Pancreatic cancer characterized with intense hydraulic tissue in tumor extracellular matrix (ECM) resists most of chemotherapeutic drugs. Increased levels of hyaluronic acid (HA) represent the primary component of the hydraulic tissue, rendering tumors protective from drug targeting. Quercetin (Que), a natural flavonoid, has the ability to inhibit tumor cell growth in a number of cancers; however, its poor water solubility and low bioavailability largely limit its application in cancer therapy. Hence, we developed an efficient drug delivery system by encapsulation of Que. into liposomes and conjugation with hyaluronidase (HAase) at liposome surface, termed as HQL. In the presence of HAase, HQL were predominantly accumulated at tumor with enhanced permeability and retention effect. Treatment of xenografted tumor mice with HQL gave rise to suppressed tumor growth, while no toxic effects were observed in mice. HQL demonstrated the strong ability to inhibit cell proliferation, promote cell apoptosis, and induce arrest at G2/M cell cycle in pancreatic cancer lines, three-dimensional cultured cell spheroids and pancreatic ductal adenocarcinoma (PDAC)-derived organoids. Mechanistically, HQL downregulated expression of cell cycle-associated protein (CCNB1, CDK1 and PLK1) and cell apoptosis-associated factors PI3K/AKT and Bcl-2. In summary, HQL degraded HA in the tumor microenvironment to enhance nano-particle penetration and inhibited tumor cell growth, eliciting efficacy of anti-tumor therapy. Thereof, HQL may provide a novel efficient drug delivery approach for the adjuvant treatment of pancreatic cancer.

Phase separation, a biophysical process that segregates subcellular environments into condensates, has been recognized for its role in transcriptional regulation. However, the extent of its influence on cellular senescence processes remains to be fully elucidated. We established that MRG15 depletion leads to cellular senescence in human mesenchymal stem cells (hMSCs). MRG15 can form phase-separated liquid condensates via its intrinsically disordered region (IDR). IDR deletion and replacement assays revealed that MRG15 condensation is crucial to hMSC senescence. According to the epigenomic and transcriptomic analysis, MRG15 depletion impacts pathways integral to the cell cycle and the senescence process, as evidenced by the diminished binding and the modified expression of key genes, including p53, CDKN1A, LMNB1, CCNB1, NPM1, MYC, and HMGB2. Our findings establish a link between phase separation and senescence regulation and present a promising new therapeutic target for the alleviation of age-related diseases and the potential extension of lifespan.

This study examines the roles of Cyclin B1 (CCNB1), Polo-Like Kinase 1 (PLK1), and Heparanase (HPSE) in breast cancer progression using a multi-omics approach. These genes are known for their involvement in various cancer-related processes, but their precise contributions to breast cancer remain unclear.

We employed an integrative analysis combining transcriptomics, proteomics, DNA methylation profiling, immune infiltration analysis, and single-cell RNA sequencing to investigate the expression patterns, regulatory mechanisms, and functional impacts of CCNB1, PLK1, and HPSE in breast cancer. Functional assays using si-RNA knockdown of CCNB1 and PLK1 were performed to assess their roles in cell proliferation.

CCNB1, PLK1, and HPSE are upregulated in breast tumors at the mRNA and protein levels. CCNB1 and PLK1 promote tumor growth and metastasis, while HPSE is linked to immune pathways. DNA methylation in BRCA correlates with prognosis, with PLK1 alterations protective for recurrence-free survival. High expression of these genes worsens prognosis, with CCNB1 as a risk factor for overall survival. Immune infiltration analysis associates these genes with tumor-infiltrating immune cells, highlighting HPSE's immunotherapeutic potential. Single-cell RNA sequencing confirms CCNB1 and PLK1 drive malignant proliferation and an immunosuppressive environment. Functional assays demonstrated that silencing CCNB1 and PLK1 significantly reduced breast cancer cell proliferation, indicating regulatory interactions among PLK1, CCNB1, and MKI67.

This study provides evidence that CCNB1, PLK1, and HPSE are key players in breast cancer progression and potential biomarkers for prognosis. Furthermore, their roles in immune regulation suggest they could be promising targets for immunotherapy.

Belimumab is a putative disease-modifying agent in systemic lupus erythematosus (SLE), yet the molecular underpinnings of its effects and the ability to predict early clinical response remain unexplored. To address these, we undertook a longitudinal, in-depth blood transcriptome study.

RNA-sequencing was performed in the blood of active SLE patients at baseline and following 6 months of belimumab treatment (n=45 paired samples). Clinical response was determined according to the SLE Responder Index (SRI)-4 and Lupus Low Disease Activity State (LLDAS). Weighted correlation network analysis (WGCNA) was used to uncover gene module trait associations. Reversibility of SLE susceptibility and severity gene signatures was assessed. Machine learning was used to build models predictive of response.

Belimumab induced widespread transcriptome changes with downregulation of pathways related to B cells, type I/II interferon, IL-6/STAT3 and neutrophil activation. These effects were more pronounced among patients with LLDAS+ compared with to SRI-4+/LLDAS- response, with amelioration of the SLE 'susceptibility' signature observed in the former group. Unsupervised analysis unveiled gene modules enriched in neutrophil degranulation, type I interferon signalling and cytokine production to correlate positively with response at 6 months. Using neural networks, a set of 50 genes (including CCL4L2, CARD10, MMP15 and KLRC2) predicted response to belimumab with a cross-validated 84% specificity (test set). Lack of response was linked to perturbations of the cell cycle checkpoints, PI3K/ Akt/mammalian target of rapamycin and TGF-beta signalling pathways.

Belimumab treatment ameliorates multiple innate and adaptive immunity dysregulations of SLE and may reverse the disease signature, consistent with the drug effects on reducing activity and preventing flares. Fingerprints of innate immunity correlate with robust improvement whereas DNA damage response with less responsive disease to BAFF inhibition.

Background: Bladder cancer (BC) is one of the ten most common cancers worldwide, with a high recurrence rate and significant variation in clinical outcomes based on tumor grade and stage. This study aimed to investigate the gene expression profiles at different cancer stages to assess their potential prognostic value. Methods: RNA was extracted from paraffin-embedded BC tissues and the gene expression levels of CDC20 and CCNB1 were analyzed using qRT-PCR. A total of 54 BC patient samples were included in the analysis and categorized into low-grade (LG) (n = 23) and high-grade (HG) (n = 31) tumors, as well as stages pTa, pT1, and pT2. Results: CDC20 gene expression was significantly higher in the HG group (mean fold-change: 16.1) compared to the LG group (mean fold-change: 10.54), indicating a significant association with tumor grade (p = 0.039). However, no significant differences were observed in CDC20 expression across the cancer stages. For CCNB1, while gene expression was significantly elevated in higher-stage tumors (pT2 vs. pTa; p = 0.038), no significant association was found between CCNB1 expression and tumor grade. Survival analysis revealed that increased CCNB1 expression and advanced cancer stage were associated with poorer overall survival, whereas no significant impact of CDC20 expression or tumor grade on survival was observed. Correlation analysis indicated a positive relationship between CDC20 expression and tumor grade (r = 0.284, p = 0.038) and between CCNB1 expression and tumor stage (r = 0.301, p = 0.027). Conclusions: Our findings suggest that CDC20 overexpression is linked to higher tumor grades, while CCNB1 overexpression is associated with more advanced cancer stages in BC. These results underscore the potential utility of CDC20 and CCNB1 as biomarkers for tumor prognosis and as therapeutic targets. Further studies with larger cohorts are needed to validate these findings and better understand the molecular mechanisms driving BC progression.

Early detection of spinal cord injury (SCI) is conducive to improving patient outcomes. In addition, many studies have revealed the role of immune cells in the progression or treatment of SCI. The objective of this study was to identify the early signature genes and clarify how they are related to immune cell infiltration in SCI.

We analysed and identified early signature genes associated with SCI via bioinformatics analysis of the GSE151371 dataset from the GEO database. These genes were subsequently verified in the GSE33886 dataset and qRT-PCR. Finally, the CIBERSORT algorithm was used to examine the immune cell infiltration in SCI and its relationship with signature genes.

Seven SCI-related signature genes, including ARG1, RETN, BPI, GGH, CCNB1, HIST1H2AC, and HIST1H2BJ, were identified, and their expression was verified via an external validation cohort and qRT-PCR. Moreover, the ROC curves revealed the diagnostic value of these genes. In addition, on the basis of immune cell infiltration analysis, plasma cells, M0 macrophages, activated CD4+ memory T cells, γδ T cells, naive CD4+ T cells, and resting CD4+ memory T cells may participate in the progression of SCI.

This study identified seven early signature genes of SCI that may serve as biomarkers for the early diagnosis of SCI and contribute to our understanding of immune changes during the pathology of SCI.

MLL-rearranged (MLLr) leukemia is characterized by a poor prognosis. Depending on the cell of origin, it differs in the aggressiveness and therapy response. For instance, in adults, volasertib blocking Polo-like kinase 1 (PLK-1) exhibited limited success. Otherwise, PLK-1 characterizes an infant MLLr signature, indicating potential sensitivity. By using our CRISPR/Cas9 MLLr model in CD34+ cells from human cord blood (huCB) and bone marrow (huBM) mimicking the infant and adult patient diseases, we were able to shed light on this phenomenon. The PLK-1 mRNA level was significantly increased in our huCB compared to the huBM model, which was underpinned by analyzing infant and adult MLLr leukemia patients. Importantly, the expression levels correlated with a functional response. Volasertib induced a significant dose-dependent decrease in proliferation and cell cycle arrest, most pronounced in the infant model. Mechanistically, upon volasertib treatment, we uncovered negative feedback only in the huBM model by compensatory upregulation of PLK-1 and related genes like AURKA involved in mitosis. Importantly, the poor response could be overcome by a combinatorial strategy with alisertib, an Aurora kinase A inhibitor. Our study emphasizes the importance of considering the cell of origin in therapeutic decision-making and provides the rationale for evaluating volasertib and alisertib in MLLr leukemia.

This study investigated the role and mechanisms of cullin-1 (CUL1) in chronic obstructive pulmonary disease (COPD).

Cigarette smoke extract (CSE)-treated mouse pulmonary microvascular endothelial cells (mPMECs) and cigarette smoke inhalation (CSI)-stimulated mice were used to construct in vitro and in vivo COPD models, respectively. CUL1 expression was assessed using reverse transcriptase-quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry were used to detect cell viability and apoptosis, respectively. We conducted an enzyme-linked immunosorbent assay on mPMECs and bronchoalveolar lavage fluid (BALF) to detect inflammatory factors. Reactive oxygen species, malondialdehyde, and superoxide dismutase were detected using the corresponding kits. The histological characteristics of the lung tissues were determined by hematoxylin and eosin staining.

CUL1 expression was downregulated in COPD. CUL1 overexpression significantly promoted cell viability, reduced cell apoptosis, and inhibited inflammatory responses and oxidative stress in CSE-treated mPMECs. These changes were reversed by the p53 agonist nutlin-3. In addition, CUL1 overexpression significantly relieved COPD in mice, as confirmed by the reduced secretion of inflammatory factors in BALF, inhibited oxidative stress response, and improved lung function.

CUL1 plays a protective role in CSE-treated mPMECs and CSI-stimulated mice by inhibiting the p53 signaling pathway.

Glioblastoma (GBM) is a common primary malignant brain tumor and the prognosis of these patients remains poor. Therefore, further understanding of cell cycle-related molecular mechanisms of GBM and identification of appropriate prognostic markers and therapeutic targets are key research imperatives. Based on RNA-seq expression datasets from The Cancer Genome Atlas database, prognosis-related biological processes in GBM were screened out. Gene Set Variation Analysis (GSVA), LASSO-COX, univariate and multivariate Cox regression analyses, Kaplan-Meier survival analysis, and Pearson correlation analysis were performed for constructing a predictive prognostic model. A total of 58 cell cycle-related genes were identified by GSVA and analysis of differential expression between GBM and control samples. By univariate Cox and LASSO regression analyses, 8 genes were identified as prognostic biomarkers in GBM. A nomogram with superior performance to predict the survival of GBM patients was established regarding risk score, cancer status, recurrence type, and mRNAsi. This study revealed the prognostic value of cell cycle-related genes in GBM. In addition, we constructed a reliable model for predicting the prognosis of GBM patients. Our findings reinforce the relationship between cell cycle and GBM and may help improve the prognostic assessment of patients with GBM. Our predictive prognostic model, based on independent prognostic factors, enables tailored treatment strategies for GBM patients. It is particularly useful for subgroups with uncertain prognosis or treatment challenges.

This study integrates pharmacology databases with bulk RNA-seq and scRNA-seq to reveal the latent anti-PDAC capacities of BBR. Target genes of BBR were sifted through TargetNet, CTD, SwissTargetPrediction, and Binding Database. Based on the GSE183795 dataset, DEG analysis, GSEA, and WGCNA were sequentially run to build a disease network. Through sub-network filtration acquired PDAC-related hub genes. A PPI network was established using the shared genes. Degree algorithm from cytoHubba screened the key cluster in the network. Analysis of differential mRNA expression and ROC curves gauged the diagnostic performance of clustered genes. CYBERSORT uncovered the potential role of the key cluster on PDAC immunomodulation. ScRNA-seq analysis evaluated the distribution and expression profile of the key cluster at the single-cell level, assessing enrichment within annotated cell subpopulations to delineate the target distribution of BBR in PDAC. We identified 425 drug target genes and 771 disease target genes, using 57 intersecting genes to construct the PPI network. CytoHubba anchored the top 10 highest contributing genes to be the key cluster. mRNA expression levels and ROC curves confirmed that these genes showed good robustness for PDAC. CYBERSORT revealed that the key cluster influenced immune pathways predominantly associated with Macrophages M0, CD8 T cells, and naïve B cells. ScRNA-seq analysis clarified that BBR mainly acted on epithelial cells and macrophages in PDAC tissues. BBR potentially targets CDK1, CCNB1, CTNNB1, CDK2, TOP2A, MCM2, RUNX2, MYC, PLK1, and AURKA to exert therapeutic effects on PDAC. The mechanisms of action appear to significantly involve macrophage polarization-related immunological responses.

KRAS gene mutations are common in pancreatic ductal adenocarcinoma (PDAC), but targeting mutant KRAS is still challenging. Here, an endoribonuclease-prepared small interfering RNA (esiRNA) library was used to screen new kinases that play critical roles in PDAC driven by KRAS gene mutations, and serine/threonine kinase 31 (STK31) was identified and characterized as a potential therapeutic target for KRAS-mutant PDAC. Our results showed that STK31 was upregulated in KRAS-mutant PDAC patients with poor survival and highly expressed in PDAC cell lines with KRASG12D mutation. Inhibition of STK31 in KRAS-mutant cell lines significantly reduced PDAC cell growth in vitro and hindered tumor growth in vivo. Gain and loss of function experiments revealed that STK31 is a downstream target of KRAS in PDAC. A pharmacological inhibition assay showed MAPK/ERK signaling involved in STK31 regulation. The further mechanistic study validated that c-Jun, regulated by KRAS/MAPK signaling, directly modulates the transcription level of STK31 by binding to its promoter region. Through RNA sequencing, we found that the cell cycle regulators CCNB1 and CDC25C are downstream targets of STK31. Taken together, our results indicate that STK31, which is the downstream target of the KRAS/MAPK/ERK/c-Jun signaling pathway in KRAS-mutant PDAC, promotes PDAC cell growth by modulating the expression of the cell cycle regulators CCNB1 and CDC25C.

Prostate cancer (PCa) is the most common non-cutaneous malignancy in men globally. Sappan lignum, which exists in the heartwood of Caesalpinia sappan L., has antitumor effects; however, its exact mechanism of action remains unclear. This study elucidated the underlying mechanisms of Sappan lignum in PCa through network pharmacology approaches and molecular docking techniques. Moreover, the therapeutic effects of Sappan lignum on PCa were verified through in vitro experiments.

The constituent ingredients of Sappan lignum were retrieved from the HERB database. Active plant-derived compounds of Sappan lignum were screened based on gastrointestinal absorption and gastric drug properties. Disease targets for PCa were screened using unpaired and paired case datasets from the Gene Expression Omnibus. Intersection targets were used for gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Core targets were identified through topological analysis parameters and their clinical relevance was validated through The Cancer Genome Atlas database. The affinity between the phytochemicals of Sappan lignum and core proteins was verified using the molecular docking technique. Validation experiments confirmed the significant potential of Sappan lignum in treating PCa.

Twenty-one plant-derived compounds of Sappan lignum and 821 differentially expressed genes associated with PCa were collected. Among 32 intersection targets, 8 were screened according to topological parameters. KEGG analysis indicated that the antitumor effects of Sappan lignum on PCa were primarily associated with the p53 pathway. The molecular docking technique demonstrated a strong affinity between 3-deoxysappanchalcone (3-DSC) and core proteins, particularly cyclin B1 (CCNB1). CCNB1 expression correlated with clinicopathological features in patients with PCa. Experimental results revealed that 3-DSC exhibited anti-proliferative, anti-migratory, and pro-apoptotic effects on 22RV1 and DU145 cells while also causing G2/M phase cell cycle arrest, potentially through modulating the p53/p21/CDC2/CCNB1 pathway.

This research highlights the promising therapeutic potential of Sappan lignum in treating PCa, with a particular focus on targeting the p53 pathway.

This study aimed to conclude the effect and mechanism of ZIC2 on immune infiltration in lung adenocarcinoma (LUAD).

Expression of ZIC2 in several kinds of normal tissues of TCGA data was analyzed and its correlation with the baseline characteristic of LUAD patients were analyzed. The immune infiltration analysis of LUAD patients was performed by CIBERSORT algorithm. The correlation analysis between ZIC2 and immune cell composition was performed. Additionally, the potential upstream regulatory mechanisms of ZIC2 were predicted to identify the possible miRNAs and lncRNAs that regulated ZIC2 in LUAD. In vitro and in vivo experiments were also conducted to confirm the potential effect of ZIC2 on cell proliferation and invasion ability of LUAD cells.

ZIC2 expression was decreased in various normal tissues, but increased in multiple tumors, including LUAD, and correlated with the prognosis of LUAD patients. Enrichment by GO and KEGG suggested the possible association of ZIC2 with cell cycle and p53 signal pathway. ZIC2 expression was significantly correlated with T cells CD4 memory resting, Macrophages M1, and plasma cells, indicating that dysregulated ZIC2 expression in LUAD may directly influence immune infiltration. ZIC2 might be regulated by several different lncRNA-mediated ceRNA mechanisms. In vitro experiments validated the promotive effect of ZIC2 on cell viability and invasion ability of LUAD cells. In vivo experiments validated ZIC2 can accelerate tumor growth in nude mouse.

ZIC2 regulated by different lncRNA-mediated ceRNA mechanisms may play a critical regulatory role in LUAD through mediating the composition of immune cells in tumor microenvironment.

Background:Pancreatic cancer is a leading cause of cancer-related mortality worldwide with increasing global incidence. We previously reported the anticancer effect of Rhus coriaria ethanolic extract (RCE) in triple negative breast and colon cancer cells. Herein, we investigated the anticancer effect of RCE on human pancreatic cancer cells. Methods: Cell viability was measured using Cell Titer-Glo and staining of viable and dead cells based on differential permeability to two DNA binding dyes. Cell cycle distribution and annexin V staining was carried out in Muse cell analyzer. Protein level was determined by Western blot. Tumor growth was assessed by in ovo chick embryo chorioallantoic membrane assay. Results: We found that RCE significantly inhibited the viability and colony growth of pancreatic cancer cells (Panc-1, Mia-PaCa-2, S2-013, AsPC-1). The antiproliferative effects of RCE in pancreatic cancer cells (Panc-1 and Mia-PaCa-2) were mediated through induction of G1 cell cycle arrest, Beclin-1-independent autophagy, and apoptosis. RCE activated both the extrinsic and intrinsic pathways of apoptosis and regulated the Bax/Bcl-2 apoptotic switch. Mechanistically, we found that RCE inhibited the AKT/mTOR pathway, downstream of which, inactivation of the cell cycle regulator p70S6K and downregulation of the antiapoptotic protein survivin was observed. Additionally, we found that RCE-induced autophagy preceded apoptosis. Further, we confirmed the anticancer effect of RCE in a chick embryo xenograft model and found that RCE inhibited the growth of pancreatic cancer xenografts without affecting embryo survival. Conclusion: Collectively, our findings demonstrate that Rhus coriaria exerts potent anti-pancreatic cancer activity though cell cycle impairment, autophagy, and apoptosis, and is hence a promising source of anticancer phytochemicals.

T cell development is fundamental to immune system establishment, yet how this development changes with age remains poorly understood. Here, we construct a transcriptional and epigenetic atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene regulatory programs and their link to age-related differences in phenotype and function. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern effector response and cell cycle regulation. Moreover, we reveal that neonates possess more accessible chromatin during early thymocyte development, likely establishing poised gene expression programs that manifest later in thymocyte development. Finally, we leverage this atlas, employing a CRISPR-based perturbation approach coupled with single-cell RNA sequencing as a readout to uncover a conserved transcriptional regulator, Zbtb20, that contributes to age-dependent differences in T cell development. Altogether, our study defines transcriptional and epigenetic programs that regulate age-specific differences in T cell development.

The association between memory CD4+ T cells and cancer prognosis is increasingly recognized, but their impact on lung adenocarcinoma (LUAD) prognosis remains unclear. In this study, using the cell-type identification by estimating relative subsets of RNA transcripts algorithm, we analyzed immune cell composition and patient survival in LUAD. Weighted gene coexpression network analysis helped identify memory CD4+ T cell-associated gene modules. Combined with module genes, a five-gene LUAD prognostic risk model (HOXB7, MELTF, ABCC2, GNPNAT1, and LDHA) was constructed by regression analysis. The model was validated using the GSE31210 data set. The validation results demonstrated excellent predictive performance of the risk scoring model. Correlation analysis was conducted between the clinical information and risk scores of LUAD samples, revealing that LUAD patients with disease progression exhibited higher risk scores. Furthermore, univariate and multivariate regression analyses demonstrated the model independent prognostic capability. The constructed nomogram results demonstrated that the predictive performance of the nomogram was superior to the prognostic model and outperformed individual clinical factors. Immune landscape assessment was performed to compare different risk score groups. The results revealed a better prognosis in the low-risk group with higher immune infiltration. The low-risk group also showed potential benefits from immunotherapy. Our study proposes a memory CD4+ T cell-associated gene risk model as a reliable prognostic biomarker for personalized treatment in LUAD patients.

Peptidyl arginine deiminases (PADIs) catalyze protein citrullination, a post-translational conversion of arginine to citrulline. The most widely expressed member of this family, PADI2, regulates cellular processes that impact several diseases. We hypothesized that we could gain new insights into PADI2 function through a systematic evolutionary and structural analysis. Here, we identify 20 positively selected PADI2 residues, 16 of which are structurally exposed and maintain PADI2 interactions with cognate proteins. Many of these selected residues reside in non-catalytic regions of PADI2. We validate the importance of a prominent loop in the middle domain that encompasses PADI2 L162, a residue under positive selection. This site is essential for interaction with the transcription elongation factor (P-TEFb) and mediates the active transcription of the oncogenes c-MYC, and CCNB1, as well as impacting cellular proliferation. These insights could be key to understanding and addressing the role of the PADI2 c-MYC axis in cancer progression.

Changes during the production cycle of dairy cattle can leave these animals susceptible to oxidative stress and reduced antioxidant health. In particular, the periparturient period, when dairy cows must rapidly adapt to the sudden metabolic demands of lactation, is a period when the production of damaging free radicals can overwhelm the natural antioxidant systems, potentially leading to tissue damage and reduced milk production. Central to the protection against free radical damage and antioxidant defense is the transcription factor NRF2, which activates an array of genes associated with antioxidant functions and cell survival. The objective of this study was to evaluate the effect that two natural NRF2 modulators, the NRF2 agonist sulforaphane (SFN) and the antagonist brusatol (BRU), have on the transcriptome of immortalized bovine mammary alveolar cells (MACT) using both the RT-qPCR of putative NRF2 target genes, as well as RNA sequencing approaches. The treatment of cells with SFN resulted in the activation of many putative NRF2 target genes and the upregulation of genes associated with pathways involved in cell survival, metabolism, and antioxidant function while suppressing the expression of genes related to cellular senescence and DNA repair. In contrast, the treatment of cells with BRU resulted in the upregulation of genes associated with inflammation, cellular stress, and apoptosis while suppressing the transcription of genes involved in various metabolic processes. The analysis also revealed several novel putative NRF2 target genes in bovine. In conclusion, these data indicate that the treatment of cells with SFN and BRU may be effective at modulating the NRF2 transcriptional network, but additional effects associated with cellular stress and metabolism may complicate the effectiveness of these compounds to improve antioxidant health in dairy cattle via nutrigenomic approaches.

Endothelial damage is the initial and crucial factor in the occurrence and development of vascular complications in diabetic patients, contributing to morbidity and mortality. Although hyperglycemia has been identified as a damaging effector, the detailed mechanisms remain elusive. In this study, identified by ATAC-seq and RNA-seq, JunB reverses the inhibition of proliferation and the promotion of apoptosis in human umbilical vein endothelial cells treated with high glucose, mainly through the cell cycle and p53 signaling pathways. Furthermore, JunB undergoes phase separation in the nucleus and in vitro, mediated by its intrinsic disordered region and DNA-binding domain. Nuclear localization and condensation behaviors are required for JunB-mediated proliferation and apoptosis. Thus, our study uncovers the roles of JunB and its coacervation in repairing vascular endothelial damage caused by high glucose, elucidating the involvement of phase separation in diabetes and diabetic endothelial dysfunction.

HERC4 has been reported to have functions in several types of tumors, but its roles in ovarian cancer have not been studied yet.

Primary tissues from ovarian cancer patients and cell lines were collected for real-time PCR. Kaplan-Meier Plotter was used to predict the prognosis of ovarian cancer patients. HERC4 was overexpressed in cells by lentivirus, and CCK-8 assay was performed to evaluate cell viability. Real-time PCR and Western blot were carried out to analyze the mRNA and protein expression, respectively. Xenograft tumor models were established to analyze HERC4 function in vivo.

Firstly, we found that HERC4 was significantly downregulated in ovarian cancer. We then found that ovarian cancer patients with high HERC4 expression had significantly higher overall survival and progression-free survival rates compared with patients with low expression. Then, HERC4 was overexpressed in ovarian cancer cells, and we found that overexpression of HERC4 significantly inhibited ovarian cancer cell growth, as well as the expression of the target protein SMO, and the key proteins in the downstream hedgehog signaling pathway. Finally, the xenograft tumor models revealed that overexpression of HERC4 significantly inhibited tumor growth in vivo.

Overall, these results indicate that overexpression of HERC4 inhibits cell proliferation of ovarian cancer in vitro and in vivo, suggesting that HERC4 may serve as an effective target for the treatment of ovarian cancer.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. However, the mechanisms underlying ESCC tumorigenesis have not been fully elucidated. Thus, we aimed to determine the key genes involved in ESCC tumorigenesis. The following bioinformatics analyses were performed: identification of differentially expressed genes (DEGs); gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis; integrated analysis of the protein-protein interaction network and Gene Expression Profiling Interactive Analysis database for validation of hub genes. Finally, western blotting and qPCR were used to explore the expression of cell division cycle 6 (CDC6) in ESCC cell lines. Immunohistochemistry analysis of ESCC samples from patients and matched clinical characteristics was used to determine the effects of CDC6. A total of 494 DEGs were identified, and functional enrichment was mainly focused on cell cycle and DNA replication. Biological pathway analysis of the hub genes was closely related to the cell cycle. We found that CDC6 was upregulated in ESCC cell lines and patient tissues and was related to the clinicopathological characteristics of ESCC. In conclusion, this study identified hub genes and crucial biological pathways related to ESCC tumorigenesis and integrated analyses indicated that CDC6 may be a novel diagnostic and therapeutic target for ESCC.

Targeting cardiac remodeling is regarded as a key therapeutic strategy for heart failure. Kielin/chordin-like protein (KCP) is a secretory protein with 18 cysteine-rich domains and associated with kidney and liver fibrosis. However, the relationship between KCP and cardiac remodeling remains unclear. Here, we aimed to investigate the role of KCP in cardiac remodeling induced by pressure overload and explore its potential mechanisms. Left ventricular (LV) KCP expression was measured with real-time quantitative PCR, western blotting, and immunofluorescence staining in pressure overload-induced cardiac remodeling in mice. Cardiac function and remodeling were evaluated in wide-type (WT) mice and KCP knockout (KO) mice by echocardiography, which were further confirmed by histological analysis with hematoxylin and eosin and Masson staining. RNA sequence was performed with LV tissue from WT and KO mice to identify differentially expressed genes and related signaling pathways. Primary cardiac fibroblasts (CFs) were used to validate the regulatory role and potential mechanisms of KCP during fibrosis. KCP was down-regulated in the progression of cardiac remodeling induced by pressure overload, and was mainly expressed in fibroblasts. KCP deficiency significantly aggravated pressure overload-induced cardiac dysfunction and remodeling. RNA sequence revealed that the role of KCP deficiency in cardiac remodeling was associated with cell division, cell cycle, and P53 signaling pathway, while cyclin B1 (CCNB1) was the most significantly up-regulated gene. Further investigation in vivo and in vitro suggested that KCP deficiency promoted the proliferation of CFs via P53/P21/CCNB1 pathway. Taken together, these results suggested that KCP deficiency aggravates cardiac dysfunction and remodeling induced by pressure overload via P53/P21/CCNB1 signaling in mice.

Cellular senescence is the state of permanent growth arrest. Chemotherapeutic drugs induce senescence, known as therapy-induced senescence. Although there are studies deciphering processes in senescence, more studies providing detailed information on therapy-induced senescence at the transcriptome level are needed. In order to understand temporal molecular changes of doxorubicin treatment in the course of senescence formation, two data sets from HeLa cells at 16 h and 72 h doxorubicin treatment were analyzed. GO BP enrichment, KEGG pathways and hub genes specific to or shared between 16 h and 72 h doxorubicin treated HeLa cells were identified. Genes functioning in p53 signaling were upregulated only in 16 h, while genes functioning in extracellular matrix organization were upregulated only in 72 h doxorubicin treated HeLa cells. Wound healing genes were gradually upregulated from 16 h to 72 h doxorubicin treatment and metabolic pathways were downregulated at both. ncRNA processing and ribosome biogenesis GO BP terms were enriched in upregulated genes at 16 h, while these terms were enriched in downregulated genes at 72 h senescent HeLa cells. According to our results, genes functioning in p53 signaling may be involved in the induction of senescence, but may not be required to maintain senescence in HeLa cells.

Ningxin-Tongyu-Zishen formula (NTZF) is a clinical experience formula for the treatment of premature ovarian insufficiency (POI) in traditional Chinese medicine (TCM), and the potential mechanism is unknown. For in vivo experiments, POI mouse models (C57BL/6 mice), were constructed by subcutaneous injection of D-galactose (D-gal, 200 mg/kg). After treatment of NTZF (10.14, 20.27, 40.54 g/kg;) or estradiol valerate (0.15 mg/kg), ovarian function, oxidative stress (OS) and protein expression of Sirt1/p53 were evaluated. For in vitro experiments, H2O2 (200 μM) was used to treat KGN to construct ovarian granulosa cells (OGCs) cell senescence model. Pretreatment with NTZF (1.06 mg/mL) or p53 inhibitor (Pifithrin-α, 1 μM) was performed before induction of senescence, and further evaluated the cell senescence, OS, mRNA and protein expression of Sirt1/p53. In vivo, NTZF improved ovarian function, alleviated OS and Sirt1/p53 signaling abnormalities in POI mice. In vitro experiments showed that NTZF reduced the level of OS and alleviated the senescence of H2O2-induced KGN. In addition, NTZF activated the protein expression of Sirt1, inhibited the mRNA transcription and protein expression of p53 and p21. Alleviating OGCs senescence and protecting ovarian function through Sirt1/p53 is one of the potential mechanisms of NTZF in the treatment of POI.

The identification and investigation of key molecules involved in the pathogenesis of multiple myeloma (MM) hold paramount clinical significance. This study primarily focuses on elucidating the role of DEPDC1B within the context of MM. Our findings robustly affirm the abundant expression of DEPDC1B in MM tissues and cell lines. Notably, DEPDC1B depletion exerted inhibitory effects on MM cell proliferation and migration while concurrently facilitating apoptosis and G2 cell cycle arrest. These outcomes stand in stark contrast to the consequences of DEPDC1B overexpression. Furthermore, we identified CCNB1 as a putative downstream target, characterized by a co-expression pattern with DEPDC1B, mediating DEPDC1B's regulatory influence on MM. Additionally, our results suggest that DEPDC1B knockdown may activate the p53 pathway, thereby impeding MM progression. To corroborate these in vitro findings, we conducted in vivo experiments that further validate the regulatory role of DEPDC1B in MM and its interaction with CCNB1 and the p53 pathway. Collectively, our research underscores DEPDC1B as a potent promoter in the development of MM, representing a promising therapeutic target for MM treatment. This discovery bears significant implications for future investigations in this field.

Lung adenocarcinoma (LUAD) is one of the most lethal types of cancer worldwide, and accurately predicting patient prognosis is an important challenge. Gene prediction models, which are known for their simplicity and efficiency, have the potential to be used for prognostic predictions. However, the availability of models with true clinical value is limited. The present study integrated tissue sequencing and the clinical information of patients with LUAD from The Cancer Genome Atlas and Gene Expression Omnibus databases using bioinformatics. This comprehensive approach enabled the identification of 252 differentially expressed genes. Subsequently, univariate and multivariate Cox analyses were performed using these genes, and 14 and 3 genes [including cell division cycle 6 (CDC6), hyaluronan mediated motility receptor and STIL centriolar assembly protein] were selected for the construction of two prognostic models. Notably, the 3‑gene prognostic model exhibited a comparable predictive ability to that of the 14‑gene model. Functionally, pathway enrichment analysis revealed that CDC6 played a role in regulating the cell cycle and promoting tumor staging. To further investigate the relevance of CDC6, in vitro experiments involving the downregulation of CDC6 expression were conducted, which resulted in significant inhibition of tumor cell migration, invasion and proliferation. Moreover, in vivo experiments demonstrated that downregulating CDC6 expression significantly reduced the burden and metastasis of in situ lung tumors in mice. These findings suggested that CDC6 may be a critical gene involved in the development and prognosis of LUAD. In summary, the present study successfully constructed a simple yet accurate prognostic prediction model consisting of 3 genes. Additionally, the functional importance of CDC6 as a key gene in the model was identified. These findings lay a crucial foundation for further exploration of prognostic prediction models and a deeper understanding of the functional mechanisms of CDC6. Notably, these results have potential clinical implications for improving personalized treatment and prognosis evaluation for patients with LUAD.

Hepatocellular carcinoma (HCC), partly because of its complexity and high heterogeneity, has a poor prognosis and an extremely high mortality rate. In this study, mRNA sequencing expression profiles and relevant clinical data of HCC patients were gathered from different public databases. Kaplan-Meier survival curves as well as ROC curves validated that OLA1|CLEC3B was an independent predictor with better predictive capability of HCC prognosis compared to OLA1 and CLEC3B separately. Further, the cell transfection experiment verified that knockdown of OLA1 inhibited cell proliferation, facilitated apoptosis, and improved sensitivity of HCC cells to gemcitabine. In this study, the prognostic model of HCC composed of OLA1/CLEC3B genes was constructed and verified, and the prediction ability was favorable. A higher level of OLA1 along with a lower level of CEC3B is a sign of poor prognosis in HCC. We revealed a novel gene pair OLA1|CLEC3B overexpressed in HCC patients, which may serve as a promising independent predictor of HCC survival and an approach for innovative diagnostic and therapeutic strategies.

Normal tension glaucoma (NTG) is referred to as a progressive degenerative disorder of the retinal ganglion cells (RGCs), resulting in nonreversible visual defects, despite intraocular pressure levels within the statistically normal range. Current therapeutic strategies for NTG yield limited benefits. Excitatory amino acid carrier 1 (EAAC1) knockout (EAAC1-/- ) in mice has been shown to induce RGC degeneration without elevating intraocular pressure, mimicking pathological characteristics of NTG. In this study, we explored whether daily oral administration of melatonin could block RGCs loss and prevent retinal morphology and function defects associated with EAAC1 deletion. We also explored the molecular mechanisms underlying EAAC1 deletion-induced RGC degeneration and the neuroprotective effects of melatonin. Our RNA sequencing and in vivo data indicated EAAC1 deletion caused elevated oxidative stress, activation of apoptosis and cellular senescence pathways, and neuroinflammation in RGCs. However, melatonin administration efficiently prevented these detrimental effects. Furthermore, we investigated the potential role of apoptosis- and senescence-related redox-sensitive factors in EAAC1 deletion-induced RGCs degeneration and the neuroprotective effects of melatonin administration. We observed remarkable upregulation of p53, whereas NRF2 and Sirt1 expression were significantly decreased in EAAC1-/- mice, which were prevented by melatonin treatment, suggesting that melatonin exerted its neuroprotective effects possibly through modulating NRF2/p53/Sirt1 redox-sensitive signaling pathways. Overall, our study provided a solid foundation for the application of melatonin in the management of NTG.

Pancreatic cancer (PC) is a digestive malignancy with worse overall survival. Tumor immune environment (TIME) alters the progression and proliferation of various solid tumors. Hence, we aimed to detect the TIME-related classifier to facilitate the personalized treatment of PC. Based on the 1612 immune-related genes (IRGs), we classified patients into Immune_rich and Immune_desert subgroups via consensus clustering. Patients in distinct subtypes exhibited a difference in sensitivity to immune checkpoint blockers (ICB). Next, the immune-related signature (IRS) model was established based on 8 IRGs (SYT12, TNNT1, TRIM46, SMPD3, ANLN, AFF3, CXCL9 and RP1L1) and validated its predictive efficiency in multiple cohorts. RT-qPCR experiments demonstrated the differential expression of 8 IRGs between tumor and normal cell lines. Patients who gained lower IRS score tended to be more sensitive to chemotherapy and immunotherapy, and obtained better overall survival compared to those with higher IRS scores. Moreover, scRNA-seq analysis revealed that fibroblast and ductal cells might affect malignant tumor cells via MIF-(CD74+CD44) and SPP1-CD44 axis. Eventually, we identified eight therapeutic targets and one agent for IRS high patients. Our study screened out the specific regulation pattern of TIME in PC, and shed light on the precise treatment of PC.

Breast cancer (BC) is a prevalent malignancy affecting women, characterized by a substantial occurrence rate. Squalene epoxidase (SQLE) is a crucial regulator of ferroptosis and has been associated with promoting cell growth and invasion in different types of human cancers. This study aimed to investigate the functional significance of SQLE in BC and elucidate the underlying molecular mechanisms involved.

SQLE expression levels in BC tissues were evaluated using quantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry. Cell viability, invasion, migration, and cell cycle distribution were assessed using a combination of assays, including the Cell Counting Kit-8, EdU, colony formation, Transwell, and wound healing assays and flow cytometry analysis. Measurement of intracellular reactive oxygen species (ROS), malondialdehyde assay, and glutathione assay were utilized to investigate ferroptosis. Furthermore, co-immunoprecipitation and immunofluorescence assays were conducted to explore the correlation between SQLE and CCNB1. The in vivo tumor growth was evaluated by conducting a xenograft tumorigenicity assay to investigate the impact of SQLE.

SQLE expression was significantly increased in BC, and higher SQLE expression levels were significantly associated with an unfavorable prognosis. In vitro functional assays revealed that the overexpression of SQLE markedly enhanced the proliferation, migration, and invasion capacities of BC cells. Furthermore, SQLE overexpression facilitated tumor growth in nude mice. Mechanistically, SQLE alleviated the ubiquitination modification of CCNB1, leading to enhanced stability of the CCNB1 protein and decreased intracellular ROS levels. Ultimately, this inhibited ferroptosis and facilitated the progression of BC. Our findings have provided insights into a crucial pathway by which elevated SQLE expression confers protection to BC cells against ferroptosis, thus promoting cancer progression. SQLE may serve as a novel oncological marker and a potential therapeutic target for BC progression.

In conclusion, this study provides evidence that SQLE plays a regulatory role in BC progression by modulating CCNB1 and ferroptosis. These findings offer valuable insights into the role of SQLE in the pathogenesis of BC and demonstrate its potential as a therapeutic target for treating BC.

CircRNAs have become a hotspot in tumor research owing to their high stability and specific functions. We investigated the function of hsa_circ_0137652 in the onset and progression of breast cancer (BC). The expression of circ_0137652, miR-1205, and CCNB1 in BC tissues and cell lines were detected using RT-qPCR and/or western blotting. Dual-luciferase reporter and RNA immunoprecipitation chip assays were used to confirm any potential connections between circ_0137652, miR-1205, and CCNB1. CCK-8 and clone formation assays (CFA) were used to measure the proliferation of BC cells. The Transwell assay was used to investigate the migration of BC cells, and the impact of circ_0137652 on BC tumor formation in vivo was validated using animal experiments. RT-qPCR results showed that circ_0137652 and CCNB1 in breast cancer tissues were notably upregulated in normal tissues, whereas miR-1205 was prominently downregulated. After silencing circ_0137652, the growth and migration of BC cells were reduced. Animal experiments showed that circ_0137652 hampers the tumorigenesis of BC cells in vivo. Additionally, we found that circ_0137652 functions as a sponge for miR-1205. Moreover, the miR-1205 inhibitor notably facilitated cell proliferation and migration and attenuated the action of circ_0137652 knockdown. Furthermore, miR-1205 inhibits BC progression by targeting CCNB1. Circ_0137652 controls the miR-1205/CCNB1 axis to induce increased breast cancer malignancy. Our findings suggest that circ_0137652 may be a novel target for BC therapy.

In recent years, significant molecules have been found in gastric cancer research. However, their precise roles in the disease's development and progression remain unclear. Given gastric cancer's heterogeneity, prognosis prediction is challenging. This study aims to assess patient prognosis and immune therapy efficacy using multiple key molecules.

The WGCNA algorithm was employed to identify modules of genes closely related to immunity. A prognostic model was established using the Lasso-Cox method to predict patients' prognosis. Single-sample gene set enrichment analysis (ssGSEA) was conducted to quantify the relative abundance of 16 immune cell types and 13 immune functions. The relationship between risk score and TMB, MSI, immune checkpoints, and DNA repair genes was examined to predict the effectiveness of immune therapy. GO and KEGG analyses were performed to explore potential pathways and mechanisms associated with the genes of interest. Single-cell RNA sequencing was utilized to investigate the expression patterns of key genes in different cell types.

Through the WGCNA algorithm and Lasso-Cox algorithm selected KL, SERPINE1, and STK40 as key genes for constructing the prognostic model. The SSGSEA algorithm was employed to evaluate the infiltration of immune cells and immune functions in different patients, and their association with the risk score was investigated. The high-risk group exhibited lower TMB and MSI compared to the low-risk group. MMR and immune checkpoint analysis revealed a significant correlation between the risk score and multiple molecules. Finally, we also believe that STK40 is the most critical senescence-related gene affecting the progression of gastric cancer. In vitro experiments showed that ROS accumulation and cell proliferation ability of gastric cancer cells were impaired when STK40 was knocked down.

In summary, we've constructed a prognostic model utilizing key genes for gastric cancer prognosis, while also showcasing its efficacy in predicting patient response to immunotherapy.

Aberrant levels of the G2/M cyclin cyclin B1 (gene CCNB1) have been associated with multiple cancers; however, the literature lacks a focused and comprehensive analysis of the regulation of this important regulator of cell proliferation in cancer. Through this work, we performed a pancancer analysis of the levels of CCNB1 and dissected aspects of regulation and how this correlates with cancer prognosis. We comprehensively evaluated the expression and promoter methylation of CCNB1 across 38 cancers based on RNA sequencing data obtained from the Cancer Genome Atlas (TCGA). The correlation of CCNB1 with prognosis and the tumor microenvironment was explored. Using lung adenocarcinoma data, we studied the potential upstream noncoding RNAs involved in the regulation of CCNB1 and validated the protein levels and prognostic value of CCNB1 for this disease site. CCNB1 was highly expressed, and promoter methylation was reduced in most cancers. Gene expression of CCNB1 correlated positively with poor prognosis of tumor patients, and these results were confirmed at the protein level using lung adenocarcinoma. CCNB1 expression was associated with the infiltration of T helper cells, and this further correlated with poor prognosis for certain cancers, including renal clear cell carcinoma and lung adenocarcinoma. Subsequently, we identified a specific upstream noncoding RNA contributing to CCNB1 overexpression in lung adenocarcinoma through correlation analysis, expression analysis and survival analysis. This study provides a comprehensive analysis of the expression and methylation status of CCNB1 across several forms of cancer and provides further insight into the mechanistic pathways regulating Cyclin B1 in the tumorigenesis process.

Family with sequence similarity three member (FAM3) plays a crucial role in the malignant development of various cancers of human. However, there remains doubtful what specific role of FAM3 family genes in pan-cancer. Our study aimed to investigate the role of FAM3 family genes in prognosis, immune subtype, tumor immune microenvironment, stemness score, and anticancer drug sensitivity of pan-cancer. We obtained data from UCSC Xena GDC and CellMiner databases, and used them to study the correlation of the expression, survival, immune subtype, tumor microenvironment, stemness score, and anticancer drug sensitivity between FAM3 family genes with pan-cancer. Furthermore, we investigated the tumor cellular functions and clinical prognostic value FAMC3 in pancreatic cancer (PAAD) using cellular experiments and tissue microarray. Cell Counting Kit-8 (CCK-8), transwell invasion, wound-healing and apoptosis assays were performed to study the effect of FAM3C on SW1990 cells' proliferation, migration, invasion and apoptosis. Immunohistochemical staining was used to study the relationship between FAM3C expression and clinical characteristics of pancreatic cancer patients. The results revealed that FAM3 family genes are significantly differential expression in tumor and adjacent normal tissues in 7 cancers (CHOL, HNSC, KICH, LUAD, LUSC, READ, and STAD). The expression of FAM3 family genes were negatively related with the RNAss, and robust correlated with immune type, tumor immune microenvironment and drug sensitivity. The expression of FAM3 family genes in pan-cancers were significantly different in immune type C1 (wound healing), C2 (IFN-gamma dominant), C3 (inflammatory), C4 (lymphocyte depleted), C5 (immunologically quiet), and C6 (TGF-beta dominant). Meanwhile, overexpression FAM3C promoted SW1990 cells proliferation, migration, invasion and suppressed SW1990 cells apoptosis. While knockdown of FAM3C triggered opposite results. High FAM3C expression was associated with duodenal invasion, differentiation and liver metastasis. In summary, this study provided a new perspective on the potential therapeutic role of FAM3 family genes in pan-cancer. In particular, FAM3C may play an important role in the occurrence and progression of PAAD.

Aim: The present study sought to investigate the therapeutic effect of resveratrol on clear cell renal cell carcinoma. Materials & methods: Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays were used to verify the cell proliferation. Transwell, real-time quantitative transcription PCR, western blot and β-galactosidase staining were used to verify the migration, macrophage polarization and senescence. The tumor inhibitory effect of resveratrol on clear cell renal cell carcinoma was verified in vivo. Results: This study confirmed that resveratrol could affect the stability of CCNB1 mRNA mediated by RBM15 and inhibit the cancer process by inhibiting the expression of EP300/CBP from the perspective of cell senescence. Conclusion: Resveratrol is able to treat clear cell renal cell carcinoma through RBM15-induced cell senescence.

Retinoblastoma (RB) is a common malignancy that primarily affects pediatric populations. Although a well-known cause of RB is RB1 mutation, MYCN amplification can also lead to the disease, which is a poor prognosis factor. Studies conducted in various tumor types have shown that MYCN inhibition is an effective approach to impede tumor growth. Various indirect approaches have been developed to overcome the difficulty of directly targeting MYCN, such as modulating the super enhancer (SE) upstream of MYCN. The drug used in this study to treat MYCN-amplified RB was THZ1, a CDK7 inhibitor that can effectively suppress transcription by interfering with the activity of SEs. The study findings confirmed the anticancer activity of THZ1 against RB in both in vitro and in vivo experiments. Therapy with THZ1 was found to affect numerous genes in RB according to the RNA-seq analysis. Moreover, the gene expression changes induced by THZ1 treatment were enriched in ribosome, endocytosis, cell cycle, apoptosis, etc. Furthermore, the combined analysis of ChIP-Seq and RNA-seq data suggested a potential role of SEs in regulating the expression of critical transcription factors, such as MYCN, OTX2, and SOX4. Moreover, ChIP-qPCR experiments were conducted to confirm the interaction between MYCN and SEs. In conclusion, THZ1 caused substantial changes in gene transcription in RB, resulting in inhibited cell proliferation, interference with the cell cycle, and increased apoptosis. The efficacy of THZ1 is positively correlated with the degree of MYCN amplification and is likely exerted by interfering with MYCN upstream SEs.

Lung adenocarcinoma (LUAD) is one of the major types of lung cancer with high morbidity and mortality. The TRAF-interacting protein (TRAIP) is a ring-type E3 ubiquitin ligase which has been recently identified to play pivotal roles in various cancers. However, the expression and function of TRAIP in LUAD remain elusive.

In this study, we used bioinformatic tools as well as molecular experiments to explore the exact role of TRAIP and the underlying mechanism.

Data mining across the UALCAN, GEPIA and GTEx, GEO and HPA databases revealed that TRAIP was significantly overexpressed in LUAD tissues than that in adjacent normal tissues. Kaplan-Meier curve showed that high TRAIP expression was associated with poor overall survival (OS) and relapse-free survival (RFS). Univariate and multivariate cox regression analysis revealed that TRAIP was an independent risk factor in LUAD. And the TRAIP-based nomogram further supported the prognostic role of TRAIP in LUAD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that TRAIP-associated genes were mainly involved in DNA replication, cell cycle and other processes. The immune infiltration analysis indicated that TRAIP expression was tightly correlated with the infiltration of diverse immune cell types, including B cell, CD8 + T cell, neutrophil and dendritic cell. Moreover, TRAIP expression was observed to be significantly associated with tumor infiltrating lymphocytes (TILs) and immune checkpoint molecules. In vitro experiments further confirmed knockdown of TRAIP inhibited cell migration and invasion, as well as decreasing chemokine production and inhibiting M2-like macrophage recruitment. Lastly, CMap analysis identified 10 small molecule compounds that may target TRAIP, providing potential therapies for LUAD.

Collectively, our study found that TRAIP is an oncogenic gene in LUAD, which may be a potential prognostic biomarker and promising therapeutic target for LUAD.

In search of an effective therapeutic target for bladder urothelial carcinoma (BLCA), the present study aimed to investigate the expression of cyclin B1 (CCNB1) and its putative mechanism in BLCA. BLCA sequencing data from Gene Expression Omnibus and The Cancer Genome Atlas were used to analyze expression of CCNB1 mRNA and high CCNB1 expression had a poorer prognosis compared with those with low expression. Immunohistochemistry (IHC) samples collected from the Human Protein Atlas database were analyzed for CCNB1 protein expression. Short hairpin (sh) CCNB1-transfected BLCA T24 and 5637 cells were used to investigate the effects of CCNB1 and inhibit the proliferation, migration and invasion of BLCA cells, affect the cell cycle distribution and promote apoptosis of 5637 cells. A sh-CCNB1 BLCA chicken embryo chorioallantoic membrane (CAM) transplantation model was established to observe the impacts of sh-CCNB1 on the tumorigenesis of BLCA in vivo. Analysis of sequencing data showed that CCNB1 mRNA was significantly elevated in tumor and BLCA compared with normal tissues [standardized mean difference (SMD)=1.21; 95% CI: 0.26-2.15; I²=95.9%]. IHC indicated that CCNB1 protein was localized in the nucleus and cytoplasm and was significantly increased in BLCA tumor tissues. The in vitro tests demonstrated that proliferation of T24 and 5637 cells transfected with sh-CCNB1 was significantly inhibited and cell migration and invasion ability were significantly decreased. sh-CCNB1 decreased the percentage of T24 cells in G0/G1, 5637 cells in the G0/G1 phase and S phase and increased percentage of 5637 cells in the G2/M phase and increased early apoptosis of 5637 cells. The in vivo experiments demonstrated that the mass of transplanted tumors was significantly decreased compared with the control group following silencing of CCNB1. The present results suggested that CCNB1 was involve in the development and prognosis of BLCA and silencing of CCNB1 may be a promising targeted therapy for BLCA.