Systemic Analysis of the DNA Replication Regulator MCM Complex in Ovarian Cancer and Its Prognostic Value

Abstract

Microliposome maintenance (MCM) 2, MCM3, MCM4, MCM5, MCM6, and MCM7 are DNA replication regulators and are involved in the progression of multiple cancer types, but their role in ovarian cancer is still unclear. The purpose of this study is to clarify the biological function and prognostic value of the MCM complex in ovarian cancer (OS) progression. We analyzed DNA alterations, mRNA and protein levels, protein structure, PPI network, functional enrichment, and prognostic value in OC based on the Oncomine, cBioPortal, TCGA, CPTAC, PDB, GeneMANIA, DAVID, KEGG, and GSCALite databases. The results indicated that the protein levels of these DNA replication regulators were increased significantly. Moreover, survival analysis showed a prognostic signature based on the MCM complex, which performed moderately well in terms of OS prognostic prediction. Additionally, protein structure, functional enrichment, and PPI network analyses indicated that the MCM complex synergistically promoted OC progression by accelerating DNA replication and the cell cycle. In conclusion, our study suggested that the MCM complex might be a potential target and prognostic marker for OC patients.

Keywords: The minichromosome maintenance (MCM) complex; comprehensive bioinformatics; ovarian cancer; prognostic value; public databases.

Figure 1

Work flow of the study. First, the transcriptional and post-transcriptional levels of the members of the MCM complex were confirmed by the Oncomine, GEPIA, UALCAN, CPTAC, and cBioPortal databases (p < 0.05 and |FDR| ≥2). There were differences at the transcriptional and post-transcriptional levels among the MCMs. Therefore, the post-transcriptional regulation (miRNA network and protein modification) among the MCM proteins was confirmed by the GSCALite and PDB databases. Then, we constructed the MCM complex network using the GeneMANIA database, which was used to predict GO functions and KEGG pathways. Immune infiltration and drug sensitivity analyses of the MCM complex were performed using the TIMER and GSCALite databases. Finally, we confirmed the effect of the MCM complex on survival based on the GEPIA database.

Figure 2

Transcriptional level of MCM complex members in 20 cancer types. The levels of the MCMs in different cancer types. The threshold (P value ≤ 0.05; ∣FDR ∣ ≥2; gene rank ≤ 10%; data type: mRNA) is expressed in colored cells. Red indicates that the gene is increased in cancer tissues compared to that in normal tissues, whereas blue indicates that the gene is downregulated in cancer tissues compared to that in normal tissues. The FDR is presented by color depth.

Figure 3

mRNA level of the MCMs in OC. The mRNA level of the MCM complex in OC compared to that in normal ovary tissues based on the GEPIA database. *p < 0.05.

Figure 4

MCM protein expression in OC. The protein expression of the MCM complex in OC based on the CPTAC database (A) and HPA database (B) ***p < 0.001.

Figure 5

Regulation of the MCMs (A) Frequency of the MCM complex based on the cBioProtal database. (B) MCM gene alterations in serous ovarian cancer. (C) Kaplan–Meier plots of the OS of OC patients with or without MCM alterations. (D) The network among MCMs and miRNAs.

Figure 6

Protein secondary structures of MCM2–7.

Figure 7

Coexpression and interactions with MCM complex. (A) The tertiary structure of MCMs based on the PDB database. (B) Spearman’s correlation analysis of the MCMs. (C) The protein–protein interaction network among the MCM members based on the GeneMANIA dataset.

Figure 8

Functional enrichment of the MCM complex and neighbouring interaction genes in OC patients. (A) Biological progression terms. (B) Cellular component terms. (C) Molecular function terms. (D) KEGG terms. (E) KEGG annotation.

Figure 9

KEGG pathway enrichment analysis (A) DNA replication terms based on the MCM complex and neighboring interaction genes. (B) Cell cycle terms based on the MCM complex and neighboring interaction genes.

Figure 10

Immune infiltration of the MCMs (Log Ratio > 10). (A) Cancer purity and immune infiltration. (B) CNV affecting the distribution based on the TIMER database. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 11

Prognostic value of the MCM complex members in OC. Survival analysis of the MCM2, MCM3, MCM4, MCM5, MCM6, and MCM7 signatures and the six-gene MCM signature in OC patients based on the GEPIA database.