Background and Objective: Endometrial cancer (EC) is a common gynecological malignancy worldwide. Despite advances in the development of strategies for treating EC, prognosis of the disease remains unsatisfactory, especially for advanced EC. The aim of this study was to identify novel genes that can be used as potential biomarkers for identifying the prognosis of EC and to construct a novel risk stratification using these genes. Methods and Results: An mRNA sequencing dataset, corresponding survival data and expression profiling of an array of EC patients were obtained from The Cancer Genome Atlas and Gene Expression Omnibus, respectively. Common differentially expressed genes (DEGs) were identified based on sequencing and expression as given in the profiling dataset. Pathway enrichment analysis of the DEGs was performed using the Database for Annotation, Visualization, and Integrated Discovery. The protein-protein interaction network was established using the string online database in order to identify hub genes. Univariate and multivariable Cox regression analyses were used to screen prognostic DEGs and to construct a prognostic signature. Survival analysis based on the prognostic signature was performed on TCGA EC dataset. A total of 255 common DEGs were found and 11 hub genes (TOP2A, CDK1, CCNB1, CCNB2, AURKA, PCNA, CCNA2, BIRC5, NDC80, CDC20 and BUB1BA) that may be closely related to the pathogenesis of EC were identified. A panel of 7 DEG signatures consisting of PHLDA2, GGH, ESPL1, FAM184A, KIAA1644, ESPL1 and TRPM4 were constructed. The signature performed well for prognosis prediction (p<0.001) and time-dependent receiver–operating characteristic (ROC) analysis displayed an area under the curve (AUC) of 0.797, 0.734, 0.729 and 0.647 for 1, 3, 5 and 10-year overall survival (OS) prediction, respectively. Conclusion: This study identified potential genes that may be involved in the pathophysiology of EC and constructed a novel gene expression signature for EC risk stratification and prognosis prediction.

/pdf/identification-of-potential-crucial-genes-associated-with-17bacqtbtf.pdf

Identification of Potential Crucial Genes Associated With the Pathogenesis and Prognosis of Endometrial Cancer.

Background: Hepatocellular carcinoma (HCC) is a malignant tumor with high mortality, and its molecular mechanism remains incompletely understood. This study aimed to identify significant differentially expressed genes (DEGs) in HCC pathogenesis and to provide a bioinformatics basis for the occurrence, prevention, and treatment of HCC. Methods: The Gene Expression Omnibus (GEO) dataset GSE121248 and The Cancer Genome Atlas (TCGA) dataset were used for bioinformatics analysis. We screened DEGs between tumor and normal tissues using the limma package and edgeR package of R. GO (Gene Ontology) functional analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis of the DEGs were conducted using the DAVID database. Next, the protein-protein interaction (PPI) network of the DEGs was constructed using the STRING database, visualized by Cytoscape. Hub genes were screened by applying the cytoHubba plug-in, followed by verification using the GEPIA and Oncomine databases. We demonstrated differences in the protein levels of hub genes using the HPA database. The GEPIA database was employed to analyze the prognostic values of hub genes. Additionally, the drug-gene interaction network was constructed using the Comparative Toxicogenomics Database (CTD). Results: A total of 763 DEGs (247 upregulated and 516 downregulated DEGs) were screened out that were mainly enriched in the oxidation-reduction process, epoxygenase P450 pathway, and metabolism-related pathways. A PPI network was constructed, and the most significantly enriched pathways were the cell cycle and P53 signaling pathway in module 1. We filtered out eight hub genes in the PPI, and they were significantly upregulated in HCC samples, findings consistent with the expression validation results. Additionally, survival analysis showed that, among these eight genes, except CCNB2, high expression levels of CDC20, CDK1, MAD2L1, BUB1, BUB1B CCNB1, and CCNA2 were associated with the poor overall survival (OS) of HCC patients. CTD analysis showed that only topotecan, oxaliplatin, and azathioprine could reduce the expression levels of all seven hub genes. Conclusion: The present study identified the crucial genes and pathways that may be involved in HCC pathogenesis. These findings provide some directive significance for the future prognosis prediction and molecular targeting therapy of HCC.

/pdf/identification-and-analysis-of-potential-key-genes-i80xt23nu8.pdf

Identification and Analysis of Potential Key Genes Associated With Hepatocellular Carcinoma Based on Integrated Bioinformatics Methods.

Glioblastoma (GBM) is the most common and lethal primary brain tumor and remains incurable. This is in part due to the cellular heterogeneity within these tumors, which includes a subpopulation of treatment-resistant cells called cancer stem-like cells (CSC). We previously identified that the anaphase-promoting complex/cylosome (APC/C), a key cell-cycle regulator and tumor suppressor, had attenuated ligase activity in CSCs. Here, we assessed the mechanism of reduced activity, as well as the efficacy of pharmacologically targeting the APC/C in CSCs. We identified hyperphosphorylation of CDH1, but not pseudosubstrate inhibition by early mitotic inhibitor 1 (EMI1), as a major mechanism driving attenuated APC/CCDH1 activity in the G1-phase of the cell cycle in CSCs. Small-molecule inhibition of the APC/C reduced viability of both CSCs and nonstem tumor cells (NSTCs), with the combination of proTAME and apcin having the biggest impact. Combinatorial drug treatment also led to the greatest mitotic arrest and chromosomal abnormalities. IMPLICATIONS: Our findings demonstrate how the activity of the APC/CCDH1 tumor suppressor is reduced in CSCs and also validates small-molecule inhibition of the APC/C as a promising therapeutic target for the treatment of GBM.

/pdf/hyperphosphorylation-of-cdh1-in-glioblastoma-cancer-stem-z7muue18qu.pdf

Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability.

Apcin is one of the few compounds that have been previously reported as a Cdc20 specific inhibitor, although Cdc20 is a very promising drug target. We reported here the design, synthesis, and biological evaluations of 2,2,2-trichloro-1-aryl carbamate derivatives as Cdc20 inhibitors. Among these derivatives, compound 9f was much more efficient than the positive compound apcin in inhibiting cancer cell growth, but it had approximately the same binding affinity with apcin in SPR assays. It is possible that another mechanism of action might exist. Further evidence demonstrated that compound 9f also inhibited tubulin polymerization, disorganized the microtubule network, and blocked the cell cycle at the M phase with changes in the expression of cyclins. Thus, it induced apoptosis through the activation of caspase-3 and PARP. In addition, compound 9f inhibited cell migration and invasion in a concentration-dependent manner. These results provide guidance for developing the current series as potential new anticancer therapeutics.

Discovery of a Dual Tubulin Polymerization and Cell Division Cycle 20 Homologue Inhibitor via Structural Modification on Apcin.

Glabridin is a prenylated isoflavan from the roots of Glycyrrhiza glabra Linne and has posed great impact on the areas of drug development and medicine, due to various biological properties such as anti-inflammation, anti-oxidation, anti-tumor, anti-microorganism, bone protection, cardiovascular protection, neuroprotection, hepatoprotection, anti-obesity, and anti-diabetes. Many signaling pathways, including NF-κB, MAPK, Wnt/β-catenin, ERα/SRC-1, PI3K/AKT, and AMPK, have been implicated in the regulatory activities of glabridin. Interestingly, glabridin has been considered as an inhibitor of tyrosinase, P-glycoprotein (P-gp), and CYP2E1 and an activator of peroxisome proliferator-activated receptor γ (PPARγ), although their molecular regulating mechanisms still need further investigation. However, poor water solubility and low bioavailability have greatly limited the clinical applications of glabridin. Hopefully, several effective strategies, such as nanoemulsions, microneedles, and smartPearls formulation, have been developed for improvement. 

/pdf/review-on-the-diverse-biological-effects-of-glabridin-182eefvz.pdf

Review on the Diverse Biological Effects of Glabridin

Licorice: Resources, applications in ancient and modern times.

The most prevalent malignant central nervous system (CNS) cancer is glioblastoma multiforme (GBM). PLKs (polo-like kinases) are a kind of serine-threonine kinase that modulate DNA replication, mitosis, and stress responses. PLKs in GBM need to be better studied and examined in terms of their expression, function, along with prognostic significance. Using an existing publicly available data set, we evaluated the expression level and prognostic relevance of PLKs in GBM patients at the molecular level. The biological processes along with cascades of the screened gene were predicted using the functional enrichment of Gene Set Enrichment Analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathways. The data illustrated that PLK1/3/4 contents were greater in GBM tissues than in non-tumorous tissues, but PLK2/5 expression levels were lower. PLK2 expression was also linked to patient outcome in GBM. Our findings imply that PLKs might be useful molecular indicators as well as prospective treatment targets for GBM. A PLK2 inhibitor has been studied for the first time in a glioma cell in this work. In glioma cells, ON1231320 has anticancer effects. Finally, a summary of PLK inhibitors is presented, along with projections for future progress.

/pdf/polo-like-kinases-as-potential-targets-and-plk2-as-a-novel-11c1er16.pdf

Polo-like kinases as potential targets and PLK2 as a novel biomarker for the prognosis of human glioblastoma

Comprehensive analysis of the LncRNAs, MiRNAs, and MRNAs acting within the competing endogenous RNA network of LGG

The malignant transformation of astrocytoma may result from the accumulation of multiple genetic alterations. Current research shows that diffuse astrocytoma (AIIs, WHO grade II) is inherently predisposed to recur locally, and to spontaneously progress to anaplastic astrocytoma (AAIIIs, WHO grade III) and eventually secondary glioblastoma (sGBMIVs, WHO grade IV). The aim of the study was to identify and validate the important gene(s) associated with malignant progression and poor prognosis of astrocytoma. Average expression levels of 82 samples (35 AIIs, 13 AAIIIs and 34 sGBMIVs) were compared to each other through no-paired student test. Candidate genes were screened by DAVID and Kaplan–Meier survival analysis. Further, the significant candidate genes were validated through real-time PCR(qPCR), western blot and immunohistochemistry (IHC) in different grades of glioma. Finally, the association of target gene and clinical molecular characterization was analyzed by Chi-squared analysis. The cell-division cycle protein 20(CDC20, p = 0.0129) and the polo-like kinase 1(PLK1, p = 0.0046) were screened by statistical and Kaplan–Meier survival analysis. The expression levels of CDC20 and PLK1 rose significantly through real-time PCR(qPCR), western blot and IHC. A chi-squared analysis showed that patients with CDC20 high-expression differ from patients with CDC20 low-expression in terms of WHO classification (p < 0.0001), karnofsky performance score (KPS, p < 0.0001), isocitrate dehydrogenase mutation (IDH1, p < 0.0001), phosphatase and tensin homolog mutation (PTEN, p = 0.027) and epidermal growth factor receptor protein amplification (EGFR, p = 0.048). Moreover, the biological processes analyses indicate CDC20 might have an essential role in astrocyte cell proliferation. We demonstrated that the expression level of CDC20 increases significantly along with malignant progression and poor prognosis of astrocytoma.

CDC20 with malignant progression and poor prognosis of astrocytoma revealed by analysis on gene expression

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Licorice: Resources, applications in ancient and modern times.

Polo-like kinases as potential targets and PLK2 as a novel biomarker for the prognosis of human glioblastoma

Comprehensive analysis of the LncRNAs, MiRNAs, and MRNAs acting within the competing endogenous RNA network of LGG

CDC20 with malignant progression and poor prognosis of astrocytoma revealed by analysis on gene expression