here, we present Tumor Immune Estimation Resource (TIMER; cistrome.shinyapps.io/timer) to comprehensively investigate molecular characterization of tumor-immune interactions. Levels of six tumor-infiltrating immune subsets are precalculated for 10,897 tumors from 32 cancer types. TIMER provides 6 major analytic modules that allow users to interactively explore the associations between immune infiltrates and a wide spectrum of factors, including gene expression, clinical outcomes, somatic mutations, and somatic copy number alterations. TIMER provides a user-friendly web interface for dynamic analysis and visualization of these associations, which will be of broad utilities to cancer researchers. Cancer Res; 77(21); e108-10. ©2017 AACR.

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Topics: Timer (51%)

1,418 Citations


Open accessJournal ArticleDOI: 10.1371/JOURNAL.PONE.0082241
18 Dec 2013-PLOS ONE
Abstract: In the last decade, optimized treatment for non-small cell lung cancer had lead to improved prognosis, but the overall survival is still very short. To further understand the molecular basis of the disease we have to identify biomarkers related to survival. Here we present the development of an online tool suitable for the real-time meta-analysis of published lung cancer microarray datasets to identify biomarkers related to survival. We searched the caBIG, GEO and TCGA repositories to identify samples with published gene expression data and survival information. Univariate and multivariate Cox regression analysis, Kaplan-Meier survival plot with hazard ratio and logrank P value are calculated and plotted in R. The complete analysis tool can be accessed online at: www.kmplot.com/lung. All together 1,715 samples of ten independent datasets were integrated into the system. As a demonstration, we used the tool to validate 21 previously published survival associated biomarkers. Of these, survival was best predicted by CDK1 (p<1E-16), CD24 (p<1E-16) and CADM1 (p = 7E-12) in adenocarcinomas and by CCNE1 (p = 2.3E-09) and VEGF (p = 3.3E-10) in all NSCLC patients. Additional genes significantly correlated to survival include RAD51, CDKN2A, OPN, EZH2, ANXA3, ADAM28 and ERCC1. In summary, we established an integrated database and an online tool capable of uni- and multivariate analysis for in silico validation of new biomarker candidates in non-small cell lung cancer.

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Topics: Survival analysis (53%), Hazard ratio (51%), Lung cancer (50%)

1,176 Citations


Open accessJournal ArticleDOI: 10.1101/GAD.262766.115
Yanan Yue1, Jianzhao Liu2, Chuan HeInstitutions (2)
Abstract: Both DNA and histone proteins undergo dynamic and reversible chemical modifications to control gene expression (Strahl and Allis 2000; Bird 2001; Suzuki and Bird 2008; Bhutani et al. 2011; Jones 2012; Kohli and Zhang 2013). Although post-transcriptional modifications are known to occur to RNAs, the impact of these modifications on gene expression regulation has only recently begun to be explored (He 2010). To date, more than a hundred structurally distinct chemical modifications have been found in eukaryotic RNAs (Cantara et al. 2011; Machnicka et al. 2013); however, the enzymes responsible for each modification and the biological consequences of these modified RNAs are largely unknown. RNA modifications were once considered to be static, but a flurry of recent discoveries has demonstrated that some chemical modifications can be dynamic and participate in the regulation of diverse physiological processes (Motorin and Helm 2011; Yi and Pan 2011; Chan et al. 2012; Fu et al. 2014; Meyer and Jaffrey 2014; Kirchner and Ignatova 2015). The presence of N6-methyladenosine (m6A) in polyadenylated mRNA was first discovered in the 1970s (Desrosiers et al. 1974; Perry and Kelley 1974; Lavi and Shatkin 1975; Wei et al. 1975; Schibler et al. 1977; Wei and Moss 1977) by researchers who were characterizing the 5′ cap structure of messenger RNA (mRNA) in mammalian cells. Since then, m6A has been identified as the most prevalent internal modification in mRNA and long noncoding RNA (lncRNA) in higher eukaryotes. It is widely conserved among eukaryotic species that range from yeast, plants, and flies to mammals as well as among viral mRNAs that replicate inside host nuclei (Krug et al. 1976; Beemon and Keith 1977; Horowitz et al. 1984; Bokar 2005). In addition to its occurrence in mRNA, m6A also exists in various classes of RNA in eukaryotes, bacteria, and archaea, including ribosomal RNAs, small nuclear RNAs, and transfer RNAs (Bjork et al. 1987; Maden 1990; Shimba et al. 1995; Gu et al. 1996; Agris et al. 2007; Piekna-Przybylska et al. 2008). Despite its widespread distribution in the mammalian transcriptome (on average, approximately three m6A sites per mRNA), functional insight has been lacking, possibly due to the low abundance of m6A mRNA and technical difficulties in global detection. Interest in the biological relevance of m6A in mRNA resurfaced after the discovery of two mammalian RNA demethylases, FTO (fat mass and obesity-associated protein) (Jia et al. 2011) and its homolog, ALKBH5 (Zheng et al. 2013), which selectively reverse m6A to adenosine in nuclear RNA. FTO is associated with human obesity (Dina et al. 2007; Frayling et al. 2007; Loos and Yeo 2014) and mental development (Hess et al. 2013), while ALKBH5 is shown to affect mouse spermatogenesis in a demethylation-dependent manner (Zheng et al. 2013), suggesting broad roles of m6A in various physiological processes. Shortly after these findings, YTHDF2 (YTH domain-containing family protein 2) was identified as the first m6A reader protein that preferentially recognizes m6A-containing mRNA (Dominissini et al. 2012; Wang et al. 2014a) and mediates mRNA decay (Wang et al. 2014a), thereby suggesting a role for m6A RNA as a negative regulator of gene expression. On the other hand, a transcriptome-wide m6A profiling method was developed to decipher the m6A RNA landscape (Dominissini et al. 2012; Meyer et al. 2012). Intriguingly, m6A sites in mammalian polyadenylated RNA are dominated by the conserved Pu[G > A]m6AC[A/C/U] motif that localizes near stop codons, in 3′ untranslated regions (UTRs), within long internal exons, and at 5′ UTRs (Dominissini et al. 2012; Meyer et al. 2012; Schwartz et al. 2013; Li et al. 2014; Luo et al. 2014), immediately raising the question of how this specificity is achieved. The m6A RNA landscape is initially sculptured by a methyltransferase complex, but for a long time, METTL3 (methyltransferase-like 3) was the only known SAM (S-adenosyl methionine)-binding subunit associated with mRNA methylation (Bokar et al. 1997). In 2014, a new mammalian methyltransferase, METTL14, was discovered to catalyze m6A methylation. Together with METTL3, these two proteins form a stable heterodimer complex that mediates cellular m6A deposition on mammalian mRNAs (Liu et al. 2014; Wang et al. 2014b). Recently, the mammalian splicing factor WTAP (Wilms’ tumor 1-associating protein) was identified as the third auxiliary factor of the core methyltransferase complex that affects cellular m6A methylation (Liu et al. 2014; Ping et al. 2014). The identification and characterization of the complete mammalian m6A methylation machinery are the first steps toward deciphering the selectivity and biological functions of m6A deposition in eukaryotic mRNAs. In this review, we mainly summarize recent progress in the study of m6A methylation in mRNA across different eukaryotes and discuss their newly discovered roles in post-transcriptional gene expression regulation. We first describe the features of m6A on a global scale and briefly introduce the mammalian m6A writers, erasers, and readers that specifically install, remove, or bind to m6A at defined sequence motifs (Fig. 1). We then discuss the evolutional conservation of the m6A methylation machinery across eukaryotic species that range from yeast, plants, and flies to mammals, highlighting the broad roles of methyltransferases and m6A in regulating cell status and embryonic development. Finally, we discuss the emerging functions of m6A in several mechanisms of post-transcriptional gene expression regulation with a special focus on the effects of m6A on differentiation and reprograming of stem cells. Figure 1. Illustration of the cellular pathways of m6A in nuclear RNAs. The m6A methyltransferases and demethylases dynamically control the m6A methylation landscape within the nucleus. The m6A reader proteins preferentially bind to the methylated RNA and mediate ...

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Topics: MRNA methylation (60%), N6-Methyladenosine (56%), RNA (55%) ... show more

479 Citations