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

被引:8
作者
Yang, Shu [2 ]
Yuan, Yixiao [6 ]
Ren, Wenjun [1 ]
Wang, Haiyu [1 ]
Zhao, Zhong [2 ]
Zhao, Heng [3 ]
Zhao, Qizhe [4 ]
Chen, Xi [5 ]
Jiang, Xiulin [7 ]
Zhang, Lei [2 ]
机构
[1] Affiliated Hosp Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Dept Cardiovasc Surg, Kunming, Yunnan, Peoples R China
[2] Affiliated Hosp Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Dept Neurol, Kunming, Yunnan, Peoples R China
[3] Affiliated Hosp Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Dept Neurosurg, Kunming, Yunnan, Peoples R China
[4] Second Affiliated Hosp Kunming Med Univ, Dept Urol, Kunming, Peoples R China
[5] Second Affiliated Hosp Kunming Med Univ, Dept Neurosurg 1, Kunming, Peoples R China
[6] First Affiliated Hosp Chongqing Med Univ, Key Lab Mol Oncol & Epigenet, Chongqing, Peoples R China
[7] Univ Chinese Acad Sci, Kunming Coll Life Sci, Beijing, Peoples R China
来源
FRONTIERS IN ONCOLOGY | 2022年 / 12卷
关键词
glioma; MCM family; prognostic model; biomarker; immune infiltration; diagnosis; GENE-EXPRESSION; PROLIFERATION; RESOURCE; MARKER; SERVER;
D O I
10.3389/fonc.2022.1004324
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
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.
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页数:23
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共 47 条
  • [1] Challenges to curing primary brain tumours
    Aldape, Kenneth
    Brindle, Kevin M.
    Chesler, Louis
    Chopra, Rajesh
    Gajjar, Amar
    Gilbert, Mark R.
    Gottardo, Nicholas
    Gutmann, David H.
    Hargrave, Darren
    Holland, Eric C.
    Jones, David T. W.
    Joyce, Johanna A.
    Kearns, Pamela
    Kieran, Mark W.
    Mellinghoff, Ingo K.
    Merchant, Melinda
    Pfister, Stefan M.
    Pollard, Steven M.
    Ramaswamy, Vijay
    Rich, Jeremy N.
    Robinson, Giles W.
    Rowitch, David H.
    Sampson, John H.
    Taylor, Michael D.
    Workman, Paul
    Gilbertson, Richard J.
    [J]. NATURE REVIEWS CLINICAL ONCOLOGY, 2019, 16 (08) : 509 - 520
  • [2] Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality
    Alvarez, Silvia
    Diaz, Marcos
    Flach, Johanna
    Rodriguez-Acebes, Sara
    Lopez-Contreras, Andres J.
    Martinez, Dolores
    Canamero, Marta
    Fernandez-Capetillo, Oscar
    Isern, Joan
    Passegue, Emmanuelle
    Mendez, Juan
    [J]. NATURE COMMUNICATIONS, 2015, 6
  • [3] An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies Targeted by Small Molecules
    Basu, Amrita
    Bodycombe, Nicole E.
    Cheah, Jaime H.
    Price, Edmund V.
    Liu, Ke
    Schaefer, Giannina I.
    Ebright, Richard Y.
    Stewart, Michelle L.
    Ito, Daisuke
    Wang, Stephanie
    Bracha, Abigail L.
    Liefeld, Ted
    Wawer, Mathias
    Gilbert, Joshua C.
    Wilson, Andrew J.
    Stransky, Nicolas
    Kryukov, Gregory V.
    Dancik, Vlado
    Barretina, Jordi
    Garraway, Levi A.
    Hon, C. Suk-Yee
    Munoz, Benito
    Bittker, Joshua A.
    Stockwell, Brent R.
    Khabele, Dineo
    Stern, Andrew M.
    Clemons, Paul A.
    Shamji, Alykhan F.
    Schreiber, Stuart L.
    [J]. CELL, 2013, 154 (05) : 1151 - 1161
  • [4] Spatiotemporal Dynamics of Intratumoral Immune Cells Reveal the Immune Landscape in Human Cancer
    Bindea, Gabriela
    Mlecnik, Bernhard
    Tosolini, Marie
    Kirilovsky, Amos
    Waldner, Maximilian
    Obenauf, Anna C.
    Angell, Helen
    Fredriksen, Tessa
    Lafontaine, Lucie
    Berger, Anne
    Bruneval, Patrick
    Fridman, Wolf Herman
    Becker, Christoph
    Pages, Franck
    Speicher, Michael R.
    Trajanoski, Zlatko
    Galon, Jerome
    [J]. IMMUNITY, 2013, 39 (04) : 782 - 795
  • [5] MCM2 and MCM5 as Prognostic Markers in Colon Cancer: A Worthwhile Approach
    Burger, Maximilian
    [J]. DIGESTIVE DISEASES AND SCIENCES, 2009, 54 (02) : 197 - 198
  • [6] A conserved Mcm4 motif is required for Mcm2-7 double-hexamer formation and origin DNA unwinding
    Champasan, Kanokwan
    Blank, Caitlin
    Friedman, Larry J.
    Gelles, Jeff
    Bell, Stephen P.
    [J]. ELIFE, 2019, 8
  • [7] Transcriptional Characterization Of The Tumor Immune Microenvironment And Its Prognostic Value For Locally Advanced Lung Adenocarcinoma In A Chinese Population
    Chen, Yuqiao
    Chen, Huan
    Mao, Beibei
    Zhou, Yuan
    Shi, Xinying
    Tang, Lu
    Jiang, Hong
    Wang, Guo
    Zhuang, Wei
    [J]. CANCER MANAGEMENT AND RESEARCH, 2019, 11 : 9165 - 9173
  • [8] Depletion of minichromosome maintenance protein 7 inhibits glioblastoma multiforme tumor growth in vivo
    Erkan, E. P.
    Stroebel, T.
    Lewandrowski, G.
    Tannous, B.
    Madlener, S.
    Czech, T.
    Saydam, N.
    Saydam, O.
    [J]. ONCOGENE, 2014, 33 (39) : 4778 - 4785
  • [9] Cdt1 stabilizes an open MCM ring for helicase loading
    Frigola, Jordi
    He, Jun
    Kinkelin, Kerstin
    Pye, Valerie E.
    Renault, Ludovic
    Douglas, Max E.
    Remus, Dirk
    Cherepanov, Peter
    Costa, Alessandro
    Diffley, John F. X.
    [J]. NATURE COMMUNICATIONS, 2017, 8
  • [10] MCM5 promotes tumour proliferation and correlates with the progression and prognosis of renal cell carcinoma
    Gong, Binbin
    Ma, Ming
    Yang, Xiaorong
    Xie, Wenjie
    Luo, Yanping
    Sun, Ting
    [J]. INTERNATIONAL UROLOGY AND NEPHROLOGY, 2019, 51 (09) : 1517 - 1526