Cell Cycle最新文献

The clinical outcomes of acute myeloid leukemia (AML) patients exhibit substantial heterogeneity, with relapse posing a formidable challenge. Herein, we developed a risk score model by integrating relapse-related genes through Cox regression analysis. The relapse-related genes were identified via differential gene expression analysis of 15 matched diagnosed and relapsed AML samples retrieved from the Gene Expression Omnibus (GEO) database. These genes include SCN9A, CFH, CD34, and CALCRL. Our findings demonstrate that higher risk scores were significantly associated with an unfavorable ELN2017 risk classification, leukemic transformation, as well as FLT3-ITD and RUNX1 mutations. Conversely, lower risk scores were linked to NPM1 mutation. Patients with higher risk scores had a shorter overall survival (OS). Furthermore, we integrated the risk score model with the European LeukemiaNet (ELN) risk classification to establish a novel composite risk classification scheme. Patients were classified into three new risk groups based on composite risk classification showing significantly distinct OS. In summary, the four-gene risk score holds promise in predicting the OS of AML patients, and the composite risk classification shows greater potential in predicting the outcomes of AML patients. These four genes may represent potential therapeutic targets in the treatment of AML.

Leucine zipper proteins are transcription factors that regulate gene activity through DNA binding and creating stable pairs. They are located in particular tissues and are involved in significant processes like metabolism, immunity, and stress response. The C/EBPβ (CCAAT/Enhancer-Binding Proteins), which is predominantly active in the liver and spleen, regulates metabolism and immune activity. The GILZ (glucocorticoid-induced leucine zipper), which is located in the brain, lungs, immune cells, and reproductive system, may protect against inflammation and stress. Hormonal signals or oxidative stress may cause these proteins to be activated and transported to the nucleus to turn off or turn on the genes. The disruption of balance, such as the loss of GILZ, drives inflammation, which may cause diseases. Therapies include small molecules, peptides, or DNA decoy therapy. The selective control of these proteins via biomarker profiling and targeted tissue delivery has potential in mitigating cancer, inflammatory, and metabolic diseases.

Bacterial proteins released into the cellular microenvironment are increasingly recognized as pivotal modulators of host key signaling pathways, with significant implications for cellular functions. This review explores the multifaceted roles of such bacterial proteins, often functioning as virulence factors, in modulating the host cell cycle. By focusing on the interactions between selected bacterial proteins and essential components of the cell cycle machinery, we describe the mechanisms through which these interactions disrupt relevant cellular functions and contribute to disease development, with a particular focus on cancer.

Cyclin-dependent kinases CDK8 and CDK19 together with their activating partner, cyclin C, regulate gene expression as a part of the Mediator complex and by phosphorylating DNA sequence-specific transcription factors. Here, we investigated the in vivo requirement for Cdk8 and Cdk19 in hematopoiesis by generating double knockout (DKO) mice lacking Cdk8 and Cdk19 expression in hematopoietic cells. DKO mice displayed relatively normal hematopoiesis and largely unperturbed gene expression in the bone marrow, indicating that the Mediator kinases are not essential for the regulation of gene expression during hematopoiesis. However, DKO mice showed an expansion of splenic macrophages. Bone marrow-derived DKO macrophages displayed an increased expression levels of both M1-like and M2-like markers, altered cytokine secretion, deregulated gene expression, precocious cell cycle exit and impaired Fc-mediated phagocytosis. Our findings reveal a highly cell type-specific role of Cdk8/19 in gene transcription during hematopoiesis.

Cisplatin (DDP) resistance substantially compromises treatment efficacy in lung adenocarcinoma (LUAD). This study investigates the role of mitochondrial long non-coding RNA (lncRNA) H19 in mediating DDP resistance. High-throughput sequencing and RT-qPCR analyses revealed pronounced H19 upregulation in DDP-resistant A549 (A549/DDP) cells relative to parental A549 cells. Subcellular localization studies indicated that H19 is primarily nuclear in A549 cells but translocates to mitochondria in A549/DDP cells. Functional assays demonstrated that H19 silencing in resistant cells attenuated chemoresistance, suppressed proliferation, migration, invasion, and colony formation in vitro, and delayed tumor growth in vivo. H19 knockdown impaired mitophagy and promoted apoptosis, mirroring autophagy inhibition and restoring DDP sensitivity. In contrast, H19 overexpression in A549 cells did not significantly alter mitophagy or cellular behavior. Furthermore, H19 silencing induced its relocalization from mitochondria back to the nucleus in resistant cells, while overexpression did not affect its nuclear localization. These findings establish that H19 translocation to mitochondria promotes DDP resistance, and its downregulation reverses this process by inhibiting mitophagy and resensitizing cells to DDP. As a nucleus-encoded mitochondria-associated lncRNA (ntmtlncRNA), H19 mediates intercompartmental communication, highlighting its potential as a therapeutic target for overcoming DDP resistance in LUAD.

Cyclin-dependent kinase subunit 2 (CKS2) has been implicated in various malignancies. This study investigates the mechanism by which CKS2 contributes to bladder cancer (BC) progression. Abnormally expressed genes were identified by differential analysis of tumor and normal tissues using Gene Expression Omnibus datasets. Subsequently, functional assays - including cell proliferation, Transwell migration, colony formation, wound healing, flow cytometry, and enzyme-linked immunosorbent assays - were performed to provide cellular evidence supporting the oncogenic function of CKS2 in BC. The results demonstrated significantly elevated CKS2 expression in BC cells than in normal urothelial cells. CKS2 overexpression promoted cell proliferation, cell migration and invasion. Mechanistically, CKS2 overexpression caused a marked reduction in PTEN protein levels, thereby inhibiting PIP3 degradation and indirectly activating the PI3K/AKT signaling pathway. Furthermore, CKS2 promoted phosphorylation and degradation of p27 Kip1 (Thr187), consequently contributing to cell cycle deregulation and further enhancing PI3K/AKT pathway activity. In contrast, CKS2 knockdown produced the opposite effects. Notably, treatment with the PI3K inhibitor LY294002 effectively reversed CKS2-induced BC cell proliferation and metastasis. In conclusion, CKS2 promoted the malignant phenotypes of BC cells by enhancing PI3K/AKT pathway activity through dual mechanisms involving PTEN downregulation and p27 Kip1-mediated cell cycle dysregulation.

Background: This study aimed to investigate the expression pattern of astrocyte-derived STC1 in TLE and elucidate the molecular mechanisms by which STC1 regulates neuroinflammation and seizures through the NF-κB signaling pathway.

Methods: A TLE model was established by intrahippocampal injection of kainic acid (KA) in mice. STC1 expression levels and cellular localization in the hippocampus of TLE mice were examined. Adeno-associated virus-mediated gene overexpression and shRNA knockdown approaches were employed to investigate the effects of STC1 on neuroinflammatory responses, neuronal survival, and seizure activity. qRT-PCR and immunofluorescence methods were further utilized to evaluate inflammatory cytokine levels and NF-κB signaling pathway activity.

Results: STC1 expression was upregulated in hippocampal tissues of TLE mice, with double immunofluorescence showing STC1 predominantly localized in GFAP-positive reactive astrocytes. STC1 overexpression significantly exacerbated KA-induced neuroinflammation, along with enhanced microglial activation. STC1 knockdown attenuated neuroinflammatory responses. Nissl staining and NeuN immunohistochemistry confirmed that STC1 aggravated KA-induced neuronal loss. STC1 overexpression promoted p65 phosphorylation and nuclear translocation, activating the NF-κB signaling pathway.

Conclusion: This study reveals the molecular mechanism by which astrocyte-derived STC1 promotes TLE-associated neuroinflammation and neuronal injury through activation of the NF-κB signaling pathway, elucidating the crucial role of the astrocyte-STC1-NF-κB axis in epileptogenesis.

Paclitaxel is a widely used chemotherapeutic agent that plays a vital role in the treatment of various cancers, including breast, ovarian, and lung cancers. Despite its success, the development of resistance significantly limits its long-term efficacy. Paclitaxel resistance involves a range of molecular mechanisms, including alterations in drug transport, mutations in β-tubulin, and activation of pro-survival signaling pathways. Recent studies have highlighted the crucial role of circular RNAs (circRNAs) in mediating paclitaxel resistance. CircRNAs are characterized by their stable, covalently closed structures, which protect them from exonuclease degradation. They regulate drug resistance through various mechanisms, including modulating transcription factors and influencing cellular processes such as apoptosis, immune response, and cancer stem cell dynamics by sponging microRNAs. This review focuses on the mechanisms by which circRNAs contribute to paclitaxel resistance and discusses their dual roles as both oncogenes and tumor suppressors. Furthermore, we explore the potential of circRNAs as novel therapeutic targets to overcome paclitaxel resistance. By targeting specific circRNAs or restoring tumor-suppressive circRNAs, it may be possible to enhance paclitaxel sensitivity and improve treatment outcomes. Future research is essential to further understand the role of circRNAs in paclitaxel resistance and to develop effective circRNA-targeted therapies for cancer treatment.

Triple-negative breast cancer (TNBC) poses challenges in treatment due to its inherent biological characteristics. Endoplasmic reticulum stress (ERS) has been associated with the development of TNBC. Hence, identifying ERS-related prognostic biomarkers is crucial for the early diagnosis and treatment of TNBC. In this study, we retrieved gene expression profiles from TNBC patients using The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) between TNBC tumor and normal tissues were identified using limma package. Using differential expression analysis, we identified 46 ERS-related DEGs. Through univariate Cox, LASSO, and multivariate COX regression analyses, we constructed a prognostic model consisting of 8 genes (IGFBP1, CFTR, THBS4, CREBRF, CLU, HDGF, DERL3, NCCRP1). This model demonstrated robust prognostic accuracy in TNBC patients, validated by the METABRIC dataset. Among the 8 prognostic genes, NCCRP1 showed the highest expression increase in BT-20 and MDA-MB-468 cells. Functional assays further revealed that NCCRP1 significantly promoted proliferation, migration, and invasion, while suppressing apoptosis and ERS in these TNBC cell lines. Our study highlights a strong association between ERS-related genes and the prognosis of TNBC patients. Moreover, we demonstrated that NCCRP1 exerts oncogenic effects in TNBC cells. It provides new insights and possible treatment targets for TNBC.

TGFβ functions as a tumor suppressor or promoter, depending on the context, making TGFβ a useful predictive biomarker. Genes related to TGFβ signaling and Aurora kinase were tested for their ability to predict the progression risk of primary prostate tumors. Using data from The Cancer Genome Atlas (TCGA), we trained an elastic-net regularized Cox regression model including a minimal set of gene expression, copy number (CN), and clinical data. A multi-step feature selection and regularization scheme was applied to minimize the number of features while maintaining predictive power. An independent hold-out cohort was used to validate the model. Expanding from prostate cancer, predictive models were similarly trained on all other eligible cancer types in TCGA. AURKA, AURKB, and KIF23 were predictive biomarkers of prostate cancer progression, and upregulation of these genes was associated with promotion of cell-cycle progression. Extending the analysis to other TCGA cancer types revealed a trend of increased predictive performance on validation data when clinical features were complemented with molecular features, with notable variation between cancer types and clinical endpoints. Our findings suggest that TGFβ signaling genes, prostate cancer related genes and Aurora kinases are strong candidates for patient-specific clinical predictions and could help guide personalized therapeutic decisions.