Multiple Functions and Mechanisms Underlying the Role of METTL3 in Human Cancers

Zheng, Wenhui; Dong, Xinhua; Zhao, Yan; Wang, Shuo; Jiang, Haiyang; Zhang, Mingdi; Zheng, Xinyu; Gu, Mancang

doi:10.3389/fonc.2019.01403

Cited by 73 publications

(80 citation statements)

References 72 publications

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“…The dysregulation of METTL3 has been found to be implicated in many aspects of human cancer cell progression, which has prompted many researchers to explore its possible molecular mechanism. Interestingly, the role of METTL3 in cancer cells is controversial (Zheng et al, 2019), which may be related to the differences in the mechanisms of origin of different cancers. In our study, METTL3 is supposed to exert an oncogenic effect, and knockdown of METTL3 can be efficient in downregulating the global m6A levels for tumor suppression in EEOC.…”

Section: Discussionmentioning

confidence: 99%

METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP

Liu

et al. 2020

Cell Biology International

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N6‐methyladenosine (m6A) RNA methylation, one of the common RNA modifications, has been determined to execute crucial functions in tumorigenesis and cancer development. The m6A “writers” including methyltransferase like 3 (METTL3), METTL14, and Wilms tumor 1‐associated protein (WTAP) contribute to the m6A modification process initiation. However, the coordination of m6A methyltransferase complex is not fully understood in endometrioid epithelial ovarian cancer (EEOC). In this study, mRNA and protein levels of METTL3, METTL14, and WTAP were detected in 33 EEOC cases using quantitative polymerase chain reaction (qPCR), immunohistochemistry, and western blot analysis. The overall m6A methylation was detected by dot plot. The METTL3 expression and overall m6A level were elevated in EEOC tissues, while the expressions of METTL14 and WTAP have no significant difference in EEOC compared to the adjacent tissues. The expression of METTL3 was an independent factor that correlated with poor malignancy and survival of EEOC patients. Moreover, METTL3 knockdown in TOV‐112D and CRL‐11731D cells weakened the capability of cell proliferation and migration, and promoted cell apoptosis compared to negative control and cells with WTAP or METTL14 knockdown using CCK‐8 assay, transwell assay, wound healing assay, and TUNEL assay. Furthermore, METTL3 knockdown also reduced m6A enrichment of the genes associated with ovarian cancer including EIF3C, AXL, CSF‐1, FZD10 in TOV‐112D, and CRL‐11731D cells by RIP‐qPCR assay. Taken together, the high expressed METTL3 indicated poor malignancy and survival of EEOC via modulating the aberrant m6A RNA methylation. METTL3‐mediated m6A modification, independent of WTAP and METTL14, was considered as a novel mechanism underlying m6A modulation and a potential therapeutic target of EEOC.

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Section: Discussionmentioning

confidence: 99%

METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP

Liu

et al. 2020

Cell Biology International

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“…These ndings demonstrated that METTL3 plays different (or even opposite) roles in different cancers [60]. IGF2BP2, a direct target of miR-485-5p, was discovered to be signi cantly up-regulated in the expression of NSCLC, and its depletion signi cantly suppressed tumor cell proliferation and invasion [61].…”

Section: Discussionmentioning

confidence: 98%

Construction of a m6A RNA Methylation Regulator-related Signature for Prognosis and Immune Response in Lung Adenocarcinoma

Sheng

Xia

et al. 2020

Preprint

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BackgroundN6-methyladenosine (m6A) RNA methylation is related to cancer pathogenesis and development. However, few studies have investigated the role of m6A regulator genes in lung adenocarcinoma (ADC).MethodsGene expressions with clinicopathological data were downloaded from The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) database. We compared the expression of twenty m6A regulator genes between tumor and normal samples. Univariate and least absolute shrinkage and selection operator (LASSO) Cox regression model were used to derive a multi-gene signature. A signature-based nomogram was developed, and the prediction performance was validated by an exterior validation set (GSE72094). Weighted gene co-expression network analysis (WGCNA) was performed to construct a co-expression network and identify the hub genes. The association of m6A signature with immunity was examined.ResultsSeventeen differentially expressed genes were identified. A five-gene prognostic signature (IGF2BP1, IGF2BP2, HNRNPA2B1, METTL3, and HNRNPC) was determined, and demonstrated as an unfavorable prognostic factor. A signature-based nomogram was developed to predict each patient’s survival probability, and the nomogram was well calibrated and showed a satisfactory discrimination. Turquoise was identified as the most risk-related module, and genes in this module were enriched in the pathway of cell cycle. Six genes were determined as the hub genes. High-risk patients had significantly higher expression of PD-L1, higher tumor mutational burden (TMB), higher proportion of immune checkpoint blockade (ICB) response, and lower proportion of T cells CD8.ConclusionsIn summary, the signature-based nomogram is useful for survival prediction, and high-risk patients were more sensitive to the ICB therapy.

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“…The key to controlling gene expression at different levels is chemical modi cation of the nucleobases, which can affect the translation of related mRNA, proteins and regulate signal pathways [6]. Among more than 100 RNA chemical modi cations identi ed, N6-methyl-adenosine (m6A) was the most common internal modi cation of mRNA and long non-coding RNA in eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

The prognostic value of METTL3 in cancer patients: a meta-analysis

Pan

et al. 2020

Preprint

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Background: M6A methylation modification of RNA can regulate the development of tumor cells. METTL3 is one of the modified methyltransferases. A growing number of studies have shown that high expression of METTL3 may be associated with the unfavorable prognosis in cancer patients and may become a new biomarker. Therefore, this meta-analysis was used to evaluate the prognostic value of METTL3 in cancer patients through the available literature information.Methods: Relevant studies were retrieved from electronic literature databases including six English databases and three Chinese databases. Correlation analysis was conducted by Stata SE 15.1 and RevMan 5.3 software. We analyzed 11 eligible studies with a total of 1638 cancer patients in this meta-analysis. We took advantage of HRs and ORs with 95% confidence intervals to evaluate the prognostic value of METTL3 in tumors. Besides,the article was qualified by MOOSE check lists and PRISMA Checklist. Results: The results of the meta-analysis indicated that high expression of METTL3 was associated with low overall survival (OS) (HR=2.67, 95%CI:2.19-3.25, P<0.00001) and disease-free survival (DFS) (HR=2.23, 95%CI:1.60-3.11, P<0.00001) in various cancers.Stratified analysis of cancer types showed that over expressed METTL3 was related to poor prognosis in digestive system cancer patients, including CRC(HR=2.29, 95%CI:1.50-3.49，P=0.0001) ,GC(HR=2.96，95%CI:2.13-4.12，P＜0.00001)，and liver cancer（HR=2.70，95%CI:1.88-3.88，P＜0.00001). Meanwhile, the elevated METTL3 expression also affected the lymph node metastasis (OR=3.40，95%CI=1.58-7.33，p=0.002) ，vascular invasion (OR=2.04，95%CI=1.06-3.95，p=0.03) and the tumors progression (III/IV vs. I/II: OR = 3.72, 95% CI: 1.94 - 7.13, P < 0.0001).Conclusion: The existing analysis indicates that METTL3 is associated with low OS and DFS in cancer patients and may serve as a biomarker to assess prognostic value.

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Multiple Functions and Mechanisms Underlying the Role of METTL3 in Human Cancers

Cited by 73 publications

References 72 publications

METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP

METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP

Construction of a m6A RNA Methylation Regulator-related Signature for Prognosis and Immune Response in Lung Adenocarcinoma

The prognostic value of METTL3 in cancer patients: a meta-analysis

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