Combined Signature of N7-methylguanosine Regulators with Their Related Genes and the Tumor Microenvironment: a Prognostic and Therapeutic Biomarker for Breast Cancer

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2023 Oct 23

PMID 37868988

Authors

Tingjun Li

Zhishan Chen

Zhitang Wang

Jingyu Lu

Debo Chen

Affiliations

Soon will be listed here.

Abstract

Background: Identifying predictive markers for breast cancer (BC) prognosis and immunotherapeutic responses remains challenging. Recent findings indicate that N-methylguanosine (m7G) modification and the tumor microenvironment (TME) are critical for BC tumorigenesis and metastasis, suggesting that integrating m7G modifications and TME cell characteristics could improve the predictive accuracy for prognosis and immunotherapeutic responses.

Methods: We utilized bulk RNA-sequencing data from The Cancer Genome Atlas Breast Cancer Cohort and the GSE42568 and GSE146558 datasets to identify BC-specific m7G-modification regulators and associated genes. We used multiple m7G databases and RNA interference to validate the relationships between BC-specific m7G-modification regulators (METTL1 and WDR4) and related genes. Single-cell RNA-sequencing data from GSE176078 confirmed the association between m7G modifications and TME cells. We constructed an m7G-TME classifier, validated the results using an independent BC cohort (GSE20685; = 327), investigated the clinical significance of BC-specific m7G-modifying regulators by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, and performed tissue-microarray assays on 192 BC samples.

Results: Immunohistochemistry and RT-qPCR results indicated that METTL1 and WDR4 overexpression in BC correlated with poor patient prognosis. Moreover, single-cell analysis revealed relationships between m7G modification and TME cells, indicating their potential as indicators of BC prognosis and treatment responses. The m7G-TME classifier enabled patient subgrouping and revealed significantly better survival and treatment responses in the m7G+TME group. Significant differences in tumor biological functions and immunophenotypes occurred among the different subgroups.

Conclusions: The m7G-TME classifier offers a promising tool for predicting prognosis and immunotherapeutic responses in BC, which could support personalized therapeutic strategies.

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References

Song B, Tang Y, Chen K, Wei Z, Rong R, Lu Z . m7GHub: deciphering the location, regulation and pathogenesis of internal mRNA N7-methylguanosine (m7G) sites in human. Bioinformatics. 2020; 36(11):3528-3536. DOI: 10.1093/bioinformatics/btaa178. View

Du D, He J, Ju C, Wang C, Li H, He F . When N-methyladenosine modification meets cancer: Emerging frontiers and promising therapeutic opportunities. Cancer Lett. 2023; 562:216165. DOI: 10.1016/j.canlet.2023.216165. View

Gentles A, Newman A, Liu C, Bratman S, Feng W, Kim D . The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015; 21(8):938-945. PMC: 4852857. DOI: 10.1038/nm.3909. View

Tang T, Cheng X, Truong B, Sun L, Yang X, Wang H . Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint. Pharmacol Ther. 2020; 219:107709. PMC: 7886970. DOI: 10.1016/j.pharmthera.2020.107709. View

Yang L, Pang Y, Moses H . TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010; 31(6):220-7. PMC: 2891151. DOI: 10.1016/j.it.2010.04.002. View

Liebermeister W, Noor E, Flamholz A, Davidi D, Bernhardt J, Milo R . Visual account of protein investment in cellular functions. Proc Natl Acad Sci U S A. 2014; 111(23):8488-93. PMC: 4060655. DOI: 10.1073/pnas.1314810111. View

Nielsen J, Sahota R, Milne K, Kost S, Nesslinger N, Watson P . CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin Cancer Res. 2012; 18(12):3281-92. DOI: 10.1158/1078-0432.CCR-12-0234. View

Newman A, Steen C, Liu C, Gentles A, Chaudhuri A, Scherer F . Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol. 2019; 37(7):773-782. PMC: 6610714. DOI: 10.1038/s41587-019-0114-2. View

Xia L, Oyang L, Lin J, Tan S, Han Y, Wu N . The cancer metabolic reprogramming and immune response. Mol Cancer. 2021; 20(1):28. PMC: 7863491. DOI: 10.1186/s12943-021-01316-8. View

10.

Spranger S, Dai D, Horton B, Gajewski T . Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell. 2017; 31(5):711-723.e4. PMC: 5650691. DOI: 10.1016/j.ccell.2017.04.003. View

11.

Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M . Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007; 109(9):3812-9. DOI: 10.1182/blood-2006-07-035972. View

12.

Li W, Yuan P, Liu W, Xiao L, Xu C, Mo Q . Hypoxia-Immune-Related Gene SLC19A1 Serves as a Potential Biomarker for Prognosis in Multiple Myeloma. Front Immunol. 2022; 13:843369. PMC: 9358019. DOI: 10.3389/fimmu.2022.843369. View

13.

Mediratta K, El-Sahli S, DCosta V, Wang L . Current Progresses and Challenges of Immunotherapy in Triple-Negative Breast Cancer. Cancers (Basel). 2020; 12(12). PMC: 7761500. DOI: 10.3390/cancers12123529. View

14.

Chen K, Song B, Tang Y, Wei Z, Xu Q, Su J . RMDisease: a database of genetic variants that affect RNA modifications, with implications for epitranscriptome pathogenesis. Nucleic Acids Res. 2020; 49(D1):D1396-D1404. PMC: 7778951. DOI: 10.1093/nar/gkaa790. View

15.

Wang Y, Chen P, Chen X, Gong D, Wu Y, Huang L . ROS-Induced DCTPP1 Upregulation Contributes to Cisplatin Resistance in Ovarian Cancer. Front Mol Biosci. 2022; 9:838006. PMC: 8865183. DOI: 10.3389/fmolb.2022.838006. View

16.

Li A, Xiao H, Zhao Z, Xiang C, Chen Z, Wang P . Prognostic and immune implications of a novel 7-methylguanosine-related microRNA signature in breast invasive carcinoma: from exploration to validation. J Cancer Res Clin Oncol. 2023; 149(11):9105-9128. DOI: 10.1007/s00432-023-04849-1. View

17.

Zhang W, Zhang S, Wang Z . Prognostic value of 12 m7G methylation-related miRNA markers and their correlation with immune infiltration in breast cancer. Front Oncol. 2022; 12:929363. PMC: 9389359. DOI: 10.3389/fonc.2022.929363. View

18.

Chan M, Chung J, Chiu-Tsun Tang P, Chan A, Ho J, Lin T . TGF-β signaling networks in the tumor microenvironment. Cancer Lett. 2022; 550:215925. DOI: 10.1016/j.canlet.2022.215925. View

19.

Huang Z, Lou K, Liu H . A novel prognostic signature based on N7-methylguanosine-related long non-coding RNAs in breast cancer. Front Genet. 2022; 13:1030275. PMC: 9608183. DOI: 10.3389/fgene.2022.1030275. View

20.

Song B, Wang X, Liang Z, Ma J, Huang D, Wang Y . RMDisease V2.0: an updated database of genetic variants that affect RNA modifications with disease and trait implication. Nucleic Acids Res. 2022; 51(D1):D1388-D1396. PMC: 9825452. DOI: 10.1093/nar/gkac750. View