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

Abstract

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.

Cigarette smoking combined with genetic variation regulates the m6A methylation of CRNKL1 and is associated with bladder cancer risk

“…CCNB1 and MCM4 have previously been shown to play important roles in accelerating the cell cycle and promoting malignant tumor proliferation. 44,45 In bladder cancer, upregulated CRNKL1 expression has been identified as an important regulator of the cell cycle in bladder tumorigenesis, 46 while increased MCM4 expression has been observed and found to promote cell cycle progression and malignant proliferation. 47 However, an accelerated cell cycle is a critical factor that promotes tumor proliferation and progression.…”

“…Furthermore, we observed a significant positive correlation between CRNKL1 expression and the expression of two genes ( CCNB1 and MCM4 ) involved in promoting the cell cycle. CCNB1 and MCM4 have previously been shown to play important roles in accelerating the cell cycle and promoting malignant tumor proliferation 44,45 . In bladder cancer, upregulated CRNKL1 expression has been identified as an important regulator of the cell cycle in bladder tumorigenesis, 46 while increased MCM4 expression has been observed and found to promote cell cycle progression and malignant proliferation 47 .…”

Enhancer-driven transcription of MCM8 by E2F4 promotes ATR pathway activation and glioma stem cell characteristics

“…Minichromosome maintenance 8 (MCM8), a homologous recombination repair factor, plays a crucial role in regulating the initiation and extension of DNA replication [ 26 ]. MCM8 contributes to the progression of various cancers, such as cholangiocarcinoma, osteosarcoma, gastric cancer and glioma [ 48 – 51 ]. Abnormal upregulation of MCM8 expression is observed in glioma, and high expression of MCM8 is associated with poor prognosis [ 51 ].…”

Mechanism of DNA unwinding by MCM8-9 in complex with HROB

“…While MCM8 has the standard domain structure, MCM9 contains an unusual C-terminal extension downstream of the AAA+ ATPase site 21 . In humans, defects associated with MCM8-9 were linked to primary ovarian failure and hence infertility 22 , 23 , and defects or overexpression of MCM8-9 may promote cancer 24 – 27 . Most reports to date suggest that MCM8-9 functions in meiosis and in DNA repair, particularly in homologous recombination (HR) in response to DNA interstrand crosslinks (ICLs), as well as to maintain replication fork stability 15 – 17 , 21 , 28 – 30 .…”