eIF3a sustains non-small cell lung cancer stem cell-like properties by promoting YY1-mediated transcriptional activation of ß-catenin.

Cancer stem cells (CSCs) are the leading cause of recurrence and poor prognosis in non-small cell lung cancer (NSCLC). Eukaryotic translation initiation factor 3a (eIF3a) participates in many tumor development processes, such as metastasis, therapy resistance, and glycolysis, all of which are closely associated with the presence of CSCs. However, whether eIF3a maintains NSCLC-CSC-like properties remains to be elucidated. In this study, eIF3a was highly expressed in lung cancer tissues and was linked to poor prognosis. eIF3a was also highly expressed in CSC-enriched spheres compared with adherent monolayer cells. Moreover, eIF3a is required for NSCLC stem cell-like traits maintenance in vitro and in vivo. Mechanistically, eIF3a activates the Wnt/ß-catenin signaling pathway, promoting the transcription of cancer stem cell markers. Specifically, eIF3a promotes the transcriptional activation of ß-catenin and mediates its nuclear accumulation to form a complex with T cell factor 4 (TCF4). However, eIF3a has no significant effect on protein stability and translation. Proteomics analysis revealed that the candidate transcription factor, Yin Yang 1 (YY1), mediates the activated effect of eIF3a on ß-catenin. Overall, the findings of this study implied that eIF3a contributes to the maintenance of NSCLC stem cell-like characteristics through the Wnt/ß-catenin pathway. eIF3a is a potential target for the treatment and prognosis of NSCLC.

Human PARP1 substrates and regulators of its catalytic activity: An updated overview.

Poly (ADP-ribose) polymerase 1 (PARP1) is a key DNA damage sensor that is recruited to damaged sites after DNA strand breaks to initiate DNA repair. This is achieved by catalyzing attachment of ADP-ribose moieties, which are donated from NAD+, on the amino acid residues of itself or other acceptor proteins. PARP inhibitors (PARPi) that inhibit PARP catalytic activity and induce PARP trapping are commonly used for treating BRCA1/2-deficient breast and ovarian cancers through synergistic lethality. Unfortunately, resistance to PARPi frequently occurs. In this review, we present the novel substrates and regulators of the PARP1-catalyzed poly (ADP-ribosyl)ation (PARylatison) that have been identified in the last 3 years. The overall aim is the presentation of protein interactions of potential therapeutic intervention for overcoming the resistance to PARPi.

Effects of Glycolysis-Related Genes on Prognosis and the Tumor Microenvironment of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a common and deadly malignancy worldwide. Current treatment methods for hepatocellular carcinoma have many disadvantages; thus, it is urgent to improve the efficacy of these therapies. Glycolysis is critical in the occurrence and development of tumors. However, survival and prognosis biomarkers related to glycolysis in HCC patients remain to be fully identified. Methods: Glycolysis-related genes (GRGs) were downloaded from "The Molecular Signatures Database" (MSigDB), and the mRNA expression profiles and clinical information of HCC patients were obtained from TCGA. Consensus clustering was performed to classify the HCC patients into two subgroups. We used the least absolute shrinkage and selection operator (LASSO) regression analysis to construct the risk signature model. Kaplan-Meier (K-M) survival analysis was performed to evaluate the prognostic significance of the risk model, and the receiver operating characteristic (ROC) curve analysis was used to evaluate the prediction accuracy. The independent prediction ability of the risk model was validated by univariate and multivariate Cox regression analyses. The differences of immune infiltrates and relevant oncogenic signaling between different risk groups were compared. Finally, biological experiments were performed to explore the functions of screened genes. Results: HCC patients were classified into two subgroups, according to the expression of prognostic-related GRGs. Almost all GRGs categorized in cluster 2 showed upregulated expressions, whereas GRGs in cluster 1 conferred survival advantages. GSEA identified a positive correlation between cluster 2 and the glycolysis process. Ten genes were selected for risk signature construction. Patients were assigned to high-risk and low-risk groups based on the median risk score, and K-M survival analysis indicated that the high-risk group had a shorter survival time. Additionally, the risk gene signature can partially affect immune infiltrates within the HCC microenvironment, and many oncogenic pathways were enriched in the high-risk group, including glycolysis, hypoxia, and DNA repair. Finally, in vitro knockdown of ME1 suppressed proliferation, migration, and invasion of hepatocellular carcinoma cells. Conclusion: In our study, we successfully constructed and verified a novel glycolysis-related risk signature for HCC prognosis prediction, which is meaningful for classifying HCC patients and offers potential targets for the treatment of hepatocellular carcinoma.

Two new steroidal glycosides with unique structural feature of 14α-hydroxy-5ß-steroids from Reineckia carnea.

Two new steroidal glycosides (1-2) were isolated from the roots of Reineckia carnea, together with three known compounds (3-5). Their structures were determined on the basis of chemical methods and spectral data. Compounds 1-2 were the unique steroidal glycosides possessing structural feature of 14α-hydroxy-5ß-steroids, and compounds 4-5 were isolated from R. carnea for the first time. The isolated compounds (1-5) were tested in vitro for their cytotoxic activities against the A549, HepG 2 and Caski cancer cell lines. Among them, the compounds 2 and 3 showed cytotoxicity against Caski cancer cell line with IC50 values of 34.4 and 3.7µM, respectively.

[Study on Quality Standard for Panax japonicus Rhizome].

OBJECTIVE: To establish a quality standard for Panax japonicus rhizome. METHODS: Ginsenoside Ro and Chikusetsusaponin IVa were used as reference substances in the TLC identification and HPLC method. Additionally, acid insoluble ash and moisture were determined according to the procedures recorded in the Appendix of Chinese Pharmacopeia (2010 edition). RESULTS: The TLC identification with GF, showed a good resolution with clear spots and its optimum developer was the underlayer of chloroform-methanol-formic acid-water = 4.5:1.5: 0.1:0.3. The content of Ginsenoside Ro and Chikusetsusaponin N a were determined by HPLC. The mixture of acetonitrile and water (0.15% phosphate) with gradient elution as the mobile phase was used at a flow rate of 1.0 mL/min, the detection wavelength at 203 nm and the column temperature at 40 °C. The calibration curve was linear in the range of 31.25-2,000 g/mL for Ginsenoside Ro and Chikusetsusaponin IVa (r = 0.9999, respectively). The average recovery was 101.19% and 102.50%, and RSD was 1.59% and 1.80% respectively. The content of Ginsenoside Ro and Chikusetsusaponin IVa was no less than 1.5% respectively. An average content of moisture was 7.36% and acid insoluble ash was 0.84%. CONCLUSION: These methods are producible, sensitive and simple, which can be used to control the quality of Panax japonicus rhizome.