Cell Cycle最新文献

Small cell lung cancer (SCLC) accounts for approximately 15% of primary lung carcinomas and has the poorest outcome in all subtypes of lung cancer. The major hurdle for SCLC treatment failure is resistance to platinum-based chemotherapy. Therefore, an unmet need is to discover new targets that promote SCLC progression and chemoresistance. Based on the signature of ubiquitination-related genes (URGs), differentially expressed genes between cisplatin-resistant and cisplatin-sensitive SCLC cell lines were identified using the Genomics of Drug Sensitivity in Cancer (GDSC) database. The URGs associated with the prognosis were further screened by Cox and LASSO regression analyses, as well as a Kaplan-Meier survival analysis. The E3 ligase NEDD4 was identified to be associated with cisplatin resistance, poor prognosis and tumor metastasis in SCLC. The functional enrichment analysis indicated that the functions and pathways regulated by NEDD4 were enriched in cell proliferation, cell invasion, as well as ubiquitination and PI3K-AKT pathways in SCLC. The knockdown and overexpression of NEDD4 demonstrated that NEDD4 induced the phosphorylation of AKT in SCLC cells. Cell viability, wound healing and transwell invasion assays demonstrated that NEDD4 promoted the proliferation, chemoresistance and invasion of SCLC cells. These results suggest that NEDD4 is a biomarker of a poor prognosis for SCLC, and that it promotes AKT activation, SCLC progression and chemoresistance.

Globally, gastric cancer (GC) continues to be the primary cause of death due to cancer. This study aimed to investigate the role of THBS1 in GC and assess the potential synergistic effects of Baicalin and THBS1 knockdown on GC cells. Differential expression analysis of GC-related datasets was conducted, and a protein-protein interaction (PPI) network was established. Key targets were screened, and prognostic genes were identified using a Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model. Functional assays assessed the effects of THBS1 knockdown and Baicalin treatment on GC cell behavior and pyroptosis. THBS1 was highly expressed in GC cells, and its knockdown reduced cell behavior, inducing G1 arrest and apoptosis. Combined with Baicalin, these effects were enhanced, synergistically inhibiting GC cell behavior. Detection kits showed that knockdown of THBS1 or baicalin treatment increased lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) levels, while their combination further exacerbated oxidative stress and cell damage. Western blot (WB) analysis revealed that baicalin combined with THBS1 knockdown synergistically promoted pyroptosis by activating the NLRP3 inflammasome and regulating the NF-κB-NLRP3-Caspase-1 axis. In vivo xenograft models demonstrated that THBS1 knockdown or combined treatment with baicalin significantly inhibited GC progression. These results suggest that THBS1 knockdown combined with baicalin can inhibit GC progression by regulating cell behavior, cell cycle, pyroptosis, and the NF-κB-NLRP3-Caspase-1 axis in GC cells. This mechanism is expected to become a new target for GC treatment.

Colorectal cancer (CRC) remains a significant global health concern, and reliable biomarkers are needed to improve early diagnosis, prognostication, and personalized treatment strategies. This study investigated the expression of cell surface proteins and serum exosomal miRNAs in CRC patients. Tissue microarrays (TMAs) constructed from primary and metastatic CRC samples were analyzed for five cell surface proteins: EphB1, EphB3, EphA2, cMet, and EphB4. Immunohistochemistry was performed on the TMAs to validate their expression levels. We found that the distribution of expression for all four receptors, except EphA2, was significantly higher (p < 0.01) in CRC samples compared to non-cancerous tissue. High expression of EphB3 was detected in 37% of patient samples, followed by cMet, which was observed in 35%. Exosomes were isolated from the serum of three CRC patients with tumors exhibiting high expression of LGR5 and/or EphB3, four healthy donors and two CRC cell lines. Serum exosomal miRNA analysis identified miR-3168 as significantly upregulated in CRC patients, showing a 3.8-fold increase compared to healthy controls (p < 0.001) and a 2.6-fold increase in CRC cell lines compared to controls (p = 0.02). Ingenuity Pathway Analysis (IPA) suggested that miR-3168 may regulate cMet, EphB3, and EphB4, along with other CRC-associated molecules and pathways. These findings highlight the potential of EphB3 and cMet as biomarkers in CRC, and miR-3168 as a promising minimally-invasive biomarker for monitoring disease progression and therapeutic response. However, further validation in larger cohorts is needed to establish their clinical utility.

Gallbladder cancer (GBC) is a biliary tract cancer with a poor prognosis. Consistent evidence suggests that fasting has extensive antitumor effects in various cancers and influences levels of poly (rC)-binding protein 2 (PCBP2). However, whether fasting and PCBP2 are involved in GBC remains unknown. We assessed the expression of PCBP2 in GBC tumor tissues and cells. Knockdown and overexpression of PCBP2, combined with in vitro and in vivo assays using fasting mimic medium or diets, were conducted to provide functional significance. The effect of PCBP2 on glycolysis was assessed by glucose uptake, lactate production, oxygen consumption rate, and limiting glycolytic-associated enzymes (PDK1, PKM2, and HK-2). We found that fasting could inhibit glycolysis and cell migration/invasion in GBC cells and that fasting mimic diets could significantly inhibit GBC cell proliferation in a mouse xenograft model. PBCP2 was upregulated in GBC tumor tissues and cells. Moreover, PCBP2 is a key downstream target of fasting, and fasting decreases PCBP2 expression in GBC cells. PCBP2 knockdown inhibits GBC cell proliferation, migration/invasion, and glycolysis, whereas PCBP2 overexpression has the opposite effect. Through co-immunoprecipitation, we identified a physical connection between PCBP2 and the angiopoietin-like protein ANGPTL4. PCBP2 can negatively regulate the expression of ANGPTL4. Hence, fasting inhibits cell proliferation, migration/invasion, and glycolysis through PCBP2/ANGPTL4 signaling. We conclude that PCBP2 is a target of fasting and is involved in cell migration/invasion and glycolysis through the negative regulation of ANGPTL4 in GBC. PCBP2 represents a potential therapeutic target for GBC.

This study aimed to explore key regulatory molecules involved in metabolic alterations clarify the heterogeneity of glioblastoma and develop novel therapeutic strategies. The microarray dataset GSE45117 was retrieved from the Gene Expression Omnibus database to analyze differentially expressed genes (DEGs) glioma stem cell (GSC) populations were enriched via microsphere suspension culture and ALDH+ cell sorting in vitro with the expression of the uridine-cytidine kinase 2 (UCK2) gene compared between stemness and non-stemness populations the UCK2 gene was stably knocked down or overexpressed in GSCs to assess cell invasion migration glucose uptake lactate production and ATP levels. Database analysis revealed high UCK2 expression in cancer stem cells (CSCs) manipulating UCK2 levels affected stemness factors and cell behaviors including proliferation migration invasion and tumor growth UCK2 was more abundant in hypoxic central tumor regions promoting increased glucose uptake and energy production knocking down UCK2 reduced glycolysis and stem cell properties under hypoxia mechanistically UCK2 stabilizes PI3K protein through deubiquitination thereby activating the Akt/HIF-1α pathway. UCK2 plays a pivotal role as a metabolic regulator in glucose metabolism by stabilizing PI3K protein expression via deubiquitination which in turn activates the Akt/HIF-1α signaling pathway.

Growth Hormone-Releasing Hormone and Somatostatin exert opposing activities in Growth Hormone (GH) regulation. Herein - and based on recent findings - we provide our insights on the potential therapeutic role of GH suppression on endothelium-dependent disorders.

Ultraviolet radiation is a major factor in causing skin aging. Compared to younger individuals, older adults exhibit a significant imbalance in the M1/M2 macrophage ratio, with an elevated proportion of M1 macrophages, but little is known about the role of macrophages in skin aging. Here, we report the critical role of M2 macrophages and PKM2 in preventing fibroblast photoaging. UVB-treated photoaged fibroblasts showed a reduction in PKM2. Compared to M1 macrophages, treatment with M2 macrophage significantly alleviated this photoaging and enhanced PKM2 synthesis in fibroblasts. Mechanistically, this is due to the secretion of CCL1 by M2 macrophages, which acts on the CCR8 receptor on the cell surface, promoting PKM2 production in photoaged fibroblasts. This further activates the TGF-β1/Smad2 pathway, thereby reducing cellular aging. This provides a potential strategy for the treatment of skin photoaging.

FAM3 metabolism-regulating signaling molecule A (FAM3A) is a mitochondrial protein belonging to the FAM3 gene family with the potential for the treatment of ischemic diseases. FAM3A promotes adenosine triphosphate (ATP) production and improves mitochondrial function by increasing ATP synthase activity and activating the protein kinase B-cyclic AMP-responsive element binding protein-forkhead box D3-ATP synthase regulatory loop, thereby reducing reactive oxygen species production and inhibiting oxidative stress-induced cell death. Additionally, FAM3A activates the nuclear factor erythroid 2-related factor 2 signaling pathway and upregulates the expression of antioxidant proteins, further enhancing the cellular oxidative defense capacity. During angiogenesis, FAM3A positively regulates vascular endothelial growth factor A and promotes endothelial cell migration, proliferation, and tube formation. FAM3A is closely related to atherosclerosis, ischemic encephalopathy, liver ischemia - reperfusion injury, myocardial ischemia, and acute kidney injury. FAM3A plays a role in the course of these diseases via multiple mechanisms, including the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, effectively reducing the inflammatory response and oxidative stress, and influencing disease development. This review comprehensively examines the role of FAM3A in the pathophysiological processes of ischemic diseases across various organs.

NRF2, a crucial antioxidant transcription factor in ovarian cancer (OC), is closely associated with CEBPB activation. However, the regulatory mechanism of NRF2 by CEBPB in OC remains poorly understood. In this study, we systematically evaluated the malignant behavior of SKOV3 and A2780 cells through comprehensive approaches, including CCK-8 kits, clone formation assays, and flow cytometry analysis. Cellular antioxidant capacity was quantitatively assessed using the DCFH-DA and total-antioxidant capacity (T-AOC) assays. Molecular mechanisms were investigated through multiple experimental approaches: the interaction between NRF2 and the DUSP1 promoter was examined using dual fluorescence reporter assays, while the activation status of CEBPB, NRF2, DUSP1, antioxidant proteins, and MAPK pathway components was analyzed via immunofluorescence and western blotting. Our findings demonstrate that CEBPB overexpression significantly enhanced cellular proliferation, clone formation, cell cycle progression, and antioxidant capacity, while simultaneously reducing apoptosis rates and reactive oxygen species (ROS) levels. Conversely, CEBPB knockdown or NRF2 inhibition produced opposing effects. These results establish that CEBPB-mediated NRF2 activation promotes OC cell proliferation and antioxidant defense mechanisms. Mechanistically, we identified that NRF2 directly binds to the DUSP1 promoter, as confirmed by dual-luciferase reporter assays. NRF2 activation led to upregulation of DUSP1 and phosphorylated ERK1/2 levels, while downregulating JNK and p38 phosphorylation. These findings were further validated in vivo, confirming that CEBPB activates NRF2 to regulate the MAPK pathway through DUSP1, thereby promoting OC cell proliferation and antioxidant capacity. In conclusion, our study reveals a novel regulatory axis in which CEBPB activates NRF2 to regulate the MAPK pathway via DUSP1, driving malignant progression and enhancing antioxidant activity in OC.

The cell-cycle regulated methyltransferase SET8 is the sole enzyme responsible for the mono-methylation of histone H4 at lysine 20 (H4K20) that is the substrate for di- and trimethylation mainly by SUV4-20Hs enzymes. Both SET8 and SUV4-20Hs have been implicated in regulating DNA repair pathway choice through the inverse affinities of BRCA1-BARD1 and 53BP1 complexes for disparate methylation states of H4K20. However, the precise and respective functions of each H4K20 methyltransferase in DNA repair pathways remain to be clarified. Here, we show that SET8 acts as a potent chromatin inhibitor of homologous recombination and that its timely degradation during DNA replication is essential for the spontaneous nuclear focal accumulation of BRCA1 and RAD51 complexes during the S phase. Strikingly, the anti-recombinogenic function of SET8 is independent of SUV4-20H activity but requires the subsequent recruitment of the ubiquitin ligase RNF168. Moreover, we show that SET8-induced BRCA1 inhibition is not necessarily related to the loss of BARD1 binding to unmethylated histone H4K20. Instead, it is largely caused by the accumulation of 53BP1 in a manner depending on the concerted activities of SET8 and RNF168 on chromatin. Conversely, the lack of SET8 and H4K20 mono-methylation on newly assembly chromatin after DNA replication led to the untimely accumulation of BRCA1 on chromatin at the subsequent G1 phase. Altogether, these results establish the de novo activity of SET8 on chromatin as a primordial epigenetic lock of the BRCA1-mediated HR pathway during the cell cycle.