Cellular signalling最新文献

{"title":"Dapagliflozin activates the RAP1B/NRF2/GPX4 signaling and promotes mitochondrial biogenesis to alleviate vascular endothelial ferroptosis","authors":"Yi Zhu ,&nbsp;Jin Yang ,&nbsp;Jia-li Zhang ,&nbsp;Hao Liu ,&nbsp;Xue-jiao Yan ,&nbsp;Ji-yong Ge ,&nbsp;Fang-fang Wang","doi":"10.1016/j.cellsig.2025.111824","DOIUrl":"10.1016/j.cellsig.2025.111824","url":null,"abstract":"<div><div>Vascular endothelial ferroptosis is a key mechanism underlying endothelial injury and atherosclerotic plaque formation. Dapagliflozin, an essential medication in the management of heart failure, has been shown to delay atherosclerosis progression. However, the underlying mechanisms remain unclear. This study aimed to elucidate the molecular pathways whereby dapagliflozin inhibits vascular endothelial ferroptosis. We utilized human umbilical vein endothelial cells (HUVECs) to construct a cell model of atherosclerosis combined with ferroptosis. Dapagliflozin significantly decreased the iron and malondialdehyde levels and the release of inflammatory factors in HUVECs treated with oxidized low-density lipoprotein or Erastin but increased the superoxide dismutase activity and the reduced glutathione / oxidized glutathione ratio. Results from transmission electron microscopy indicated that dapagliflozin alleviated the mitochondrial shrinkage and the reduction in the number of cristae in these HUVECs. RNA sequencing revealed that dapagliflozin upregulates <em>RAP1B</em>. In vitro experiments showed that RAP1B upregulates NRF2 and promotes its nuclear translocation, activating the xCT/GPX4 signaling pathway and inhibiting lipid peroxidation. Additionally, dapagliflozin induces mitochondrial biogenesis and enhances oxidative phosphorylation through the RAP1B/NRF2 pathway, reducing iron overload and excessive production of mitochondrial reactive oxygen species, ultimately mitigating ferroptosis. At the animal level, we constructed an atherosclerosis model by using <em>Apoe</em>^−/−; <em>Rap1b</em>^−/− double-knockout mice. <em>Rap1b</em> knockout blocked the inhibitory effects of dapagliflozin on atherosclerotic plaque formation and ferroptosis activation. We confirmed in vivo that dapagliflozin upregulates GPX4 and key factors of mitochondrial biogenesis via RAP1B, promoting oxidative phosphorylation. When mitochondrial oxidative phosphorylation was pharmacologically inhibited, ferroptosis was reactivated, promoting atherosclerotic plaque formation. In conclusion, this study demonstrated that dapagliflozin activates the RAP1B/NRF2/GPX4 signaling pathway and promotes mitochondrial biogenesis, thereby alleviating vascular endothelial ferroptosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111824"},"PeriodicalIF":4.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LAPTM5 confers cisplatin resistance in NSCLC by suppressing LAMP1 ubiquitination to stabilize lysosomal membranes and sustain autophagic flux","authors":"Fan Wu ,&nbsp;Chunlan Li ,&nbsp;Xianrang Song ,&nbsp;Li Xie","doi":"10.1016/j.cellsig.2025.111834","DOIUrl":"10.1016/j.cellsig.2025.111834","url":null,"abstract":"<div><div>Cisplatin is a widely used chemotherapeutic agent in the treatment of non-small cell lung cancer (NSCLC), but cisplatin resistance remains a significant clinical challenge. Lysosomal transmembrane protein 5 (LAPTM5) is a lysosomal membrane protein implicated in macroautophagy/autophagy, although its precise mechanism has yet to be fully elucidated.In this study, we demonstrated that LAPTM5 promotes cisplatin resistance in NSCLC by maintaining lysosomal membrane stability and preserving autophagic flux. Mechanistic investigations showed that LAPTM5 competes with LAMP1 for binding to WWP2, thereby inhibiting LAMP1 ubiquitination and degradation, which ultimately preserves lysosomal membrane stability. LAPTM5 knockdown increases lysosomal membrane permeability, leading to the release of cathepsin D (CTSD), which elevates intracellular reactive oxygen species (ROS) levels; further destabilizing the lysosomal membrane and accelerating cell death. Our findings elucidate the mechanism by which LAPTM5 contributes to cisplatin resistance through lysosomal membrane stabilization and identify LAPTM5 as a potential therapeutic target for overcoming cisplatin resistance in NSCLC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111834"},"PeriodicalIF":4.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MDL800, a SIRT6 activator, mitigates neuroinflammation-induced retinal damage by modulating microglial M1/M2 polarization in experimental glaucoma","authors":"Fangyuan Hu ,&nbsp;Daowei Zhang ,&nbsp;Jihong Wu","doi":"10.1016/j.cellsig.2025.111832","DOIUrl":"10.1016/j.cellsig.2025.111832","url":null,"abstract":"<div><h3>Purpose</h3><div>Glaucoma is a group of irreversible neurodegenerative disorders of the optic nerve, characterized by distinct optic nerve damage and progressive visual field loss, with its pathological foundation involving the apoptosis of retinal ganglion cells (RGCs) and axonal degeneration. Neuroinflammation driven by the polarization of retinal microglia significantly contributes to RGCs apoptosis. This study investigates the neuroprotective effects of the SIRT6 activator MDL800 on microglial polarization in experimental glaucoma.</div></div><div><h3>Methods</h3><div>We used a lipopolysaccharide (LPS)-induced BV2 microglial inflammation model and an ocular hypertension (OHT) rat model. The regulatory effects of MDL800 on BV2 cell M1/M2 polarization were evaluated. After inhibiting SIRT6, MDL800's impact on MAPK and AMPK-Nrf2-HO-1/NQO-1 pathways was studied. A co-culture system of BV2 cells and retinal precursor cells R28 was established to observe the effect of MDL800-regulated BV2 cell polarization on R28 cell survival. In the rat model, the effects of MDL800 on microglial polarization, retinal structure, and RGCs apoptosis in glaucoma were assessed.</div></div><div><h3>Results</h3><div>MDL800 facilitated BV2 cell polarization from M1 to M2 under LPS stimulation, exerting anti-inflammatory effects. It activated SIRT6 to regulate BV2 cell polarization by inhibiting the MAPK pathway and activating the AMPK-Nrf2-HO-1/NQO-1 axis. In a co-culture system of BV2 cells and R28 cells, MDL800 regulated the release of LPS-induced inflammatory factors by mediating the polarization of BV2 cells, which in turn inhibited the mitochondrial apoptotic pathway in R28 cells and promoted their survival. In the OHT rat model, MDL800 significantly inhibited retinal microglia proliferation and activation, promoted their polarization from M1 to M2, and reduced RGCs apoptosis.</div></div><div><h3>Conclusions</h3><div>MDL800 shows promise for clinical development and treatment of glaucoma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111832"},"PeriodicalIF":4.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of NNMT affects trophoblast function via inhibiting COMP/CD36/ERK1/2 axis in recurrent spontaneous abortion","authors":"Jialyu Huang ,&nbsp;Zhengwei Wan ,&nbsp;Jiaqi Li ,&nbsp;Xiangpeng Xiong ,&nbsp;Ruiyin Jiang ,&nbsp;Bin Yang ,&nbsp;Chaoyi Xiong ,&nbsp;Hong Chen ,&nbsp;Xinxia Wan ,&nbsp;Qimei Luo ,&nbsp;Yan Zhao ,&nbsp;Jiaying Lin ,&nbsp;Xiaoyan Ai","doi":"10.1016/j.cellsig.2025.111831","DOIUrl":"10.1016/j.cellsig.2025.111831","url":null,"abstract":"<div><div>Recurrent spontaneous abortion (RSA) is closely associated with trophoblast dysfunction, yet the underlying regulatory mechanisms remain poorly understood. Herein, we found a significantly decreased level of nicotinamide <em>N</em>-methyltransferase (NNMT) in RSA villous tissues compared to normal pregnancies. NNMT knockdown suppressed trophoblast proliferation, migration and invasion <em>in vitro</em>, and increased embryo absorption rate <em>in vivo</em>. Upstream of NNMT, FOXA1 was identified as its transcriptional regulator, which was also downregulated in RSA villous tissues. Mechanistically, reduced NNMT led to the accumulation of methyl donor S-adenosyl methionine, thus promoting the methylation of histone H3 at lysine 27. This epigenetic modification further inhibited the expression of cartilage oligomeric matrix protein (COMP), along with its binding to CD36 receptor and subsequent activation of ERK1/2 pathway in trophoblast. Together, our study demonstrates the crucial role of NNMT at the maternal-fetal interface, provides mechanistic insights into the pathogenesis of RSA, and lays a basis for developing targeted therapies.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111831"},"PeriodicalIF":4.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of FUN14 domain-containing 1 enhances the migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis through mitochondrial dysregulation","authors":"Ye Lu ,&nbsp;Ya-Xiong Fang ,&nbsp;Zhi-Ming Ou-Yang ,&nbsp;Tao Wu ,&nbsp;Qian Zhang ,&nbsp;Yao-Wei Zou ,&nbsp;Hu-Wei Zheng ,&nbsp;Jun Jing ,&nbsp;Le-Hang Lin ,&nbsp;Jian-Da Ma ,&nbsp;Zhuoyi Liang ,&nbsp;Lie Dai","doi":"10.1016/j.cellsig.2025.111829","DOIUrl":"10.1016/j.cellsig.2025.111829","url":null,"abstract":"<div><h3>Background</h3><div>Fibroblast-like synoviocytes (FLS) display aggressive phenotypes contributing to synovitis and joint destruction in rheumatoid arthritis (RA). Disrupted mitochondrial homeostasis has been proposed to aggravate the RA pathogenesis, however, the underlying mechanism remains to be elucidated. This study aimed to elucidate the role of mitophagy receptor FUN14 domain-containing 1 (FUNDC1) on RA-FLS migration and invasion.</div></div><div><h3>Methods</h3><div>We analyzed the correlation of synovial FUNDC1 expression with joint destruction and disease activity in RA patients. Single cell sequencing data analysis combined with immunofluorescence indicated the specific expression and localization of FUNDC1 in synovial tissue and RA-FLS. The roles of FUNDC1 in the migration, invasion, and cytokine secretion of RA-FLS were examined by patient-derived primary culture as well as SCID mouse models. We investigated the effects and mechanism of FUNDC1 on mitophagy and mitochondrial quality control network in primary RA-FLS.</div></div><div><h3>Results</h3><div>We found that the FUNDC1 was mainly expressed in FLS and exhibited a decreased level in RA synovium, which was correlated with severe joint destruction. Deficiency of FUNDC1 enhanced migration, invasion as well as secretion of matrix metalloproteinases in RA-FLS. On the contrary, overexpression of FUNDC1 in RA-FLS with low FUNDC1 inhibited the migration, invasion and secretion capacity of RA-FLS. Mechanistically, repressed FUNDC1 level in RA-FLS impaired mitophagy, imbalanced mitochondrial quality control, and increased mitochondrial reactive oxygen species (mtROS) production, leading to the overactivation of the MAPK pathway. Treatment with mtROS scavenger mtTEMPO can reverse this process and diminish the invasiveness of RA-FLS.</div></div><div><h3>Conclusions</h3><div>Deficiency of FUNDC1 dysregulates mitochondrial quality-control system and induces aggressive phenotype of RA-FLS, resulting in joint destruction during RA progression.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111829"},"PeriodicalIF":4.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"tRF-3019A/STAU1/BECN1 axis promotes autophagy and malignant progression of colon cancer","authors":"Xiwei Yuan ,&nbsp;Wei Li ,&nbsp;Jingjing Li ,&nbsp;Wujun Zhang ,&nbsp;Yue Xiong ,&nbsp;Han Tang ,&nbsp;Baozhen Lan ,&nbsp;Jinye Huang ,&nbsp;Ye Chen ,&nbsp;Wei Liu ,&nbsp;Chuanyi Zhou","doi":"10.1016/j.cellsig.2025.111813","DOIUrl":"10.1016/j.cellsig.2025.111813","url":null,"abstract":"<div><h3>Background</h3><div>Tumor incidence, progression, and metastasis may be linked to the aberrant levels of novel non-coding RNA tRNA-derived fragments (tRFs). Uncertainty surrounds the role and possible mechanism of tRF-3019 A in causing colon cancer to proceed malignantly.</div></div><div><h3>Methods</h3><div>By using qRT-PCR, transcription levels of tRF-3019 A were found in colon cancer cell lines and clinical samples. Locked nucleic acid (LNA)-tRF-3019 A or small molecule mimic was utilized to control the levels of tRF-3019 A in cells, and the CCK8 test was employed to assess the cells' capacity for proliferation. The rate of cell migration and invasiveness were assessed using the Transwell Assay. GFP-LC3B formation was seen using fluorescence microscopy, and autophagy-related protein expression was found using western blot analysis. The interactions between STAU1 and BECN1 and between tRF-3019 A and STAU1 were confirmed by RNA pull-down assay and RNA immunoprecipitation analyses. The mRNA and protein expression of STAU1 and BECN1 were found using qRT-PCR and western blot (WB). A xenograft tumor model was constructed to observe the growth of mouse tumors. qRT-PCR was used to detect the transcription levels of tRF-3019 A, STAU1, and BECN1, while WB was used to detect the expression of STAU1, BECN1, autophagy-related proteins, and epithelial-mesenchymal transition (EMT) -related proteins in tumor tissues.</div></div><div><h3>Results</h3><div>In colon cancer tissues and cells, tRF-3019 A was overexpressed, and by triggering autophagy, it may encourage cell division, migration, and invasion. From a mechanistic perspective, tRF-3019 A competitively bound to the STAU1 protein with BECN1 mRNA, thereby enhancing the stable expression of the autophagy-related protein BECN1. In the model of xenograft tumor mice with knockdown of STAU1, blocking tRF-3019 A led to a substantial decrease in the pace of tumor development, a reduction in the expression of EMT-related proteins and autophagy, and an inhibition of autophagy.</div></div><div><h3>Conclusion</h3><div>tRF-3019A activated tumor cell autophagy and promoted the malignant progression of colon cancer by competitively binding to the STAU1 protein with BECN1 mRNA.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111813"},"PeriodicalIF":4.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HnRNPR promotes non-small cell lung cancer progression by protecting XB130 mRNA from XRN1- and DIS3L2-mediated degradation","authors":"Qin-Rong Wang ,&nbsp;Ling-Ling Liu ,&nbsp;Xuan-Jing Gou ,&nbsp;Ying Liu ,&nbsp;Yan Zhao ,&nbsp;Ting Zhang ,&nbsp;Yin-Hui Jiang ,&nbsp;Jian-Jiang Zhou ,&nbsp;Jiang-Lun Li ,&nbsp;Jian Zhang ,&nbsp;Yuan Xie","doi":"10.1016/j.cellsig.2025.111816","DOIUrl":"10.1016/j.cellsig.2025.111816","url":null,"abstract":"<div><div>The adaptor protein XB130 is critically implicated in tumorigenesis. However, the mechanisms regulating its expression in tumors are not well understood. Our previous studies have identified hnRNPR as a potential binding protein of XB130 3’UTR in non-small cell lung cancer (NSCLC). This study aimed to clarify hnRNPR's role in NSCLC progression and its specific mechanisms regulating XB130 expression. The expression of hnRNPR in NSCLC and normal tissues was assessed using NSCLC tissue microarray and the TCGA database. Subsequently, in vitro and in vivo experiments were conducted to investigate the impact of hnRNPR on NSCLC cell proliferation and epithelial-mesenchymal transition (EMT) by modulating XB130 expression. The underlying molecular mechanisms of hnRNPR regulating XB130 expression were explored utilizing a range of molecular biology techniques including Western blotting, Real-time quantitative PCR, Immunohistochemistry, Dual-luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation. We identified the overexpression of hnRNPR in NSCLC, with heightened hnRNPR levels significantly associated with poor prognosis in patients with lung adenocarcinoma. Functionally, hnRNPR overexpression promoted NSCLC cell proliferation and EMT and activated the Akt signaling pathway. Mechanistically, hnRNPR protected XB130 mRNA from XRN1- and DIS3L2-mediated degradation by binding to specific regions within XB130 3’UTR, consequently elevating XB130 expression. Lastly, XB130 overexpression counteracted the effects of hnRNPR silencing on NSCLC cells. Overall, our study unveils the potential of targeting the hnRNPR/XB130 axis as a promising therapeutic strategy for NSCLC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111816"},"PeriodicalIF":4.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking PSMD14-mediated E2F1/ERK/AKT signaling pathways suppresses the progression of anaplastic thyroid cancer","authors":"Yuxuan Wang ,&nbsp;Yuansheng Duan ,&nbsp;Kai Yue ,&nbsp;Linqi Li,&nbsp;Jiayan Cao,&nbsp;Weifeng Shi,&nbsp;Jin Liu,&nbsp;Yansheng Wu,&nbsp;Xudong Wang,&nbsp;Chao Jing","doi":"10.1016/j.cellsig.2025.111826","DOIUrl":"10.1016/j.cellsig.2025.111826","url":null,"abstract":"<div><div>Anaplastic thyroid cancer (ATC) is the most aggressive subtype of thyroid cancer with few effective therapeutic strategies. Recent studies have identified the deubiquitinating enzyme (DUB) 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) as a promising therapeutic target for multiple cancers; however, the role of PSMD14 in ATC remains largely unknown. Here, we found that PSMD14 was upregulated in ATC tissues and that its aberrant expression was negatively associated with the overall survival of patients with ATC. Functionally, PSMD14 promotes the proliferation and invasiveness of ATC cells, whereas the depletion of PSMD14 or PSMD14 inhibitor thiolutin (THL) inhibits the growth, invasiveness, and epithelial-mesenchymal transition ((EMT) of ATC cells. In addition, the cell cycle was arrested and apoptosis was increased in PSMD14-depleted ATC or ATC cells treated with THL <em>in vitro</em>. An <em>in vivo</em> assay indicated that THL exerted a potent inhibitory effect on ATC xenografts. Mechanistically, PSMD14 increased E2F1 stabilization by binding to and deubiquitinating E2F1. PSMD14-regulated E2F1 improved the activation of the ERK and AKT signaling pathways, which are instrumental in ATC tumorigenesis and progression. Overall, our findings reveal the oncogenic role of PSMD14 in ATC and provide a promising therapeutic target for the treatment of ATC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111826"},"PeriodicalIF":4.4,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CKS1B regulates the radiosensitivity of lung cancer via activating the PI3K/AKT signaling pathway","authors":"Jiangyue Lu ,&nbsp;Lehui Du ,&nbsp;Pei Zhang ,&nbsp;Na Ma ,&nbsp;Qian Zhang ,&nbsp;Xingdong Guo ,&nbsp;Xianwen Li ,&nbsp;Xiao Lei ,&nbsp;Baolin Qu","doi":"10.1016/j.cellsig.2025.111828","DOIUrl":"10.1016/j.cellsig.2025.111828","url":null,"abstract":"<div><div>Radiotherapy is the mainstay and first-line treatment for non-small-cell lung cancer (NSCLC). However, there are no effective strategies for regulating tumor radiosensitivity. This study aimed to examine whether CDC28 protein kinase regulatory subunit 1B (CKS1B) knockdown can radiosensitize NSCLC cells. The results indicated that CKS1B overexpression promoted the proliferation, migration, and invasion of NSCLC cells following exposure to ionizing radiation (IR). In addition, A549 cell xenografts with CKS1B knockdown exhibited significantly enhanced radiosensitivity compared to wild-type xenografts. Mechanistically, it was observed that CKS1B silencing stimulated apoptosis, inhibited cell cycle progression, and weakened DNA damage repair, thereby increasing the sensitivity of NSCLC cells to IR treatment. Moreover, the CKS1B-induced radioresistance was mediated by the PI3K/AKT signaling pathway. These findings demonstrate that CKS1B influences the NSCLC treatment, suggesting that it is a potential prognostic marker for predicting the radiosensitivity of NSCLC cells.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111828"},"PeriodicalIF":4.4,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NR2F2 and its contribution to lymph node metastasis in oral squamous cell carcinoma","authors":"Xuan-Hao Liu ,&nbsp;Nian-Nian Zhong ,&nbsp;Jing-Rui Yi ,&nbsp;Guang-Rui Wang ,&nbsp;Yao Xiao ,&nbsp;Zheng-Rui Zhu ,&nbsp;Qi-Wen Man ,&nbsp;Zheng Li ,&nbsp;Bing Liu ,&nbsp;Lin-Lin Bu","doi":"10.1016/j.cellsig.2025.111814","DOIUrl":"10.1016/j.cellsig.2025.111814","url":null,"abstract":"<div><h3>Objectives</h3><div>To investigate the role of cancer stem cells (CSCs) in lymph node metastasis (LNM) of oral squamous cell carcinoma (OSCC), focusing on the expression and biological significance of nuclear receptor subfamily 2 group F member 2 (NR2F2).</div></div><div><h3>Methods</h3><div>Single-cell RNA sequencing data from OSCC patients were analyzed using the CytoTRACE algorithm to assess stemness. Gene set scores were calculated with the irGSEA and GSVA R packages. GO and KEGG analyses identified enriched pathways. NR2F2 and CD44 expression in OSCC and lymph nodes (LNs) were validated <em>via</em> immunohistochemistry and immunofluorescence. <em>NR2F2/Nr2f2</em> overexpression and knockdown cell lines were established, with stemness markers confirmed by Western blot. Functional assays evaluated stemness, proliferation, migration, and invasion capabilities of OSCC cells. <em>In vivo</em> experiments evaluated the ability of NR2F2 to promote tumor growth and metastasis. Bulk RNA sequencing and drug sensitivity analyses explored NR2F2-related mechanisms and drug responses.</div></div><div><h3>Results</h3><div>CSCs in OSCC were divided into five subgroups, with NR2F2 identified as the key gene in CSC4, the subgroup with the highest stemness, and found to be overexpressed in metastatic LNs. Immunohistochemistry showed NR2F2 overexpression in OSCC, associated with LNM. Immunofluorescence confirmed co-expression of NR2F2 and CD44 in metastatic OSCC and LNs. Overexpression of NR2F2 enhanced stemness, proliferation, and migration of OSCC cells. <em>In vivo</em> experiments showed that NR2F2 promoted the growth and LNM of OSCC. Bulk RNA sequencing revealed that NR2F2 is involved in multiple pathways and plays a role in LNM. Trametinib was identified as a sensitive drug.</div></div><div><h3>Conclusion</h3><div>NR2F2 is associated with the maintenance of tumor stemness and may influence LNM in OSCC by promoting tumor cell proliferation and migration.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111814"},"PeriodicalIF":4.4,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}