MCM4 is a novel prognostic biomarker and promotes cancer cell growth in glioma

Shu Yang; Yixiao Yuan; Wenjun Ren; Haiyu Wang; Zhong Zhao; Heng Zhao; Qizhe Zhao; Xi Chen; Xiulin Jiang; Lei Zhang

doi:10.3389/fonc.2022.1004324

MCM4 is a novel prognostic biomarker and promotes cancer cell growth in glioma

Front Oncol. 2022 Nov 17:12:1004324. doi: 10.3389/fonc.2022.1004324. eCollection 2022.

Authors

Shu Yang¹, Yixiao Yuan², Wenjun Ren³, Haiyu Wang³, Zhong Zhao¹, Heng Zhao⁴, Qizhe Zhao⁵, Xi Chen⁶, Xiulin Jiang⁷, Lei Zhang¹

Affiliations

¹ Department of Neurology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China.
² Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
³ Department of Cardiovascular Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China.
⁴ Department of Neurosurgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China.
⁵ Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
⁶ First Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
⁷ Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China.

Abstract

Background: Gliomas account for 75% of all primary malignant brain tumors in adults and result in high mortality. Accumulated evidence has declared the minichromosome maintenance protein complex (MCM) gene family plays a critical role in modulating the cell cycle and DNA replication stress. However, the biological function and clinic characterization of nine MCM members in low-grade glioma are not yet clarified.

Methods: In this study, we utilized diverse public databases, including The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Rembrandt, Human Protein Atlas (HPA), Linkedomics, cbioportal, Tumor and Immune System Interaction Database (TISIDB), single-sample GSEA (ssGSEA), Tumor Immune Estimation Resource (TIMER), Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal databases to explore the mRNA and protein expression profiles, gene mutation, clinical features, diagnosis, prognosis, signaling pathway, tumor mutational burden (TMB), immune subtype, immune cell infiltration, immune modulator and drug sensitivity of nine MCMs. Afterward, qRT-PCR was utilized to detect the expression of the MCM family in glioblastoma multiforme (GBM) cell lines. The one-, three-, or five-year survival rate was predicted by utilizing a nomogram established by cox proportional hazard regression.

Results: In this study, we found that nine MCMs were consistently up-regulated in glioma tissues and glioma cell lines. Elevated nine MCMs expressions were significantly correlated with a higher tumor stage, isocitrate dehydrogenase (IDH) mutates, 1p/19q codeletion, histological type, and primary therapy outcome. Survival analyses showed that higher expression of MCM2-MCM8 (minichromosome maintenance protein2-8) and MCM10 (minichromosome maintenance protein 10) were linked with poor overall survival (OS) and progression-free survival (PFS) in glioma patients. On the other hand, up-regulated MCM2-MCM8 and MCM10 were significantly associated with shorter disease-specific survival (DSS) in glioma patients. Univariate and multivariate analyses revealed that MCM2 (minichromosome maintenance protein2), MCM4 (minichromosome maintenance protein 4), MCM6 (minichromosome maintenance protein 6), MCM7 (minichromosome maintenance protein 7) expression and tumor grade, 1p/19q codeletion, age, and primary therapy outcome were independent factors correlated with the clinical outcome of glioma patients. More importantly, a prognostic MCMs model constructed using the above five prognostic genes could predict the overall survival of glioma patients with medium-to-high accuracy. Furthermore, functional enrichment analysis indicated that MCMs principal participated in regulating cell cycle and DNA replication. DNA copy number variation (CNV) and DNA methylation significantly affect the expression of MCMs. Finally, we uncover that MCMs expression is highly correlated with immune cell infiltration, immune modulator, TMB, and drug sensitivity.

Conclusions: In summary, this finding confirmed that MCM4 is a potential target of precision therapy for patients with glioma.

Keywords: MCM family; biomarker; diagnosis; glioma; immune infiltration; prognostic model.