Origin recognition complex 6 overexpression promotes growth of glioma cells.

The discovery of novel oncotargets for glioma is of immense significance. We here explored the expression patterns, biological functions, and underlying mechanisms associated with ORC6 (origin recognition complex 6) in glioma. Through the bioinformatics analyses, we found a significant increase in ORC6 expression within human glioma tissues, correlating with poorer overall survival, higher tumor grade, and wild-type isocitrate dehydrogenase status. Additionally, ORC6 overexpression is detected in glioma tissues obtained from locally-treated patients and across various primary/established glioma cells. Further bioinformatics scrutiny revealed that genes co-expressed with ORC6 are enriched in multiple signaling cascades linked to cancer. In primary and immortalized (A172) glioma cells, depleting ORC6 using specific shRNA or Cas9-sgRNA knockout (KO) significantly decreased cell viability and proliferation, disrupted cell cycle progression and mobility, and triggered apoptosis. Conversely, enhancing ORC6 expression via a lentiviral construct augmented malignant behaviors in human glioma cells. ORC6 emerged as a crucial regulator for the expression of key oncogenic genes, including Cyclin A2, Cyclin B2, and DNA topoisomerase II (TOP2A), within glioma cells. Silencing or KO of ORC6 reduced the mRNA and protein levels of these genes, while overexpression of ORC6 increased their expression in primary glioma cells. Bioinformatics analyses further identified RBPJ as a potential transcription factor of ORC6. RBPJ shRNA decreased ORC6 expression in primary glioma cells, while its overexpression increased it. Additionally, significantly enhanced binding between the RBPJ protein and the proposed ORC6 promoter region was detected in glioma tissues and cells. In vivo experiments demonstrated a significant reduction in the growth of patient-derived glioma xenografts in the mouse brain subsequent to ORC6 KO. ORC6 depletion, inhibited proliferation, decreased expression of Cyclin A2/B2/TOP2A, and increased apoptosis were detected within these ORC6 KO intracranial glioma xenografts. Altogether, RBPJ-driven ORC6 overexpression promotes glioma cell growth, underscoring its significance as a promising therapeutic target.

Upregulation of CCNB2 and a novel lncRNAs-related risk model predict prognosis in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the main type of renal cell carcinoma. Cyclin B2 (CCNB2) is a subtype of B-type cyclin that is associated with the prognosis of several cancers. This study aimed to identify the relationship between CCNB2 and progression of ccRCC and construct a novel lncRNAs-related model to predict prognosis of ccRCC patients. METHODS: The data were obtained from public databases. We identified CCNB2 in ccRCC using Kaplan-Meier survival analysis, univariate and multivariate Cox regression, and Gene Ontology analysis. External validation was then performed. The risk model was constructed based on prognostic lncRNAs by the LASSO algorithm and multivariate Cox regression. Receiver operating characteristics (ROC) curves were used to evaluate the model. Consensus clustering analysis was performed to re-stratify the patients. Finally, we analyzed the tumor-immune microenvironment and performed screening of potential drugs. RESULTS: CCNB2 associated with late clinicopathological parameters and poor prognosis in ccRCC and was an independent predictor for disease-free survival. In addition, CCNB2 shared the same expression pattern with known suppressive immune checkpoints. A risk model dependent on the expression of three prognostic CCNB2-related lncRNAs (SNHG17, VPS9D1-AS1, and ZMIZ1-AS1) was constructed. The risk signature was an independent predictor of ccRCC. The area under the ROC (AUC) curve for overall survival at 1-, 3-, 5-, and 8-year was 0.704, 0.702, 0.741, and 0.763. The high-risk group and cluster 2 had stronger immunogenicity and were more sensitive to immunotherapy. CONCLUSION: CCNB2 could be an important biomarker for predicting prognosis in ccRCC patients. Furthermore, we developed a novel lncRNAs-related risk model and identified two CCNB2-related molecular clusters. The risk model performed well in predicting overall survival and immunological microenvironment of ccRCC.

Prognostic value of cyclin B1 and cyclin B2 expression in breast cancer: A systematic review and updated meta-analysis.

BACKGROUND: Cyclin B1 and cyclin B2 are key regulators of cell cycle progression and have been implicated in the prognostic significance of various cancers. This meta-analysis aimed to evaluate the prognostic value of cyclin B1 and B2 expression in breast cancer. METHODS: A comprehensive literature search was conducted on Pubmed, Embase, MEDLINE, Web of Science, and Cochrane library. Studies with survival data and clinicopathological parameters associated with cyclin B1 and B2 or CCNB1 and CCNB2 genes were included. Survival data and clinicopathological parameters associated with cyclin B1 and B2 expression were extracted. Pooled hazard ratios and odds ratios with 95% confidence intervals were calculated. Subgroup analysis was conducted to assess heterogeneity. Publication bias was evaluated. RESULTS: A total of 23 studies were included in the analysis. High expression of cyclin B1 was significantly associated with worse overall survival (hazard ratio [HR] = 1.69, P < .01), disease-specific survival (HR = 1.71, P < .01), and disease-free survival (HR = 2.01, P = .01). High expression of cyclin B2 was associated with worse disease-specific survival (HR = 2.46, P = .02). Clinicopathological parameters did not show significant associations with cyclin B1 and B2 expressions. When data on cyclin B1 and B2 were combined, a significant age-related difference was found (odds ratio = 0.62, P = .04). CONCLUSIONS: This meta-analysis provides evidence supporting the prognostic significance of cyclin B1 and B2 expression in breast cancer. High expression of cyclin B1 and B2 is associated with worse survival, indicating their potential as prognostic markers in breast cancer.

Cyclin B2 impairs the p53 signaling in nasopharyngeal carcinoma.

BACKGROUND: Cyclin B2 (CCNB2), a member of the cyclin family, is an oncogene in multiple cancers, including nasopharyngeal carcinoma (NPC). However, the epigenetics mechanism for CCNB2 overexpression in NPC remains unclear. This study dissects the regulatory role of CCNB2 in NPC and the molecular mechanism. METHODS: Differentially methylated genes (DMG) and differentially expressed genes (DEG) were screened out in GSE52068 and GSE13597 databases, respectively, and candidate targets were identified by the Venn diagram. GO annotation and pathway enrichment analyses were performed on selected DMG and DEG, and a PPI network was constructed to pinpoint hub genes. PCR and qMSP were conducted to detect the expression and methylation of CCNB2 in cells. The siRNA targeting CCNB2 was transfected into NPC cells, and the migration, proliferation, cell cycle, epithelial-mesenchymal transition (EMT), tumorigenesis, and metastasis were examined. The upstream factor responsible for CCNB2 overexpression in NPC was explored. The p53 activity in NPC cells was assessed using western blot analysis. RESULTS: CCNB2 showed hypomethylation and overexpression in NPC. CCNB2 silencing inhibited cell migration, proliferation, cell cycle entry, and EMT. JMJD6 was overexpressed in NPC and upregulated CCNB2 through demethylation. JMJD6 reversed the effects of CCNB2 downregulation, resulting in elevated cellular activity in vitro and tumorigenic and metastatic activities in vivo. CCNB2 blocked the p53 pathway, while the p53 pathway inhibitor reversed the effect of CCNB2 silencing to increase the activity of NPC cells. CONCLUSIONS: JMJD6 enhanced CCNB2 transcription by demethylating CCNB2, thereby repressing the p53 pathway and promoting NPC progression.

CCNB2 as a potential biomarker of bladder cancer via the high throughput technology.

Bladder cancer and oral squamous cell carcinoma (OSCC) seriously affect people's health. However, the relationship between bladder cancer and OSCC remains unclear. Got GSE138206, GSE146483, GSE184616, and bladder cancer datasets GSE65635, GSE100926 from Gene Expression Omnibus database. Weighted gene co-expression network analysis was used to identify the significant module. Functional enrichment analysis was performed via the Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes. Furthermore, the Gene Set Enrichment Analysis was also used to complete the enrichment analysis. Comparative Toxicogenomics Database found most relevant diseases to core genes. TargetScan is used to forecast analysis of microRNA and target genes. In Gene Ontology analysis, differentially expressed genes were mostly concentrated in cell differentiation, extrallular region, structural molecule activity, and actin binding. In Kyoto Encyclopedia of Genes and Genomes analysis, the differentially expressed genes were mainly enriched in PI3K-Akt signaling pathway, pathway in cancer, and extracellular matrix-receptor interaction. Seven hub genes (cyclin B2 [CCNB2], TK1, CDC20, PCNA, CKS1B, CDCA5, MCM4) were obtained. Hub genes (CCNB2, CDC20) are highly expressed in OSCC and bladder cancer samples. CCNB2 was one common oncogene of bladder cancer and OSCC.

Extracellular vesicle-derived CircWhsc1 promotes cardiomyocyte proliferation and heart repair by activating TRIM59/STAT3/Cyclin B2 pathway.

INTRODUCTION: Extracellular vesicles (EVs)-mediated cell-to-cell communication is crucial for hypoxia-induced cell proliferation and tissue repair, but its function in endogenous cardiac regeneration is still unknown. OBJECTIVES: Herein, we aimed to determine whether hypoxia-inducible circWhsc1 in endothelial EVs promoted cardiomyocyte (CM) proliferation and cardiac regeneration. METHODS: RNA-sequence data was used to identify EV circRNAs that were involved into endogenous cardiac regeneration. Quantitative polymerase chain reactions were conducted to determine circRNA expression in tissue, cells and EVs. Gain- and loss-of-function assays were performed to explore the function of EV-derived circWhsc1 during cardiac regeneration. Western blotting and RNA pulldown assays were used to investigate its underlying mechanism. RESULTS: We found that circWhsc1 was enriched in neonatal mouse hearts, particularly in cardiac ECs, and was further upregulated both in ECs and EC-derived EVs under hypoxic conditions. When cocultured with hypoxia-preconditioned neonatal ECs or their secreted EVs, both neonatal and adult CMs exhibited an increased proliferation rate and G2/M ratio, which could be attenuated by knockdown of circWhsc1 in ECs. In vivo, EC-restricted overexpression of circWhsc1 and EV-mediated delivery of circWhsc1 induced CM proliferation, alleviated cardiac fibrosis and restored cardiac function following myocardial infarction in adult mice. Mechanistic studies revealed that EV-derived circWhsc1 activated TRIM59 by enhancing its phosphorylation, thereby reinforcing the binding of TRIM59 to STAT3, phosphorylating STAT3 and inducing CM proliferation. CONCLUSION: The current study demonstrated that hypoxia-inducible circWhsc1 in EC-derived EVs induces CM proliferation and heart regeneration. EC-CM communication mediated by EV-derived circWhsc1 might represent a prospective therapeutic target for inducing cardiac repair post-myocardial infarction.

Identification of prognostic genes for early basal-like breast cancer with weighted gene co-expression network analysis.

BACKGROUND: Breast cancer (BC) has become the leading cause of death for women's malignancies and increasingly threatens the health of women worldwide. However, there is a lack of effective targeted drugs for basal-like BC. Therefore, biomarkers related to the prognosis of early BC need to be identified. METHODS: The RNA-seq data of 87 cases of early basal-like BC and 111 cases of normal breast tissue from The Cancer Genome Atlas were explored by the weighted gene co-expression network analysis method and Limma package. Then, intersected genes were identified, and hub genes were selected by the maximal clique centrality method. The prognostic effect of the hub genes was also evaluated in early basal-like BC. RESULTS: In total, 601 IGs were identified in this study. An APPI network was constructed, and the top 10 hub genes were selected, namely, cyclin B1, cyclin A2, cyclin-dependent kinase 1, cell division cycle 20, DNA topoisomerase II alpha, BUB1 mitotic checkpoint serine/threonine kinase, aurora kinase B (AURKB), cyclin B2, kinesin family member 11, and assembly factor for spindle microtubules. Only AURKB was found to be significantly associated with the overall prognosis of early basal-like BC. The immune cell infiltration analysis showed that the infiltration numbers of CD4 + T cells and naïve CD8 + T cells were positively correlated with the AURKB expression level, while those of naïve B cells and macrophage M2 cells were negatively correlated with the AURKB expression level in basal-like BC. CONCLUSION: AURKB might be a potential prognostic indicator in early basal-like BC.

CCNB1 and CCNB2 involvement in the pathogenesis of psoriasis: a bioinformatics study.

OBJECTIVE: The cell cycle-related proteins cyclin B1 (CCNB1) and cyclin B2 (CCNB2) are potentially involved in the underlying mechanisms of psoriasis. The present study aimed to explore this possibility using bioinformatics approaches. METHODS: CCNB1 and CCNB2 protein levels were evaluated in 14 psoriasis patients and five healthy controls by enzyme-linked immunosorbent assays, and their mRNA levels were evaluated using data from four publicly available datasets (GSE53552, GSE41664, GSE14905, and GSE13355). Comparison of high- and low-expressing groups were performed to reveal CCNB1- and CCNB2-related differentially expressed genes, which were then assessed based on gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Correlation analyses between CCNB1 and CCNB2 levels and immune infiltration, as well as typical targets of psoriasis, were also performed. RESULTS: Overall, 12 CCNB1 and CCNB2 common immune-related targets potentially involved in psoriasis were identified. These could regulate the cell cycle of through multiple pathways. In addition, CCNB1 and CCNB2 were found to potentially support the release of key molecular targets of psoriasis through the regulation of mast cell activation and macrophage polarization. CONCLUSIONS: These findings suggest that CCNB1 and CCNB2 may represent valuable molecular biomarkers of psoriasis, contributing to its onset and progression.

CCNB2 expression correlates with worse outcomes in breast cancer patients: a pooled analysis.

Cyclin B2 (CCNB2) is upregulated in Breast Cancer (BC) and associated with worse relapse-free survival (RFS). However, its correlation with other clinical outcomes in BC was yet to be clarified. Therefore, this study aimed to explore the clinical significance of CCNB2 in BC. A comprehensive search was performed in PrognoScan and Gene Expression Omnibus (GEO) databases by searching the keywords of CCNB2 and breast cancer. Pooled hazard ratios (HRs) of overall survival (OS), relapse-free survival (RFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and disease-free survival (DFS), and their corresponding 95 percent confidence intervals (CI) were calculated. Sensitivity analysis by omitting one study at a time and publication bias assessment by Egger's test and Begg's test were conducted. The clinical outcomes were externally verified via Kaplan-Meier Plotter. All of the statistical analyses were performed through STATA 17.0, and P values of less than 0.05 were taken to be statistically significant. Seven records with 1,074 participants were included for OS, with HR of 1.71 (95 percent CI = 1.24-2.35). Verification through Kaplan-Meier Plotter online tool based on 1,897 patients showed an HR of 1.75 (95 percent CI = 1.45-2.12, P < .01). For RFS, 11 records with 1,253 participants were included with the pooled HR of 1.37 (95 percent CI: 1.10-1.71). Verification based on 4,929 patients found and HR of 1.97 (95 percent CI = 1.78-2.19, P < .01). Regarding DMFS, the pooled HR of 10 records with 1,395 participants was 1.60 (95 percent CI: 1.24-2.05) and verification based on 2,765 patients revealed an HR of 1.97 (95 percent CI = 1.68-2.31, P < .01). For DSS, four records with 689 participants were included for DSS, with HR of 1.38 (95 percent CI = 0.59-3.24). The HR of DFS was 1.60 (95 percent CI: 0.46-5.51) after pooling 3 records with 379 participants. High expression of CCNB2 in BC is associated with worse OS, RFS, and DMFS, but not with DSS and DFS. More well-designed studies from different populations and different BC types are still needed.

Hsa_circ_0000285 knockdown inhibits the progression of hepatocellular carcinoma by sponging miR-582-3p to regulate CCNB2 expression.

AIM: Hsa_circ_0000285, a novel circular RNA, has been proven to extensively take part in the pathogenesis of numerous tumors. In hepatocellular carcinoma (HCC), very little is known about hsa_circ_0000285 until now. Hence, this research aims to determine hsa_circ_0000285's functional role and underlying mechanisms in HCC. METHODS: The expressions of miR-582-3p, hsa_circ_000028, and cyclin B2 (CCNB2) among the HCC cells and tumor samples were determined by performing western blotting and qRT-PCR analyses. The impacts of hsa_circ_000028 on the proliferative and migratory abilities of HCC cells were examined through the execution of CCK-8 and wound-healing assays. Meanwhile, the expressions of the proteins Bcl-2 and Bax were detected via western blotting. Tumor xenograft models were established to examine how hsa_circ_000028 functions during the mediation of HCC tumor growth in vivo. RNA immunoprecipitation and luciferase reporter experiments were performed for the validation of the interactions of miR-582-3p, hsa_circ_000028, and CCNB2 with each other. RESULTS: Elevated hsa_circ_0000285 and CCNB2 expressions, and a decreased miR-582-3p expression were observed among the HCC cell lines and tumors. Hsa_circ_0000285 bound to miR-582-3p competitively to improve CCNB2 levels. Silencing of hsa_circ_0000285 promoted apoptosis and repressed proliferation and migration among HCC cells. Moreover, silencing hsa_circ_0000285 also impeded the growth of HCC tumors in vivo. Inhibiting hsa_circ_0000285 or CCNB2 reversed the miR-582-3p-knockdown-mediated promotion of malignant HCC cell phenotypes. CONCLUSION: Our study has demonstrated that hsa_circ_0000285 fosters the development of malignant HCC cells phenotypes through the modulation of the miR-582-3p/CCNB2 axis. Thus, these results suggest that hsa_circ_0000285 is a prospective target for HCC treatment.

Mad2 promotes Cyclin B2 recruitment to the kinetochore for guiding accurate mitotic checkpoint.

Accurate mitotic progression relies on the dynamic phosphorylation of multiple substrates by key mitotic kinases. Cyclin-dependent kinase 1 is a master kinase that coordinates mitotic progression and requires its regulatory subunit Cyclin B to ensure full kinase activity and substrate specificity. The function of Cyclin B2, which is a closely related family member of Cyclin B1, remains largely elusive. Here, we show that Mad2 promotes the kinetochore localization of Cyclin B2 and that their interaction at the kinetochores guides accurate chromosome segregation. Our biochemical analyses have characterized the Mad2-Cyclin B2 interaction and delineated a novel Mad2-interacting motif (MIM) on Cyclin B2. The functional importance of the Cyclin B2-Mad2 interaction was demonstrated by real-time imaging in which MIM-deficient mutant Cyclin B2 failed to rescue the chromosomal segregation defects. Taken together, we have delineated a previously undefined function of Cyclin B2 at the kinetochore and have established, in human cells, a mechanism of action by which Mad2 contributes to the spindle checkpoint.

Cyclin B2 overexpression promotes tumour growth by regulating jagged 1 in hepatocellular carcinoma.

BACKGROUND: Our previous study showed that Cyclin B2 (CCNB2) is closely related to the occurrence and progression of hepatocellular carcinoma (HCC). AIM OF THE STUDY: This study aimed to clarify the effect of CCNB2 gene silencing on tumorigenesis in nude mice and to detect the potential mechanism. METHODS: The effect of CCNB2 on HCC was tested in vivo. The downstream target genes of CCNB2 were predicted by proteomics and confirmed by western blot assay. The regulatory functions of CCNB2 in the proliferation and migration of HCC cells were determined through functional recovery experiments. The expression of the downstream target genes of CCNB2 was detected by immunohistochemistry. RESULTS: Knockdown of CCNB2 decreased tumour formation rate and tumour volume and weight and inhibited tumour proliferation. A total of 130 differentially expressed proteins were detected by proteomics, and Jagged 1 (JAG1) was predicted as the potential downstream target of CCNB2. Western blot assay revealed that CCNB2 and JAG1 expression was significantly correlated in HCC cells. The results of functional recovery experiments suggested that CCNB2 knockdown weakened the proliferation and migration ability of HCC cells, while JAG1 overexpression restored this ability of HCC cells that was weakened by CCNB2 knockdown. Immunohistochemistry showed that JAG1 expression was higher in HCC tissues than in paracancerous tissues and was related to tumour size and number and tumour thrombus formation. CONCLUSIONS: The proliferation of HCC cells in vivo was inhibited by CCNB2 knockdown. CCNB2 may accelerate the proliferation and metastasis of HCC cells by increasing JAG1 expression.

CRHBP is degraded via autophagy and exerts anti-hepatocellular carcinoma effects by reducing cyclin B2 expression and dissociating cyclin B2-CDK1 complex.

Autophagy is the predominant self-eating catabolic pathway activated in response to nutrient starvation and hypoxia within the microenvironment of varied malignancies, including hepatocellular carcinoma (HCC). SQSTM1/p62 links its cargos to autophagosomes for degradation, and reportedly acts as a contributor for hepatocarcinogenesis. Five GEO gene microarrays identified corticotropin releasing hormone (CRH) binding protein (CRHBP) as a significantly downregulated gene in HCC (log2 Fold change < -3 and p < 0.001), and an earlier human interactome study indicated that CRHBP may interact with p62. This study aimed to explore (1) the role of CRHBP in HCC development, and (2) whether p62-mediated autophagy was responsible for low CRHBP expression within HCC tissue. Following functional experiments first revealed an anti-proliferative, anti-metastatic, and anti-angiogenic role of CRHBP in HCC cells (Huh-7, Li-7 and HCCLM3) and xenografts. CRHBP negatively regulated cyclin B2 expression, and dissociated cyclin B2-CDK1 complex in HCC cells, thereby leading to cell cycle arrest at G2 phase. To simulate HCC microenvironment in vitro, Huh-7 cells were incubated in Earle's Balanced Salt Solution (nutrient starvation) or exposed to 1% O2 (hypoxic exposure). In addition to activating autophagy, nutrient starvation and hypoxic exposure also induced CRHBP degradation. Interestingly, CRHBP was demonstrated as a novel cargo targeted by p62 for degradation in autophagosomes. Blocking autophagy with 3-MA, chloroquine or siSQSTM1 prevented CRHBP degradation in HCC cells. Collectively, our study uncovers a role for CRHBP in retarding HCC development, reducing cyclin B2 expression and impairing cyclin B2-CDK1 interaction. CRHBP downregulation in HCC may attribute to p62-mediated autophagy.

Knockdown of Circ_CCNB2 Sensitizes Prostate Cancer to Radiation Through Repressing Autophagy by the miR-30b-5p/KIF18A Axis.

Background: Circular RNAs (circRNAs) have recently emerged as crucial regulatory molecules in prostate cancer (PCa), but few researches focus on the effects of circRNAs on PCa radiosensitivity. The issue will be addressed in this study using circRNA Cyclin B2 (circ_CCNB2) as an object. Materials and Methods: All RNA and protein levels were severally examined using quantitative real-time polymerase chain reaction and Western blot. Colony formation assay and flow cytometry were implemented for detecting cell colony capacity and apoptotic cells, respectively. Cellular migration and invasion abilities were evaluated by transwell assay. The combination between potential target molecules was analyzed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The effect of circ_CCNB2 on PCa radiosensitivity in vivo was explored using xenograft models in mice. Results: Circ_CCNB2 was upregulated in irradiation-resistant PCa tissues and cells. Circ_CCNB2 knockdown had promoted effect on the radiosensitivity of irradiation-resistant PCa cells by inhibiting autophagy. Besides, circ_CCNB2 could directly sponge miR-30b-5p, and the promotion of circ_CCNB2 knockdown on PCa radiosensitivity was achieved by elevating miR-30b-5p. MiR-30b-5p enhanced the radiosensitivity of irradiation-resistant PCa cells through repressing the expression of its target kinesin family member 18A (KIF18A). Furthermore, circ_CCNB2 regulated the KIF18A level through targeting miR-30b-5p. Circ_CCNB2 downregulation facilitated PCa radiosensitivity in vivo through inhibiting autophagy by miR-30b-5p/KIF18A. Conclusions: In this study, knockdown of circ_CCNB2 was shown to promote PCa radiosensitivity through autophagy repression by miR-30b-5p/KIF18A axis, developing a molecular resistance mechanism of PCa radiotherapy and a feasible strategy to increase radiosensitivity.

Protective role of m6A binding protein YTHDC2 on CCNB2 in manganese-induced spermatogenesis dysfunction.

Human infertility has become the third largest serious disease in the world, seriously affecting the quality of human fertility. Studies have shown that manganese (Mn) can accumulate in the testis through the blood-testicular barrier and damage the male reproductive system. However, the mechanism has not been explored clearly. Recent studies have reported that YTH domain-containing 2 (YTHDC2) can regulate reproductive function. However, none has explored the role of YTHDC2 in Mn-induced reproductive toxicity. The present study investigated whether YTHDC2/CyclinB2 (CCNB2) pathway participates in Mn-induced reproductive toxicity using Kunming mice, spermatogonia, and the seminal plasma of male workers. The mice were received intraperitoneal (i.p.) injections of 0, 12.5, 25, and 50 mg/kg MnCl2 once daily for 2 weeks. The cells were treated with 0, 100, 200 and 400 µM MnCl2 for 24 h. Here, we found that occupational Mn exposure significantly increased Mn levels in the seminal plasma of male workers, while decreased sperm density, semen quality, and the levels of YTHDC2, CCNB1, and CCNB2. We found that Mn can inhibit the YTHDC2/CCNB2 signaling pathway and block the G2/M phase of the cell cycle. Moreover, the morphology of cells and the histomorphology of mice testis were injured. Notably, over-expression (OE) of YTHDC2 increased CCNB2 levels, reduced cell cycle arrest, and improved reproductive toxicity after Mn exposure. These findings suggest that the YTHDC2/CCNB2 signaling pathway participates in Mn-induced reproductive toxicity, and OE of YTHDC2 can mitigate the toxicity of Mn.

CCNB2 is a novel prognostic factor and a potential therapeutic target in low-grade glioma.

BACKGROUND: Cyclin B2 (CCNB2) is an important component of the cyclin pathway and plays a key role in the occurrence and development of cancer. However, the correlation between prognosis of low-grade glioma (LGG), CCNB2, and tumor infiltrating lymphocytes is not clear. METHODS: The expression of CCNB2 in LGG was queried in Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and TIMER databases. The relationships between CCNB2 and the clinicopathological features of LGG were analyzed using the Chinese Glioma Genome Atlas (CGGA) database. The relationship between CCNB2 expression and overall survival (OS) was evaluated by GEPIA2. The correlation between CCNB2 and LGG immune infiltration was analyzed by the TIMER database. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect CCNB2 expression. RESULTS: The expression of CCNB2 differed across different tumor tissues, but was higher in LGG than in normal tissues. LGG patients with high expression of CCNB2 have poorer prognosis. The expression of CCNB2 was correlated with age, WHO grade, IDH mutational status, 1p/19q codeletion status, and other clinicopathological features. The expression of CCNB2 in LGG was positively correlated with the infiltration level of B cells, dendritic cells, and macrophages. qRT-PCR results revealed that the expression of CCNB2 in LGG tissues was higher than normal tissues and higher expression of CCNB2 was associated with worse prognosis. CONCLUSION: CCNB2 may be used as a potential biomarker to determine the prognosis of LGG and is also related to immune infiltration.

Cyclin-dependent kinase 1 as a potential target for lycorine against hepatocellular carcinoma.

The pathological changes and possible underlying molecular mechanisms of hepatocellular carcinoma (HCC) are currently unclear. Effective treatment of this pathological state remains a challenge. The purpose of this study is to obtain some key genes with diagnostic and prognostic meaning and to identify potential therapeutic agents for HCC treatment. Here, CDK1, CCNB1 and CCNB2 were found to be highly expressed in HCC patients and accompanied by poor prognosis, and knockdown of them by siRNA drastically induced autophagy and senescence in hepatoma cells. Simultaneously, the anti-HCC effect of lycorine was comparable to that of interfering with these three genes, and lycorine significantly promoted the decrease both in protein and mRNA expression of CDK1. Molecular validation mechanistically demonstrated that lycorine might attenuate the degradation rate of CDK1 via interaction with it, which had been confirmed by cellular thermal shift assay and drug affinity responsive targets stability assay. Taken together, these findings suggested that CDK1, CCNB1 and CCNB2 could be regarded as potential diagnostic and prognostic biomarkers for HCC, and CDK1 might serve as a promising therapeutic target for lycorine against HCC.

A five-gene methylation signature predicts overall survival of patients with clear cell renal cell carcinoma.

BACKGROUND: In this study, we aimed to screen methylation signatures associated with the prognosis of patients with clear cell renal cell carcinoma (ccRCC). METHODS: Gene expression and methylation profiles of ccRCC patients were downloaded from publicly available databases, and differentially expressed genes (DEGs)-differentially methylated genes (DMGs) were obtained. Subsequently, gene set enrichment and transcription factor (TF) regulatory network analyses were performed. In addition, a prognostic model was constructed and the relationship between disease progression and immunity was analyzed. RESULTS: A total of 23 common DEGs-DMGs were analyzed, among which 14 DEGs-DMGs were obtained with a cutoff value of PCC < 0 and p < 0.05. The enrichment analysis showed that the 14 DEGs-DMGs were enriched in three GO terms and three KEGG pathways. In addition, a total of six TFs were shown to be associated with the 14 DEGs-DMGs, including RP58, SOX9, NF-κB65, ATF6, OCT, and IK2. A prognostic model using five optimized DEGs-DMGs which efficiently predicted survival was constructed and validated using the GSE105288 dataset. Additionally, four types of immune cells (NK cells, macrophages, neutrophils, and cancer-associated fibroblasts), as well as ESTIMATE, immune, and stromal scores were found to be significantly correlated with ccRCC progression (normal, primary, and metastasis) in addition to the five optimized DEGs-DMGs. CONCLUSION: A five-gene methylation signature with the predictive ability for ccRCC prognosis was investigated in this study, consisting of CCNB2, CDKN1C, CTSH, E2F2, and ERMP1. In addition, potential targets for methylation-mediated immunotherapy were highlighted.

CCNB2/SASP/Cathepsin B & PGE2 Axis Induce Cell Senescence Mediated Malignant Transformation.

Glioma is the most frequent and aggressive adult brain tumor with maximum mortality. However, the gene alteration and mechanism underlying malignant transformation of glioma remain largely unknown. We aimed to find key factors regulating tumor progression and malignant transformation of glioma. Here we compared the gene expression profiles of 693 glioma patients by HGG vs. LGG model, and identified a key factor CCNB2 for malignant transformation in glioma. CCNB2 induced a senescence-associated secretory phenotype (SASP) of glioma cells, and the malignant progression, such as invasion and excessive proliferation was mediated by secreting SASP cytokines, Cathepsin B and PGE2. These findings demonstrated a previously undiscovered link between senescence, CCNB2/SASP/Cathepsin B & PGE2 axis and malignant transformation in glioma. This might provide novel insights on developing new therapeutic regimens for abrogating aggressiveness of glioma.

Cyclin B2 (CCNB2) Stimulates the Proliferation of Triple-Negative Breast Cancer (TNBC) Cells In Vitro and In Vivo.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Currently, targeting therapy makes great advances for the treatment of TNBC, whereas more effective therapeutic targets are urgently needed. Cyclin B2 (CCNB2), which belongs to B-type cyclins, is known as a cell cycle regulator. CCNB2 is synthesized at G1 phase in cancer cells and downregulated at anaphase. The defects of CCNB2 led to the abnormal cell cycle and tumorigenesis. Though there are wide effects of CCNB2 on multiple types of tumors, the potential role of CCNB2 in TNBC progression is still unclear. Herein, we found that CCNB2 was highly expressed in human TNBC tissues and correlated with the prognosis and clinical pathological features including tumor size (p = 0.022∗) and pTNM stage (p = 0.021∗) of patients with TNBC. CCNB2 could promote the proliferation of TNBC cells in vitro and in mice. Our findings therefore confirmed the involvement of CCNB2 in TNBC progression and provided the evidence that CCNB2 could serve as a promising molecular target of TNBC.