Methyladenosine Modification in RNAs: Classification and Roles in Gastrointestinal Cancers

He, Weiling; Wan, Guohui

doi:10.3389/fonc.2020.586789

Cited by 14 publications

(36 citation statements)

References 175 publications

(291 reference statements)

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“…40 Most classifications focus on a single biological and molecular feature and in this study, a new classifier was developed by combining the hypoxic state and immune cell infiltration of gastric cancer. 41,42 Due to the complexity of immune activity and hypoxia in the tumor micro environment, few transcriptome-based biomarkers could evaluate hypoxia and immune status, so we took advantage of ssGSEA to calculate the enrichment scores of related immune and hypoxia gene sets as our evaluation index. 43,44 Of course, the gene sets of these hypoxia-related processes have been verified in GSE114083 and the results show that they can represent tumor hypoxia traits in gastric cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

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Identification and Development of Subtypes with Poor Prognosis in Gastric Cancer Based on Both Hypoxia and Immune Cell Infiltration

Wang¹,

Sun²,

Yang³

et al. 2021

IJGM

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Hypoxia and immune cell infiltration play an important role in the progression and metastasis of gastric cancer. However, the molecular classification of gastric cancer combined with hypoxia and immune cell infiltration remains unknown. Materials and Methods: ssGSEA was used to evaluate the hypoxic state and immune cell infiltration of 1059 gastric cancer samples collected from the GEO and TCGA database. Based on the results, unsupervised clustering was performed to obtain different gastric cancer subtypes. The differentially expressed genes related to OS between these subtypes were utilized for LASSO analysis to construct a prognostic signature (HIscore). Subsequently, small-molecule drugs were predicted using the Connectivity Map (CMAP) database. Results: We obtained three hypoxic-immune infiltration patterns (HIcluster A-C) with different prognoses and classified them as low hypoxic/low immune, high hypoxic/high immune, and low hypoxic/high immune subtypes. Based on the differential genes between HIclusters, we have also obtained other three gastric cancer subtypes (genecluster A-C) and a 13-gene signature (HIscore). At the same time, we extensively explored the clinical and transcriptome traits in different clusters and groups with high or low HIscore. We proved that HIscore is an independent prognostic biomarker and an indicator of genome stability and EMT. Using the CMAP database, we found 96 small-molecule drugs that could reverse the poor prognosis and could serve as therapeutic drugs, especially for gastric cancer patients with high HIscore. Conclusion: Our study evaluated the hypoxic state and immune cell infiltration in gastric tumors, and identified different gastric cancer subtypes. In addition, we established a hypoxia-immune signature to predict prognosis which is tightly linked to tumor EMT and genomic stability. Based on HIscore, we used the CMAP database to explore smallmolecule drugs that may have the potential in serving as therapeutic drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification and Development of Subtypes with Poor Prognosis in Gastric Cancer Based on Both Hypoxia and Immune Cell Infiltration

Wang¹,

Sun²,

Yang³

et al. 2021

IJGM

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“…In the last decade, extensive studies have shown that epigenetic alterations may occur not only at the DNA also at the RNA level, thus leading to crucial modifications in gene expression and pathway activation. In particular, dysregulation of RNA methylation (due to altered expression of specific enzymes) has been linked to the hyperactivation of the MAPK/ERK and the WNT/beta-catenin pathways in the absence of mutations of the main players of the pathway itself [26]. Finally, aberrant epigenetic regulation has been reported to occur via altered expression of members of the long non-coding RNAs (lncRNAs) family.…”

Section: Figurementioning

confidence: 99%

Identifying Novel Actionable Targets in Colon Cancer

Cerrito

Grassilli

2021

Biomedicines

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Colorectal cancer is the fourth cause of death from cancer worldwide, mainly due to the high incidence of drug-resistance toward classic chemotherapeutic and newly targeted drugs. In the last decade or so, the development of novel high-throughput approaches, both genome-wide and chemical, allowed the identification of novel actionable targets and the development of the relative specific inhibitors to be used either to re-sensitize drug-resistant tumors (in combination with chemotherapy) or to be synthetic lethal for tumors with specific oncogenic mutations. Finally, high-throughput screening using FDA-approved libraries of “known” drugs uncovered new therapeutic applications of drugs (used alone or in combination) that have been in the clinic for decades for treating non-cancerous diseases (re-positioning or re-purposing approach). Thus, several novel actionable targets have been identified and some of them are already being tested in clinical trials, indicating that high-throughput approaches, especially those involving drug re-positioning, may lead in a near future to significant improvement of the therapy for colon cancer patients, especially in the context of a personalized approach, i.e., in defined subgroups of patients whose tumors carry certain mutations.

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“…This modification is catalyzed by RNA methyltransferases known as writers, such as methyltransferase-like 14 (METTL14), and is removed by demethylases known as erasers, such as fat mass and obesity-associated protein (FTO). Additionally, m 6 A is recognized by m 6 A-binding proteins known as readers, such as IGF2BPs, which promote RNA stability and translation (2). Altogether, these proteins determine the dynamic and reversible regulation of m 6 A RNA modification (3), which can become disrupted if the expression or function of these proteins are altered, resulting in the development of human diseases and cancers (4).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Methyltransferase-Like 14 Promotes Ovarian Cancer Cell Proliferation Through Stabilizing TROAP mRNA

Peng

Jiang

et al. 2022

Front. Oncol.

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Altered expression levels of the proteins that regulate N6-methyladenosine (m6A) RNA methylation, including methyltransferase-like 14 (METTL14), are associated with cancer development. Based on our analysis of m6A methylation regulators using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, we focused on the regulatory role of METTL14 in ovarian cancer. We performed bioinformatics and survival analyses with these datasets and also used METTL14-overexpressing SKOV-3 ovarian cancer cells for in vitro studies. Trophinin associated protein (TROAP) siRNA and treatment with or without actinomycin D was used in the cells for qRT-PCR, western blot, cDNA microarray, cell viability, colony formation, luciferase gene reporter, methylated RNA immunoprecipitation (MeRIP)-qPCR, total RNA methylation, and RNA stability assays. Additionally, ovarian cancer and normal tissue samples were analyzed by immunohistochemistry, qRT-PCR, and western blot assays. The TCGA and GEO data confirmed copy number variations (CNVs) of these m6A RNA methylation regulators in ovarian cancer tissues. Furthermore, reduced METTL14 expression was associated with alterations in CNVs as well as poor patient survival in ovarian cancer. Moreover, the METTL14 and m6A RNA methylation levels were both significantly reduced in ovarian cancer tissues than in normal tissues. Restoration of METTL14 expression suppresses ovarian cancer cell proliferation by inhibition of TROAP expression. Further in vivo and in vitro experiments confirmed that METTL14 is a negative regulator of ovarian cancer cell proliferation via TROAP expression and that m6A RNA methylation regulates TROAP mRNA stability. In conclusion, METTL14 overexpression decreased ovarian cancer proliferation by inhibition of TROAP expression via an m6A RNA methylation-dependent mechanism.

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Methyladenosine Modification in RNAs: Classification and Roles in Gastrointestinal Cancers

Cited by 14 publications

References 175 publications

Identification and Development of Subtypes with Poor Prognosis in Gastric Cancer Based on Both Hypoxia and Immune Cell Infiltration

Identification and Development of Subtypes with Poor Prognosis in Gastric Cancer Based on Both Hypoxia and Immune Cell Infiltration

Identifying Novel Actionable Targets in Colon Cancer

Downregulation of Methyltransferase-Like 14 Promotes Ovarian Cancer Cell Proliferation Through Stabilizing TROAP mRNA

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