MCM7

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide. Minichromosome maintenance proteins (MCMs), particularly MCM2-7, are upregulated in various cancers, including HCC. The aim of the present study was to investigate the role of MCM2-7 in human liver HCC (LIHC) and the regulation of the protein homeostasis of MCM6 by a specific E3 ligase. Bioinformatics analyses demonstrated that MCM2-7 were highly expressed in LIHC compared with corresponding normal tissues at the mRNA and protein levels, and patients with LIHC and high mRNA expression levels of MCM2, MCM3, MCM6 and MCM7 had poor overall survival rates. Cell Counting Kit-8 and colony formation assays revealed that the knockdown of MCM2, MCM3, MCM6 or MCM7 in Huh7 and Hep3B HCC cells inhibited cell proliferation and colony formation. In addition, pull-down, co-immunoprecipitation and ubiquitination assays demonstrated that RNF125 interacts with MCM6 and mediates its ubiquitination. Furthermore, co-transfection experiments indicated that RNF125 promoted the proliferation of HCC cells mainly through MCM6. In summary, the present study suggests that the RNF125-MCM6 axis plays an important role in the regulation of HCC cell proliferation and is a promising therapeutic target for the treatment of LIHC.

To exploit hepatocellular carcinoma (HCC) diagnostic substances, we identify potential predictive markers based on machine learning and to explore the significance of immune cell infiltration in this pathology.

Three HCC gene expression datasets were used for weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest were applied to identify candidate biomarkers. The diagnostic value of HCC diagnostic gene biomarkers was further assessed by the area under the ROC curve observed in the validation dataset. CIBERSORT was used to analyze 22 immune cell fractions from HCC patients and to analyze their correlation with diagnostic markers. In addition, the prognostic value of the markers and the sensitivity of the drugs were analyzed.

WGCNA and differential expression analysis were used to screen 396 distinct gene signatures in HCC tissues. They were mostly engaged in cytoplasmic fusion and the cell division cycle, according to gene enrichment analyses. Five genes were shown to have a high diagnostic value for use as diagnostic biomarkers for HCC, including EFHD1 (AUC = 0.77), KIF4A (AUC = 0.97), UBE2C (AUC = 0.96), SMYD3 (AUC = 0.91), and MCM7 (AUC = 0.93). T cells, NK cells, macrophages, and dendritic cells were found to be related to diagnostic markers in HCC tissues by immune cell infiltration analysis, indicating that these cells are intimately linked to the onset and spread of HCC. Concurrently, these five genes and their constructed models have considerable prognostic value.

These five genes (EFHD1, KIF4A, UBE2C, SMYD3, and MCM7) may serve as new candidate molecular markers for HCC, providing new insights for future diagnosis, prognosis, and molecular therapy of HCC.

Osteosarcoma is an aggressive bone tumor that primarily affects children and adolescents. This malignancy is highly aggressive, associated with poor clinical outcomes, and primarily metastasizes to the lungs. Due to its rarity and biological heterogeneity, limited studies on its molecular basis exist, hindering the development of effective therapies. The WW domain-containing oxidoreductase (WWOX) is frequently altered in human osteosarcoma. Combined deletion of Wwox and Trp53 using Osterix1-Cre transgenic mice has been shown to accelerate osteosarcoma development. In this study, we generated a traceable osteosarcoma mouse model harboring the deletion of Trp53 alone (single-knockout) or combined deletion of Wwox/Trp53 (double-knockout) and expressing a tdTomato reporter. By tracking Tomato expression at different time points, we detected the early presence of tdTomato-positive cells in the bone marrow mesenchymal stem cells of non-osteosarcoma-bearing mice (young BM). We found that double-knockout young BM cells, but not single-knockout young BM cells, exhibited tumorigenic traits both in vitro and in vivo. Molecular and cellular characterization of these double-knockout young BM cells revealed their resemblance to osteosarcoma tumor cells. Interestingly, one of the observed significant transcriptomic changes in double-knockout young BM cells was the upregulation of Myc and its target genes compared to single-knockout young BM cells. Intriguingly, Myc-chromatin immunoprecipitation sequencing revealed its increased enrichment on Myc targets, which were upregulated in double-knockout young BM cells. Restoration of WWOX in double-knockout young BM cells reduced Myc protein levels. As a prototype target, we demonstrated the upregulation of MCM7, a known Myc target, in double-knockout young BM relative to single-knockout young BM cells. Inhibition of MCM7 expression using simvastatin resulted in reduced proliferation and tumor cell growth of double-knockout young BM cells. Our findings reveal BM mesenchymal stem cells as a platform to study osteosarcoma and Myc and its targets as WWOX effectors and early molecular events during osteosarcomagenesis.