The Prognostic and Immunological Role of MCM3 in Pan-cancer and Validation of Prognosis in a Clinical Lower-grade Glioma Cohort

Overview

Journal Front Pharmacol

Date 2024 May 3

PMID 38698811

Authors

Qian-Rong Huang

Qian Jiang

Ju-Yuan Tan

Ren-Bao Nong

Jun Yan

Xia-Wei Yang

Li-Gen Mo

Guo-Yuan Ling

Teng Deng

Yi-Zhen Gong

Affiliations

Soon will be listed here.

Abstract

Previous studies have shown that MCM3 plays a key role in initiating DNA replication. However, the mechanism of MCM3 function in most cancers is still unknown. The aim of our study was to explore the expression, prognostic role, and immunological characteristics of MCM3 across cancers. We explored the expression pattern of MCM3 across cancers. We subsequently explored the prognostic value of MCM3 expression by using univariate Cox regression analysis. Spearman correlation analysis was performed to determine the correlations between MCM3 and immune-related characteristics, mismatching repair (MMR) signatures, RNA modulator genes, cancer stemness, programmed cell death (PCD) gene expression, tumour mutation burden (TMB), microsatellite instability (MSI), and neoantigen levels. The role of MCM3 in predicting the response to immune checkpoint blockade (ICB) therapy was further evaluated in four immunotherapy cohorts. Single-cell data from CancerSEA were analysed to assess the biological functions associated with MCM3 in 14 cancers. The clinical correlation and independent prognostic significance of MCM3 were further analysed in the TCGA and CGGA lower-grade glioma (LGG) cohorts, and a prognostic nomogram was constructed. Immunohistochemistry in a clinical cohort was utilized to validate the prognostic utility of MCM3 expression in LGG. MCM3 expression was upregulated in most tumours and strongly associated with patient outcomes in many cancers. Correlation analyses demonstrated that MCM3 expression was closely linked to immune cell infiltration, immune checkpoints, MMR genes, RNA modulator genes, cancer stemness, PCD genes and the TMB in most tumours. There was an obvious difference in outcomes between patients with high MCM3 expression and those with low MCM3 expression in the 4 ICB treatment cohorts. Single-cell analysis indicated that MCM3 was mainly linked to the cell cycle, DNA damage and DNA repair. The expression of MCM3 was associated with the clinical features of LGG patients and was an independent prognostic indicator. Finally, the prognostic significance of MCM3 in LGG was validated in a clinical cohort. Our study suggested that MCM3 can be used as a potential prognostic marker for cancers and may be associated with tumour immunity. In addition, MCM3 is a promising predictor of immunotherapy responses.

Citing Articles

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PMID: 39095516 PMC: 11297030. DOI: 10.1038/s41598-024-68134-y.

References

Dudley J, Lin M, Le D, Eshleman J . Microsatellite Instability as a Biomarker for PD-1 Blockade. Clin Cancer Res. 2016; 22(4):813-20. DOI: 10.1158/1078-0432.CCR-15-1678. View

Valverde L, de Freitas R, Pereira T, de Resende M, Agra I, Dos Santos J . MCM3: A Novel Proliferation Marker in Oral Squamous Cell Carcinoma. Appl Immunohistochem Mol Morphol. 2016; 26(2):120-125. DOI: 10.1097/PAI.0000000000000397. View

Gao Z, Man X, Li Z, Bi J, Liu X, Li Z . Correction: PLK1 promotes proliferation and suppresses apoptosis of renal cell carcinoma cells by phosphorylating MCM3. Cancer Gene Ther. 2022; 29(5):627. DOI: 10.1038/s41417-022-00458-1. View

Yang W, Pan Y, You C . CDK1, CCNB1, CDC20, BUB1, MAD2L1, MCM3, BUB1B, MCM2, and RFC4 May Be Potential Therapeutic Targets for Hepatocellular Carcinoma Using Integrated Bioinformatic Analysis. Biomed Res Int. 2019; 2019:1245072. PMC: 6815605. DOI: 10.1155/2019/1245072. View

Kang E, Millstein J, Popovic G, Meagher N, Bolithon A, Talhouk A . MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma. Virchows Arch. 2021; 480(4):855-871. PMC: 9035053. DOI: 10.1007/s00428-021-03232-0. View

Weinstein J, Collisson E, Mills G, Mills Shaw K, Ozenberger B, Ellrott K . The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 2013; 45(10):1113-20. PMC: 3919969. DOI: 10.1038/ng.2764. View

Xie J, Zhang J, Tian W, Zou Y, Tang Y, Zheng S . The Pan-Cancer Multi-Omics Landscape of FOXO Family Relevant to Clinical Outcome and Drug Resistance. Int J Mol Sci. 2022; 23(24). PMC: 9778770. DOI: 10.3390/ijms232415647. View

Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W . Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013; 4:2612. PMC: 3826632. DOI: 10.1038/ncomms3612. View

Ettinger D, Wood D, Aggarwal C, Aisner D, Akerley W, Bauman J . NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 1.2020. J Natl Compr Canc Netw. 2019; 17(12):1464-1472. DOI: 10.6004/jnccn.2019.0059. View

10.

Li H, Wei B, Li Z, Wang X, Jia W, Xu Y . Diagnostic and prognostic value of MCM3 and its interacting proteins in hepatocellular carcinoma. Oncol Lett. 2020; 20(6):308. PMC: 7573876. DOI: 10.3892/ol.2020.12171. View

11.

Pan S, Sun S, Liu B, Hou Y . Pan-cancer Landscape of the RUNX Protein Family Reveals their Potential as Carcinogenic Biomarkers and the Mechanisms Underlying their Action. J Transl Int Med. 2022; 10(2):156-174. PMC: 9328034. DOI: 10.2478/jtim-2022-0013. View

12.

Deegan T, Diffley J . MCM: one ring to rule them all. Curr Opin Struct Biol. 2016; 37:145-51. DOI: 10.1016/j.sbi.2016.01.014. View

13.

Zou Y, Ye F, Kong Y, Hu X, Deng X, Xie J . The Single-Cell Landscape of Intratumoral Heterogeneity and The Immunosuppressive Microenvironment in Liver and Brain Metastases of Breast Cancer. Adv Sci (Weinh). 2022; 10(5):e2203699. PMC: 9929130. DOI: 10.1002/advs.202203699. View

14.

Lim M, Xia Y, Bettegowda C, Weller M . Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018; 15(7):422-442. DOI: 10.1038/s41571-018-0003-5. View

15.

Newman J, Seetharamu N, Saif M . Burden of Proof: Evaluating the Efficacy of Tumor Mutational Burden (TMB) in Predicting Response to Immune Checkpoint Inhibitors. Cancer Med J. 2020; 3(Suppl 2):17-21. PMC: 7769129. View

16.

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

17.

Matthews H, Bertoli C, de Bruin R . Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2021; 23(1):74-88. DOI: 10.1038/s41580-021-00404-3. View

18.

Giustini N, Bazhenova L . Recognizing Prognostic and Predictive Biomarkers in the Treatment of Non-Small Cell Lung Cancer (NSCLC) with Immune Checkpoint Inhibitors (ICIs). Lung Cancer (Auckl). 2021; 12:21-34. PMC: 8006757. DOI: 10.2147/LCTT.S235102. View

19.

Madine M, Swietlik M, Pelizon C, Romanowski P, Mills A, Laskey R . The roles of the MCM, ORC, and Cdc6 proteins in determining the replication competence of chromatin in quiescent cells. J Struct Biol. 2000; 129(2-3):198-210. DOI: 10.1006/jsbi.2000.4218. View

20.

Li Y, Zou J, Zhang Q, Quan F, Cao L, Zhang X . Systemic Analysis of the DNA Replication Regulator MCM Complex in Ovarian Cancer and Its Prognostic Value. Front Oncol. 2021; 11:681261. PMC: 8220296. DOI: 10.3389/fonc.2021.681261. View