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.

Background and Objectives. The prognostic role of adjacent nontumor tissue in patients with breast cancer (BC) is still unclear. The activity changes in immunologic and hallmark gene sets in normal tissues adjacent to BC may play a crucial role in predicting the prognosis of BC patients. The aim of this study was to identify BC subtypes and ribosome-associated prognostic genes based on activity changes of immunologic and hallmark gene sets in tumor and adjacent nontumor tissues to improve patient prognosis. Materials and Methods. Gene set variation analysis (GSVA) was applied to assess immunoreactivity changes in the overall sample and three immune-related BC subtypes were identified by non-negative matrix factorization (NMF). KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) analyses were after determining the prognostic gene set using the least absolute shrinkage and selection operator (LASSO) method. Ribosome-related genes were identified by PPI (protein-protein interaction) analysis, and finally a prognostic risk model was constructed based on the expression of five ribosomal genes (RPS18, RPL11, PRLP1, RPL27A, and RPL38). Results. A comprehensive analysis of immune and marker genomic activity changes in normal breast tissue and BC tissue identified three immune-related BC subtypes. BC subtype 1 has the best prognosis, and subtype 3 has the worst overall survival rate. We identified a prognostic gene set in nontumor tissue by the least absolute shrinkage and selection operator (LASSO) method. We found that the results of both KEGG and GO analyses were indistinguishable from those of ribosome-associated genes. Finally, we determined that genes associated with ribosomes exhibit potential as a reliable predictor of overall survival in breast cancer patients. Conclusions. Our research provides an important guidance for the treatment of BC. After a mastectomy, the changes in gene set activity of both BC tissues and the nontumor tissues adjacent to it should be thoroughly evaluated, with special attention to changes in ribosome-related genes in the nontumor tissues.

Low-grade gliomas (LGG) are a group of heterogeneous brain tumors that originate from glial cells, and lack effective biomarkers for diagnosis and predicting prognosis. In this study, we found that both transcriptional and protein levels of TBC1 domain family member 1 (TBC1D1) are significantly increased in tumors, and indicated poor prognosis of LGG patients. In addition, the nomogram constructed based on TBC1D1 showed that TBC1D1 exerted satisfactory performance in predicting the survival probability of LGG patients. Notably, high TBC1D1 expression in M2-like pro-tumor macrophages is closely correlated with the immunosuppressive microenvironment of the glioma. Collectively, these findings support that high TBC1D1 expression indicate immunosuppressive microenvironment and predicted poor prognosis in LGG patients.

Osteoarthritis (OA) is a common disease characterized by cartilage degradation. Growing evidence showed that glucose metabolism impacts joint homeostasis and an imbalance between glycolysis and oxidative phosphorylation (OXPHOS) may exacerbate OA progression, however, a definitive link is yet to be established. Here, we report that pyruvate metabolism and oxidative phosphorylation pathway is enriched in OA cartilage through gene set enrichment analysis (GSEA) and expression of Pyruvate Dehydrogenase Kinase 1 (PDK1), an enzyme that can phosphorylate Pyruvate Dehydrogenase (PDH), and inhibit pyruvate fluxes into the tricarboxylic acid (TCA) cycle and to OXPHOS, in articular cartilage is notably reduced through destabilization of medial meniscus (DMM). Moreover, by inhibiting PDK1, cartilage loss is markedly accelerated in DMM-induced OA through extracellular matrix (ECM) degradation and apoptosis of chondrocytes. These results indicate that PDK1 is involved in the progression of OA through accelerating cartilage matrix degradation and synovium inflammation to ameliorate cartilage degeneration.