The Role of RNA Methyltransferase METTL3 in Hepatocellular Carcinoma: Results and Perspectives

Fan, Ping; Lin, Xiaoyang; Hao, Liping; Chen, Xiaoyuan; Wan, Huaibin; Wang, Rui

doi:10.3389/fcell.2021.674919

Cited by 29 publications

(15 citation statements)

References 98 publications

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“…Also, METTL3 was found to be consistently upregulated, and high METTL3 expression was associated with the prognosis of oral squamous cell carcinoma patients. It is also reported that METTL3 overexpression promotes the proliferation and migration of hepatocellular carcinoma cells [45]. Besides, m6A modification in cancer treatment indicates new directions for the treatment of various cancers [15].…”

Section: Discussionmentioning

confidence: 98%

Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

Yu¹,

Ye²,

He³

et al. 2022

Int. J. Biol. Sci.

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Although m6A modifications are associated with tumor progression, and anti-tumor immune responses, the role of m6A regulators in HPV-related carcinogenesis has not been well resolved. To provide evidence for the role of m6A regulators in HPV-related carcinogenesis and identify potential therapeutic targets for HPV-related cancers, integrative analyses of m6A regulators in 1,485 head and neck squamous cell carcinoma (HNSC) patients and 507 cervical squamous cell carcinoma (CESC) patients was performed and identified that an m6A regulator, METTL3, was highly expressed in tumors and was related to the poor prognosis in HNSC and CESC. In HPV-positive tumors, METTL3 was positively associated with tumor HPV status, such as HPV integration status, E6 and unspliced-E6 expression, and p16 expression. Further analysis demonstrated that METTL3 high status was negatively correlated with tumor immune cell infiltrations and facilitated the expression of immunosuppressive immune checkpoint molecules (i.e., PD-L1). Cell-derived xenograft models demonstrated that METTL3 inhibitor combined with anti-PD1 therapy promoted immunotherapy of CESC in vivo. Overall, this study identified that METTL3 high status, is associated with poor prognosis and HPV status, and serves as a mediator of the immunosuppressive tumor microenvironment in HPV-associated cancer, which provides a promising therapeutic target for anti-cancer immunotherapy.

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Section: Discussionmentioning

confidence: 98%

Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

Yu¹,

Ye²,

He³

et al. 2022

Int. J. Biol. Sci.

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“…METTL3 is a pivotal methyltransferase and essential to the performance of m6A modification. 16 METTL3 can regulate RNA expression in a m6A-dependent manner and contributes to the carcinogenesis, tumor progression and drug resistance of HCC. YTHDF2, which is also known as an m6A “reader”,is capable of recognizing and binding to m6A modified sequences.…”

Section: Discussionmentioning

confidence: 99%

Identification of Prognostic Genes in Hepatocellular Carcinoma

Bai

Cheng

Xiong

et al. 2022

IJGM

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Background Previous studies have demonstrated the important role of tumor stem cells (TSCs) in the development of hepatocellular carcinoma (HCC); however, TSC-related genetic markers have not been investigated. Aim The aim of the present study was to identify stem cell-related signature genes to predict the prognosis of HCC, using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Methods In total, 423 liver HCC tissue samples, including 373 tumor and 50 adjacent normal tissue samples from TCGA, and 115 primary tumor and 52 adjacent non-tumor tissue samples from the GEO GSE76427 database, were used in the present study. The non-negative matrix factorization (NMF) algorithm, t-distributed stochastic neighbor embedding (t-SNE) algorithm and Cox regression analysis were combined for model construction and validation. Results Overall, six clusters were identified using the NMF and t-SNE algorithms with 470 stem cell-related genes. The results demonstrated that patients in cluster 5 had the worst prognosis. For multivariate Cox survival analysis, 15 genes with optimal lambda values were chosen and eight genes were incorporated into the final regression model using the optimal Akaike information criterion value. Validation of the risk model using the aforementioned eight signature genes demonstrated the models strong reliability and stable predictive performance. Conclusion The results of the present study indicated that the eight-gene (Hes family BHLH transcription factor 5, KIT ligand, methyltransferase-like 3, proteasome 26S subunit non-ATPase 1, Ras-related protein Rab-10, treacle ribosome biogenesis factor 1, YTH N6-methyladenosine RNA binding protein 2 and Zinc Finger CCCH-Type Containing 13) signature constructed by the model may be reliable in predicting the prognosis of patients with HCC.

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“…METTL3 plays a dual role as either an oncogene or a tumor suppressor gene in various types of cancers, including hepatocellular carcinoma (HCC) [ 60 , 61 ], hepatoblastoma [ 62 ], gastric cancer (GC) [ 63 ], colorectal cancer (CRC) [ 64 ], non-small cell lung cancer (NSCLC) [ 65 , 66 ], and bladder cancer (BLC) [ 67 , 68 ]. Abnormal expression of METTL3 in tumor cells affects the infiltration of immune cells.…”

Section: Role Of M 6 a Modification In Remodeling ...mentioning

confidence: 99%

Targeting the RNA m6A modification for cancer immunotherapy

et al. 2022

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N6-methyladenosine (m6A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m6A often affects oncogenic and tumor-suppressing networks, m6A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m6A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m6A modifications intrinsically affect immune cells and how alterations in tumor cell m6A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m6A regulators with immune checkpoint blockers; generating an effective programmable m6A gene-editing system that enables efficient manipulation of individual m6A sites; establishing an effective m6A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m6A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m6A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.

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The Role of RNA Methyltransferase METTL3 in Hepatocellular Carcinoma: Results and Perspectives

Cited by 29 publications

References 98 publications

Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

Identification of Prognostic Genes in Hepatocellular Carcinoma

Targeting the RNA m6A modification for cancer immunotherapy

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