Di-Long Chen

Ganoderma lucidum polysaccharide (GLPS) can inhibit hepatocellular carcinoma (HCC). But the mechanism of GLPS's effect is little known. This data showed that GLPS can regulate MAPK/NF-κB signaling responsible for M1 polarization in anti-HCC.

Purpose: Due to poor prognosis and immunotherapy failure of skin cutaneous melanoma (SKCM), this study sought to find necroptosis-related biomarkers to predict prognosis and improve the situation with predicted immunotherapy drugs. Experimental Design: The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression Program (GTEx) database were utilized to recognize the differential necroptosis-related genes (NRGs). Univariate Cox (uni-Cox) and least absolute shrinkage and selection operator (LASSO) Cox analysis were utilized for prognostic signature establishment. The signature was verified in the internal cohort. To assess the signature’s prediction performance, the area under the curve (AUC) of receiver operating characteristic (ROC) curves, Kaplan-Meier (K-M) analyses, multivariate Cox (multi-Cox) regression, nomogram, and calibration curves were performed. The molecular and immunological aspects were also reviewed using single-sample gene set enrichment analysis (ssGSEA). Cluster analysis was performed to identify the different types of SKCM. Finally, the expression of the signature gene was verified by immunohistochemical staining. Results: On basis of the 67 NRGs, 4 necroptosis-related genes (FASLG, PLK1, EGFR, and TNFRSF21) were constructed to predict SKCM prognosis. The area’s 1-, 3-, and 5-year OS under the AUC curve was 0.673, 0.649, and 0.677, respectively. High-risk individuals had significantly lower overall survival (OS) compared to low-risk patients. Immunological status and tumor cell infiltration in high-risk groups were significantly lower, indicating an immune system that was suppressed. In addition, hot and cold tumors could be obtained by cluster analysis, which is helpful for accurate treatment. Cluster 1 was considered a hot tumor and more susceptible to immunotherapy. Immunohistochemical results were consistent with positive and negative regulation of coefficients in signature. Conclusion: The results of this finding supported that NRGs could predict prognosis and help make a distinction between the cold and hot tumors for improving personalized therapy for SKCM.

Berberine hydrochloride (BBR) could inhibit the proliferation, migration, and invasion of various cancer cells. As the only enzyme for the de novo synthesis of ribonucleotides, RRM2 is closely related to the development of tumorigenesis. However, not much is currently known about the functional roles of RRM2 in breast cancer (BRCA), and whether BBR regulates the migration and invasion of BRCA cells by regulating the expression of RRM2 remains to be determined. We study the effects of BBR on BRCA cell proliferation in vitro and tumorigenesis in vivo by using colony formation assays, EdU assays, and xenograft models. Transcriptome sequencing, the random forest algorithm, and KEGG analysis were utilized to explore the therapeutic target genes and relative pathways. The expression of RRM2 in BRCA patients was analyzed with The Cancer Genome Atlas (TCGA) dataset, the GEPIA website tool, the Gene Expression Omnibus (GEO) database, and the UALCAN database. The survival probability of BRCA patients could be predicted by survival curve and nomogram analysis. Molecular docking was used to explore the affinity between BBR and potential targets. Gain- and loss-of-function methods were employed to explore the biological process in RRM2 participants. We comprehensively investigated the pharmacological characteristics of BBR on BRCA cell lines and discovered that BBR could inhibit the proliferation of BRCA cells in vitro and in vivo. Combining transcriptome sequencing and KEGG analysis, we found that BBR mainly affected the biological behavior of BRCA cells via HIF-1α and AMPK signal pathways. Additionally, by using bioinformatics and molecular docking, we demonstrated that RRM2 plays an oncogenic role in BRCA samples and that it acts as the hub gene of BBR on BRCA cells. Knockdown and overexpression studies indicated that RRM2 promoted BRCA cell migration as well as invasion in vitro by affecting the epithelial-to-mesenchymal transition (EMT). Our study demonstrated the significance of BBR regulating HIF-1α and AMPK signaling pathways in BRCA cells. Moreover, we revealed the carcinogenic role and potential mechanism of RRM2 as a core regulatory factor of BBR in BRCA in controlling BRCA invasion, migration, and EMT, suggesting that RRM2 may be a therapeutic target and prognostic biomarker for BRCA therapy.

Original Article Construction and validation of a pyroptosis-related gene signature in hepatocellular carcinoma based on RNA sequencing Jiaming He, Jianhua Ran, Jing Li, Dilong Chen

The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes are not only related to tumorigenesis and tumor development but also associated with poor survival in hepatocellular, breast, and colorectal cancers (CRC), etc. Cytoplasmic ornithine, the intermediate product of the urea cycle, is a specific substrate for ornithine decarboxylase (ODC, also known as ODC1) for the production of putrescine and is required for tumor growth. Polyamines (spermidine, spermine, and their precursor putrescine) play central roles in more than half of the steps of colorectal tumorigenesis. Given the close connection between polyamines and cancer, the regulation of polyamine metabolic pathways has attracted attention regarding the mechanisms of action of chemical drugs used to prevent CRC, as the drug most widely used for treating type 2 diabetes (T2D), metformin (Met) exhibits antitumor activity against a variety of cancer cells, with a vaguely defined mechanism. In addition, the influence of metformin on the UC and putrescine generation in colorectal cancer has remained unclear. In our study, we investigated the effect of metformin on the UC and putrescine generation of CRC in vivo and in vitro and elucidated the underlying mechanisms. In nude mice bearing HCT116 tumor xenografts, the administration of metformin inhibited tumor growth without affecting body weight. In addition, metformin treatment increased the expression of monophosphate (AMP)-activated protein kinase (AMPK) and p53 in both HCT116 xenografts and colorectal cancer cell lines and decreased the expression of the urea cycle enzymes, including carbamoyl phosphate synthase 1 (CPS1), arginase 1 (ARG1), ornithine trans-carbamylase (OTC), and ODC. The putrescine levels in both HCT116 xenografts and HCT116 cells decreased after metformin treatment. These results demonstrate that metformin inhibited CRC cell proliferation via activating AMPK/p53 and that there was an association between metformin, urea cycle inhibition and a reduction in putrescine generation.

Ginseng polysaccharide (GPS), a polymer of glucose and the primary constituent extracted from panax ginseng, has been documented to exert various pharmacological properties, including anti‑tumor properties. To provide further insights into the anti‑tumor functions of GPS, the present study was designed to investigate the effect of GPS on apoptosis and the cell cycle of human leukemia cell line K562 cells, and its underlying mechanisms. The results demonstrated that GPS could inhibit K562 cell proliferation and induce apoptosis in vitro in a concentration‑ and time‑dependent manner. The transcription of P38 and c‑Jun NH2‑terminal kinase (JNK) mRNA were significantly augmented, while the transcription of extracellular signal‑regulated kinase (ERK) mRNA were significantly reduced following treatment with GPS compared with the control group (all P<0.05). In addition, GPS treatment markedly suppressed the expression of phosphorylated (p)‑ERK, nuclear factor (NF)‑κB p65 and cyclin D1, and increased the synthesis of p‑P38 and p‑JNK protein expression, as evidenced by immunofluorescence and western blotting analyses. In conclusion, the results indicate that the GPS‑mediated MAPK/NF‑κB/cyclin D1 signaling pathway serves a crucial role in cell cycle arrest and apoptosis of K562 cells.

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Previous research has shown that total saponins of Panax ginseng (TSPG) and other ginsenoside monomers inhibit the proliferation of leukemia cells. However, the effect has not been compared among them. Cell viability was determined by Cell Counting Kit-8 assay, and ultra-structural characteristics were observed under transmission electron microscopy. Cell cycle distribution and apoptosis were determined by flow cytometry (FCM). Real-time fluorescence quantitative‑PCR, western blotting and immunofluorescence were used to measure the expression of β-catenin, TCF4, cyclin D1 and NF-κBp65. β-catenin/TCF4 target gene transcription were observed by ChIP-PCR assay. We found that 20(S)-ginsenoside Rh2 [(S)Rh2] inhibited the proliferation of KG-1a cells more efficiently than the other monomers. Moreover, (S)Rh2 arrested KG-1a cells in the G0/G1 phase and induced apoptosis. In addition, the levels of β-catenin, TCF4, cyclin D1 mRNA and protein were decreased. The ChIP-PCR showed that (S)Rh2 downregulated the transcription of β-catenin/TCF4 target genes, such as cyclin D1 and c-myc. These results indicated that (S)Rh2 induced cell cycle arrest and apoptosis through the Wnt/β-catenin signaling pathway, demonstrating its potential as a chemotherapeutic agent for leukemia therapy.