m5C RNA Methylation Primarily Affects the ErbB and PI3K–Akt Signaling Pathways in Gastrointestinal Cancer

Xiang, Shixin; Ma, YingLiang; Shen, Jing; Zhao, Yueshui; Wu, Xu; Li, Mingxing; Xiao-mi, Yang; Kaboli, Parham Jabbarzadeh; Du, Fukuan; Ji, Huijiao; Zheng, Yan; Li, Xiang; Li, Jing; Wen, Qinglian; Xiao, Zhangang

doi:10.3389/fmolb.2020.599340

Cited by 22 publications

(16 citation statements)

References 78 publications

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“…RNA m5C, characterised by the addition of a methyl group at the carbon-5 position of the cytosine base, has been detected not only in rRNA and tRNA but also in mRNA by high-throughput sequencing-based transcriptome-wide mapping approaches. 7 m5C is well-conserved and dynamically regulated in cellular mRNAs, and it localises to the untranslated regions (UTRs) of mRNA transcripts. It may influence a wide variety of biological functions by regulating RNA metabolism.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of 5-Methylcytosine Profiles of Messenger RNA in Human High-Grade Serous Ovarian Cancer by MeRIP Sequencing

Li¹,

Zhang²,

Huang³

2021

CMAR

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Background Accumulating evidence has indicated that methylation status is closely related to tumourigenesis and a few aggressive features of diverse cancers. However, as an important methylation regulation modification, the distribution of 5-methylcytosine (m5C) in high-grade serous ovarian cancer (HGSOC) remains unclear. Materials and Methods We collected three pairs of human HGSOC tissues and adjacent non-tumour tissues to analyse the transcriptome-wide m5C methylation of messenger RNAs (mRNAs) by methylated RNA immunoprecipitation sequencing. Gene ontology (GO) enrichment analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis were performed to eExplore the potential biological functions of these genes and important cancer pathways. We used immunohistochemistry to analyse the expression of the m5C modification regulatory gene MAP2K3 in 80 HGSOC tissue samples, and their associations with clinical parameters were analyzed using the Spearman-rho test. Univariate and multivariate Cox regression analyses were performed to identify potential prognostic factors. Kaplan–Meier analysis was performed to analyze overall survival. Results We identified 2050 dysregulated m5C peaks, 1767 of which were significantly upregulated, while 283 were significantly downregulated. GO enrichment analysis showed that genes altered by the m5C peak played a key role in system development, transporter complex, and transporter activity. KEGG pathway analysis revealed that these genes were enriched in some important pathways in cancer regulation, such as inflammatory mediator regulation of the TRP channels pathway, Wnt signalling pathway, and focal adhesion pathways. In addition, through joint analysis of MeRIP-seq and RNA-seq data, we identified 125 differentially methylated m5C peaks and synchronous differentially expressed genes. These genes play key roles in cell growth, maintenance, plasma membranes, and cell adhesion molecule activity. Immunohistochemical staining results showed that high expression of MAP2K3 was significantly correlated with CA125 level (p < 0.001), tumour size (p = 0.001), lymph node metastasis (p = 0.008), depth of myometrial invasion (p < 0.001), and FIGO stage (p < 0.001), indicating a poor prognosis. Conclusion Our results reveal the different distribution patterns of m5C in HGSOC and adjacent tissues and the possible involvement of m5C in HGSOC cell functions. Our study provides new insights into the epi-transcriptomic dysregulation of m5C in the tumourigenesis of HGSOC.

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Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of 5-Methylcytosine Profiles of Messenger RNA in Human High-Grade Serous Ovarian Cancer by MeRIP Sequencing

Li¹,

Zhang²,

Huang³

2021

CMAR

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“…We studied the potential carcinogenic mechanisms and pathways of these m 5 C RNA methylation regulators in ccRCC by conducting a KEGG analysis, the results agree with published data suggesting that the PI3K/AKT signaling pathway is involved in these mechanisms. 30 , 31 A recent study demonstrated that the PI3K/AKT signaling pathway is implicated in proliferation and migration processes in ccRCC, 32 laying a theoretical foundation for further studies on the function of m 5 C RNA methylation regulators and the mechanisms underlying their regulatory effects. These findings confirm to some extent that m 5 C RNA methylation regulators participate in the progression of ccRCC.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of an m5C RNA Methylation Regulator-Related Signature for Clear Cell Renal Cell Carcinoma

Li¹,

Jiang²,

Huang³

et al. 2021

CMAR

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Purpose Clear cell renal cell carcinoma (ccRCC) is highly heterogeneous and is one of the most lethal types of cancer within the urinary system. Aberrant expression of 5-methylcytosine (m 5 C) RNA methylation regulators has been shown to result in occurrence and progression of tumors. However, the role of these regulators in ccRCC remains unclear. Materials and Methods We extracted RNA sequencing expression data with corresponding clinical information of patients with ccRCC from The Cancer Genome Atlas (TCGA) database. We then compared the expression profiles of m 5 C RNA methylation regulators between normal and ccRCC tissues, and determined different subtypes through consensus clustering analysis. In addition, we constructed a prognostic signature and evaluated it using a range of bioinformatics approaches. The expression of signature-related genes was subsequently verified in the clinical samples using qRT-PCR. Results We identified 12 differentially expressed m 5 C RNA methylation regulators between cancer and normal control samples. Two clusters of patients with ccRCC and diverse clinicopathological characteristics and prognoses were then determined through consensus clustering analysis. Functional annotations revealed that m 5 C RNA regulators were significantly correlated with the ccRCC progression. Moreover, we constructed a four-gene risk score signature (comprised of NOP2, NSUN4, NSUN6, and TET2) and divided the patients with ccRCC into high- and low-risk groups based on the median risk score. The risk score was associated with clinicopathological features and was an independent prognostic indicator of ccRCC. Our stratified analysis results suggest that the signature has high prognostic value. Based on qRT-PCR results, the NOP2 and NSUN4 mRNA expressions were higher and those of NSUN6 and TET2 were lower in ccRCC tissues than in normal tissues. Conclusion Our results demonstrate that m 5 C RNA methylation regulators may affect ccRCC progression and could be exploited for diagnostic and prognostic purposes.

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“…Similarly, cytosine DNA methyltransferase Dnmt2 is frequently found to be mis-regulated or mutated in tumors ( Elhardt et al, 2015 ; Wang et al, 2020 ). RNA cytosine-5 methylation has also been shown to be important for normal development and cellular stress responses, in addition to cancer ( Blanco et al, 2011 ; Metodiev et al, 2014 ; Popis et al, 2016 ; Gkatza et al, 2019 ; Xiang et al, 2020 ). Our data suggests that alterations in post-transcriptional modification of RNA might be an early event during oncogene induced preneoplastic development.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Alterations in Preneoplastic Development Revealed by Untargeted Metabolomic Analysis

Myllymäki

Johansson

Porro

et al. 2021

Front. Cell Dev. Biol.

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Metabolic rewiring is a critical hallmark of tumorigenesis and is essential for the development of cancer. Although many key features of metabolic alteration that are crucial for tumor cell survival, proliferation and progression have been identified, these are obtained from studies with established tumors and cancer cell lines. However, information on the essential metabolic changes that occur during pre-neoplastic cell (PNC) development that enables its progression to full blown tumor is still lacking. Here, we present an untargeted metabolomics analysis of human oncogene HRASG12V induced PNC development, using a transgenic inducible zebrafish larval skin development model. By comparison with normal sibling controls, we identified six metabolic pathways that are significantly altered during PNC development in the skin. Amongst these altered pathways are pyrimidine, purine and amino acid metabolism that are common to the cancer metabolic changes that support rapid cell proliferation and growth. Our data also suggest alterations in post transcriptional modification of RNAs that might play a role in PNC development. Our study provides a proof of principle work flow for identifying metabolic alterations during PNC development driven by an oncogenic mutation. In the future, this approach could be combined with transcriptomic or proteomic approaches to establish the detailed interaction between signaling networks and cellular metabolic pathways that occur at the onset of tumor progression.

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m5C RNA Methylation Primarily Affects the ErbB and PI3K–Akt Signaling Pathways in Gastrointestinal Cancer

Cited by 22 publications

References 78 publications

Comprehensive Analysis of 5-Methylcytosine Profiles of Messenger RNA in Human High-Grade Serous Ovarian Cancer by MeRIP Sequencing

Comprehensive Analysis of 5-Methylcytosine Profiles of Messenger RNA in Human High-Grade Serous Ovarian Cancer by MeRIP Sequencing

Prognostic Value of an m5C RNA Methylation Regulator-Related Signature for Clear Cell Renal Cell Carcinoma

Metabolic Alterations in Preneoplastic Development Revealed by Untargeted Metabolomic Analysis

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