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

作者全名："Yang, Shu; Yuan, Yixiao; Ren, Wenjun; Wang, Haiyu; Zhao, Zhong; Zhao, Heng; Zhao, Qizhe; Chen, Xi; Jiang, Xiulin; Zhang, Lei"

作者地址："[Ren, Wenjun; Wang, Haiyu] Affiliated Hosp Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Dept Cardiovasc Surg, Kunming, Yunnan, Peoples R China; [Yang, Shu; Zhao, Zhong; Zhang, Lei] Affiliated Hosp Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Dept Neurol, Kunming, Yunnan, Peoples R China; [Zhao, Heng] Affiliated Hosp Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Dept Neurosurg, Kunming, Yunnan, Peoples R China; [Zhao, Qizhe] Second Affiliated Hosp Kunming Med Univ, Dept Urol, Kunming, Peoples R China; [Chen, Xi] Second Affiliated Hosp Kunming Med Univ, Dept Neurosurg 1, Kunming, Peoples R China; [Yuan, Yixiao] First Affiliated Hosp Chongqing Med Univ, Key Lab Mol Oncol & Epigenet, Chongqing, Peoples R China; [Jiang, Xiulin] Univ Chinese Acad Sci, Kunming Coll Life Sci, Beijing, Peoples R China"

通信作者："Zhang, L (通讯作者)，Affiliated Hosp Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Dept Neurol, Kunming, Yunnan, Peoples R China.; Jiang, XL (通讯作者)，Univ Chinese Acad Sci, Kunming Coll Life Sci, Beijing, Peoples R China."

来源：FRONTIERS IN ONCOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000892748400001

JCR分区：Q2

影响因子：4.7

年份：2022

卷号：12

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：glioma; MCM family; prognostic model; biomarker; immune infiltration; diagnosis

摘要："BackgroundGliomas 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. MethodsIn 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. ResultsIn 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. ConclusionsIn summary, this finding confirmed that MCM4 is a potential target of precision therapy for patients with glioma."

基金机构："China International Medical Foundation: Cerebrovascular Disease Youth Innovation Fund [2022LCZXKF-XZ01]; Open Project of The First People's Hospital of Yunnan Province Clinical Medicine Center [2022B24]; Graduate Student Innovation Fund, Kunming Medical University; [Z-2016-20-2101]"

基金资助正文："This work was supported by the China International Medical Foundation: Cerebrovascular Disease Youth Innovation Fund (Grant No.Z-2016-20-2101); The Open Project of The First People's Hospital of Yunnan Province Clinical Medicine Center (Grant No. 2022LCZXKF-XZ01); Graduate Student Innovation Fund, Kunming Medical University (Grant No. 2022B24)."