Cellular signalling最新文献

A STAT1-GBP3-STING positive feedback loop governs inflammation, oxidative stress, and DNA damage to trigger acute aortic dissection STAT1-GBP3-STING正反馈回路控制炎症、氧化应激和DNA损伤，从而引发急性主动脉夹层

IF 4.4 2区生物学

Cellular signalling Pub Date : 2025-07-24 DOI: 10.1016/j.cellsig.2025.112015

Si-ming Bu , Wen-li Wang , Yi-mei Liu , Qing Li , Jing-yu Sun , Xu-rao Zhao , Xu-bin Miao , Yong-bo Zhao , Ya-pei Zhao , Zhi-xue Song , Dong Ma

{"title":"A STAT1-GBP3-STING positive feedback loop governs inflammation, oxidative stress, and DNA damage to trigger acute aortic dissection","authors":"Si-ming Bu , Wen-li Wang , Yi-mei Liu , Qing Li , Jing-yu Sun , Xu-rao Zhao , Xu-bin Miao , Yong-bo Zhao , Ya-pei Zhao , Zhi-xue Song , Dong Ma","doi":"10.1016/j.cellsig.2025.112015","DOIUrl":"10.1016/j.cellsig.2025.112015","url":null,"abstract":"<div><div>Acute aortic dissection (AAD) is a degenerative aortic remodeling disease characterized by exceedingly high mortality without effective pharmacologic therapies. Although oxidative stress, DNA damage, and inflammation are associated with AAD, the precise interplay among these responses has remained unclear. In this study, aortas from mouse AD models were subjected to integrative ATAC-seq and RNA-seq analysis. The pathogenic targets governing oxidative stress, DNA damage, and inflammation were identified by single-cell RNA sequencing, ROS staining, chromatin immunoprecipitation combined with PCR (ChIP-PCR), and co-immunoprecipitation (CoIP) analysis in the IFN-γ-stimulated vascular smooth muscle cells (VSMCs), mouse AAD model, and human ascending aortas. The transcriptional profiles of 191 differentially expressed genes revealed the IFN-γ response, oxidative stress-related NOD-like receptor, STING signaling pathways and marked elevation of STAT1, activated inflammation, DNA damage and ROS. Mechanistically, the activation of STAT1 binding on promoters of GBP3, H2aX and IFN-γ gene in nuclear as well as the interaction of GBP3 and STING protein in cytoplasm, determining a STAT1-GBP3-STING positive feedback loop triggering inflammation, DNA damage, and oxidative stress. Targeting this loop using STAT1 inhibitor Fludarabine impedes aortic degeneration while improving survival (60 % vs. 90 %) and reducing aortic expansion (2.34 ± 0.18 mm vs. 1.55 ± 0.15 mm) in the mouse AAD model. This study provides novel insights into a transcriptional program permitting aortic degeneration, warranting consideration of a critical target STAT1 for an anti-inflammation, anti-DNA damage, and anti-oxidative stress intervention as an attractive strategy to manage temporal-specific AD by modulating the STAT1-GBP3-STING positive feedback loop.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112015"},"PeriodicalIF":4.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144712495","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}

引用次数: 0

The biological clock gene PER2 promotes PANoptosis in oral squamous cell carcinoma by facilitating the formation of the Caspase-8/RIPK3/ASC complex 生物钟基因PER2通过促进Caspase-8/RIPK3/ASC复合物的形成，促进口腔鳞状细胞癌的PANoptosis

IF 4.4 2区生物学

Cellular signalling Pub Date : 2025-07-24 DOI: 10.1016/j.cellsig.2025.112021

Hengyan Li, Mingyuan Liu, Shilin Yin, Zhiwei Zhang, Kai Yang

{"title":"The biological clock gene PER2 promotes PANoptosis in oral squamous cell carcinoma by facilitating the formation of the Caspase-8/RIPK3/ASC complex","authors":"Hengyan Li, Mingyuan Liu, Shilin Yin, Zhiwei Zhang, Kai Yang","doi":"10.1016/j.cellsig.2025.112021","DOIUrl":"10.1016/j.cellsig.2025.112021","url":null,"abstract":"<div><div>Current research indicates that the circadian clock gene PER<em>2</em> plays a significant role in preventing tumor. However, its specific mechanism of action in oral squamous cell carcinoma (OSCC) remains unclear. While it is known that PANoptosis is critical for tumor suppression, whether PER2 exerts its anti-cancer effects by regulating this process has not been determined. Through bioinformatics analysis, our analysis revealed that PANoptosis-related genes (<em>MAP3K7</em>, <em>CASP8</em>) significantly correlate with the prognosis of OSCC patients. In OSCC cell lines (NOK, CAL27, SCC25, SCC15) and clinical samples, <em>PER2</em> expression demonstrated an extremely positive correlation with <em>CASP8</em> and a negative association with <em>MAP3K7</em>. The overexpression of PER2 significantly suppressed OSCC cell proliferation, promoted apoptosis, and increased both lactate dehydrogenase release and the expression of PANoptosis markers (cleaved caspase-3, N-GSDME, p-MLKL). In agreement with the in vitro findings, tumor xenograft experiments in vivo demonstrated that elevated PER2 expression inhibits tumor growth and upregulates the expression of PANoptosis markers. Mechanistically, PER2 binds to and stabilizes Caspase-8 protein, facilitating formation of the Caspase-8/RIPK3/ASC complex in OSCC cells. Notably, treatment with the Caspase-8 inhibitor <em>Z</em>-IETD-FMK markedly reversed PANoptosis in OSCC cells. This study provides the first evidence that PER2 overexpression suppresses OSCC proliferation by regulating the Caspase-8/RIPK3/ASC complex-mediated PANoptosis, offering a promising therapeutic strategy for OSCC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112021"},"PeriodicalIF":4.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713990","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}

引用次数: 0

Role of 3-mercaptopyruvate sulfurtransferase in cancer. 3-巯基丙酮酸硫转移酶在癌症中的作用。

IF 4.4 2区生物学

Cellular signalling Pub Date : 2025-07-24 DOI: 10.1016/j.cellsig.2025.112020

Xue-Li Wang, Lei Cao, Yan-Wen Wang, Ti Chu, Yong-Qi Fan, Yu-Hang Chen, Yi Zhang, Wei-Rong Si, Qi-Ying Jiang, Dong-Dong Wu

{"title":"Role of 3-mercaptopyruvate sulfurtransferase in cancer.","authors":"Xue-Li Wang, Lei Cao, Yan-Wen Wang, Ti Chu, Yong-Qi Fan, Yu-Hang Chen, Yi Zhang, Wei-Rong Si, Qi-Ying Jiang, Dong-Dong Wu","doi":"10.1016/j.cellsig.2025.112020","DOIUrl":"https://doi.org/10.1016/j.cellsig.2025.112020","url":null,"abstract":"<p><p>The enzyme 3-Mercaptopyruvate sulfurtransferase (3-MST) is widely present across different biological entities and is essential for the production of hydrogen sulfide (H₂S). This enzyme functions both in the cytosol and mitochondria, and 3-MST mediates the reaction of 3-Mercaptopyruvate (3-MP) with dihydrolipoic acid and thioredoxin to produce hydrogen sulfide. In addition to 3-MST, H₂S can also be produced through the actions of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). H₂S, a gaseous signaling molecule with therapeutic potential, has been found to have therapeutic and alleviating effects on various diseases, including cancer, cardiovascular disease, and neurological disorders. While the roles of CBS and CSE in cancer have been extensively studied and well-described, relatively little information is available in the scientific literature regarding the function and importance of 3-MST in cancer. This article focuses on the role of 3-MST in breast cancer, lung cancer, bladder cancer, and colon cancer, emphasizing its potential as a therapeutic target.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112020"},"PeriodicalIF":4.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717578","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}

引用次数: 0

Crosstalk between hippo and Wnt pathways in intestinal stem cells regeneration. 肠干细胞再生中hippo和Wnt通路的串扰。

IF 4.4 2区生物学

Cellular signalling Pub Date : 2025-07-24 DOI: 10.1016/j.cellsig.2025.112023

Yanqiu Li, Yujun Hou, Yue He, Kexin Cheng, Ying Chen, Ying Li, Siyuan Zhou

引用次数: 0

PDCD4 exacerbates myocardial ischemia-reperfusion injury via AKT-mediated apoptosis PDCD4通过akt介导的细胞凋亡加重心肌缺血再灌注损伤

IF 4.4 2区生物学

Cellular signalling Pub Date : 2025-07-23 DOI: 10.1016/j.cellsig.2025.111999

Zhiming Zhang , Zhihui Yang , Hangbin Ge , Chenyang Liu , Renchenghan Fan , Chenying Yuan , Shengban You , Chenglv Hong

{"title":"PDCD4 exacerbates myocardial ischemia-reperfusion injury via AKT-mediated apoptosis","authors":"Zhiming Zhang , Zhihui Yang , Hangbin Ge , Chenyang Liu , Renchenghan Fan , Chenying Yuan , Shengban You , Chenglv Hong","doi":"10.1016/j.cellsig.2025.111999","DOIUrl":"10.1016/j.cellsig.2025.111999","url":null,"abstract":"<div><div>Myocardial ischemia-reperfusion (I/R) injury is a critical complication following reperfusion therapy for myocardial infarction. As a marker of I/R injury, apoptosis plays an important role in myocardial ischemia-reperfusion injury. Programmed Cell Death 4 (PDCD4) regulates apoptosis in MI/RI, but the mechanism is not yet fully elucidated. In this study, we demonstrate that PDCD4 expression was significantly upregulated in a myocardial I/R injury model. Genetic deletion of PDCD4 markedly reduced infarct size, serum biomarkers of injury (CK-MB, cTnT, LDH), and apoptosis in vivo. Mechanistically, PDCD4 directly interacts with AKT, inhibiting its phosphorylation by reducing ubiquitination. This suppression of AKT activity decreased BCL-2 levels, promoting mitochondrial apoptosis. Silencing PDCD4 restored AKT phosphorylation, attenuated apoptosis, and alleviated myocardial damage. Our findings establish PDCD4 as a key driver of myocardial I/R injury via AKT-mediated apoptosis and highlight its therapeutic potential.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 111999"},"PeriodicalIF":4.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144704779","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}

引用次数: 0

Blocking IL-6 down-regulates PD-L1 expression and mitigates pulmonary fibrosis by inhibiting the STAT3 signaling pathway 阻断IL-6可通过抑制STAT3信号通路下调PD-L1表达，减轻肺纤维化

IF 4.4 2区生物学

Cellular signalling Pub Date : 2025-07-21 DOI: 10.1016/j.cellsig.2025.112019

Xiao Hu , Jie Tan , Yujuan Wang , Rumei Luan , Dongyan Ding , Ming Yue , Meng Zhao , Qianfei Xue , Junling Yang

{"title":"Blocking IL-6 down-regulates PD-L1 expression and mitigates pulmonary fibrosis by inhibiting the STAT3 signaling pathway","authors":"Xiao Hu , Jie Tan , Yujuan Wang , Rumei Luan , Dongyan Ding , Ming Yue , Meng Zhao , Qianfei Xue , Junling Yang","doi":"10.1016/j.cellsig.2025.112019","DOIUrl":"10.1016/j.cellsig.2025.112019","url":null,"abstract":"<div><div>Pulmonary fibrosis is a fatal lung disease. Owing to its unknown pathogenesis, treatment options are limited. Interleukin (IL)-6, a multifunctional cytokine, is overexpressed in pulmonary fibrosis and may contribute to its development through multiple pathways, mainly the signal transduction and transcriptional activator 3 (STAT3) signaling pathway. Moreover, programmed cell death ligand 1 (PD-L1), an immune checkpoint molecule, is crucial in immune regulation and also shows abnormal expression in pulmonary fibrosis, potentially involved in fibrogenesis. PD-L1 may be regulated by IL-6 in pulmonary disorders. Given the pivotal role of IL-6 and PD-L1 in the pathogenesis of pulmonary fibrosis, this study aimed to explore the effect and mechanism of blocking IL-6 on PD-L1 expression and pulmonary fibrosis. We established the pulmonary fibrosis model by instilling bleomycin (BLM) intratracheally into mice and stimulating human fetal lung fibroblasts 1 (HFL1s) with transforming growth factor-beta 1 (TGF-β1). Upon inhibition of IL-6 signaling or reduction of PD-L1 expression, we analyzed the tissue morphology, protein expression and function. We observed elevated expression of IL-6 and PD-L1 in pulmonary fibrosis models. Blocking IL-6 relieved BLM-induced lung tissue destruction, diminished collagen production and deposition and inhibited the expression of alpha smooth muscle actin (α-SMA), Vimentin, and Collagen I. Blocking IL-6 could reverse fibroblast-to-myofibroblast transformation induced by TGF-β1 in HFL1s via inhibiting the STAT3 signaling pathway. Interestingly, targeting IL-6/STAT3 signaling could also down-regulate PD-L1 expression. Inhibiting PD-L1 could mitigate pulmonary fibrosis. Our findings provide new molecular targets for exploring the pathogenesis and treatment of pulmonary fibrosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112019"},"PeriodicalIF":4.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695112","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}

引用次数: 0

Melatonin inhibits adipogenesis and enhances osteogenesis of BMSCs through increasing KLF5 expression 褪黑素通过增加KLF5的表达抑制骨髓间充质干细胞的脂肪生成和促进成骨

IF 4.4 2区生物学

Cellular signalling Pub Date : 2025-07-21 DOI: 10.1016/j.cellsig.2025.112017

Shenghong Wang , Cong Tian , Jinmin Liu , Zhiwei Feng , Dacheng Zhao , Ao Yang , Dejian Xiang , Changshun Chen , Yayi Xia , Bin Geng

{"title":"Melatonin inhibits adipogenesis and enhances osteogenesis of BMSCs through increasing KLF5 expression","authors":"Shenghong Wang , Cong Tian , Jinmin Liu , Zhiwei Feng , Dacheng Zhao , Ao Yang , Dejian Xiang , Changshun Chen , Yayi Xia , Bin Geng","doi":"10.1016/j.cellsig.2025.112017","DOIUrl":"10.1016/j.cellsig.2025.112017","url":null,"abstract":"<div><div>Bone marrow-derived mesenchymal stem cells (BMSCs) maintain bone homeostasis by balancing adipogenesis and osteogenesis, with disruption of this balance favoring adipogenesis contributing to osteoporosis. Melatonin, known for regulating bone metabolism, promotes osteogenesis and inhibits adipogenesis, but the mechanisms remain unclear. This study investigates whether melatonin regulates BMSC differentiation by modulating the methylation of the Krüppel-like factor 5 (KLF5) promoter, a transcription factor involved in both adipogenesis and osteogenesis. Using an ovariectomy (OVX)-induced osteoporosis mouse model, we found that melatonin treatment significantly reversed OVX-induced bone loss, increased bone mineral density, and reduced bone marrow adiposity, accompanied by increased KLF5 expression in bone tissue. In vitro, melatonin promoted osteogenic differentiation and suppressed adipogenic differentiation in BMSCs, with decreased methylation of the KLF5 promoter. Knockdown of KLF5 suppressed osteogenesis and enhanced adipogenesis, while KLF5 overexpression promoted osteogenesis and inhibited adipogenesis. Melatonin-induced demethylation of the KLF5 promoter was associated with increased KLF5 expression, which in turn promoted osteogenic differentiation and inhibited adipogenic differentiation. These findings reveal a novel epigenetic mechanism underlying melatonin's bone-protective effects and suggest KLF5 promoter methylation as a potential therapeutic target for osteoporosis and related bone disorders.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112017"},"PeriodicalIF":4.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695109","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}

引用次数: 0

Amlodipine synergizes with temozolomide against glioma stem cells by modulating MGMT expression through downregulation of the AKT/GSK3β/β-catenin axis 氨氯地平与替莫唑胺协同对抗胶质瘤干细胞，通过下调AKT/GSK3β/β-catenin轴调节MGMT表达。

IF 4.4 2区生物学

Cellular signalling Pub Date : 2025-07-21 DOI: 10.1016/j.cellsig.2025.112012

Xiaopei Zhang , Zengyang Li , Ping Wen , Nanheng Yin , Zhicheng Zhang , Tao Zhong , Feiyu Xia , Jiaxin Pan , Liang Liu , Jun Dong

{"title":"Amlodipine synergizes with temozolomide against glioma stem cells by modulating MGMT expression through downregulation of the AKT/GSK3β/β-catenin axis","authors":"Xiaopei Zhang , Zengyang Li , Ping Wen , Nanheng Yin , Zhicheng Zhang , Tao Zhong , Feiyu Xia , Jiaxin Pan , Liang Liu , Jun Dong","doi":"10.1016/j.cellsig.2025.112012","DOIUrl":"10.1016/j.cellsig.2025.112012","url":null,"abstract":"<div><div>Temozolomide (TMZ) is the primary chemotherapeutic agent used for the treatment of glioblastoma. However, the high chemoresistance observed in glioblastoma remains a significant clinical challenge, which is associated with the repair of DNA alkylation sites by O6-methylguanine-DNA methyltransferase (MGMT). Exploring new strategies to enhance the tumoricidal activity of TMZ against chemoresistant glioma stem cells (GSCs), is crucial for improving patient outcomes. As a classical calcium channel blocker (CCB) against hypertension, amlodipine has been reported to have definite antitumor and chemo-sensitizing effects. However, it remains unclear whether it exhibits anti-glioblastoma activity or synergizes with TMZ in targeting GSCs. The present study revealed that amlodipine inhibited the GSC viability and induced apoptosis, cell cycle arrest in vitro. Furthermore, amlodipine significantly reduced tumor volume and prolonged median survival of tumor-bearing mice in vivo. Additionally, amlodipine enhanced the cytotoxicity of TMZ against GSCs by downregulating MGMT expression through the suppression of the Akt/GSK3β/β-catenin axis. Overexpression of MGMT reversed the synergistic effects of amlodipine with TMZ. Pharmacological inhibition of GSK-3β with CHIR-99021 or overexpression of β-catenin reversed amlodipine-induced downregulation of β-catenin and MGMT, reduction of cell viability and enhancement of TMZ cytotoxicity against GSCs. The intracranial xenograft model also showed that the synergy between amlodipine and TMZ could be achieved by downregulating β-catenin and MGMT, which prolonged the survival time of tumor-bearing mice. These results indicate that amlodipine has novel potential for repurposing as a synergetic chemotherapy against GSCs, aiming to disrupt the progression of therapy-resistant glioblastoma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112012"},"PeriodicalIF":4.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697718","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}

引用次数: 0

TFAP2A-mediated downregulation of UBE2C is crucial for endometrial decidualization and embryo implantation tfap2a介导的UBE2C下调对子宫内膜脱胞和胚胎着床至关重要

IF 4.4 2区生物学

Cellular signalling Pub Date : 2025-07-21 DOI: 10.1016/j.cellsig.2025.112016

Li Yu , Yifan Luo , Yixia Yang , Liqun Lou , Xinbao Zhang , Jiamin Zhu , Yan Zhang , Hong Liao , Mingzhu Bai , Zuoshu Qin , Zhenbo Zhang

{"title":"TFAP2A-mediated downregulation of UBE2C is crucial for endometrial decidualization and embryo implantation","authors":"Li Yu , Yifan Luo , Yixia Yang , Liqun Lou , Xinbao Zhang , Jiamin Zhu , Yan Zhang , Hong Liao , Mingzhu Bai , Zuoshu Qin , Zhenbo Zhang","doi":"10.1016/j.cellsig.2025.112016","DOIUrl":"10.1016/j.cellsig.2025.112016","url":null,"abstract":"<div><div>Decidualization triggered by human endometrial stromal cells (HESCs) is a critical step in the establishment of endometrial receptivity, which provides an ideal environment for embryo implantation. However, the specific regulatory networks and core genes involved in the decidualization process remain incompletely characterized. Here, we identified ubiquitin-conjugating enzyme 2C (UBE2C), a key cell cycle regulator, as a pivotal factor in decidualization through comprehensive <em>in vitro</em> and <em>in vivo</em> investigations. RNA sequencing revealed UBE2C as a potential hub gene in the human endometrium. We found UBE2C expression was significantly downregulated in secretory-phase endometrium and <em>in vitro</em> decidual HESCs. Functional studies demonstrated that UBE2C overexpression attenuated decidual marker expression and disrupted normal proliferation in HESCs, mechanistically linked to NF-κB signaling pathway. Consistent with <em>in vitro</em> findings, mice studies showed UBE2C downregulation in peri-implantation uterine tissue, with uterine-specific UBE2C overexpression impairing both embryo implantation and decidualization. Further mechanistic exploration identified transcription factor AP-2 alpha (TFAP2A) as a novel mediator of UBE2C. Decidual stimulation promoted TFAP2A degradation <em>via</em> the ubiquitination pathway. Clinical relevance was established through the observation of elevated UBE2C and TFAP2A expression in secretory endometrium from recurrent implantation failure (RIF) patients. In conclusion, for endometrial decidualization and embryo implantation, TFAP2A-mediated downregulation of UBE2C is required. Dysregulation of this axis may compromise endometrial receptivity, suggesting UBE2C and TFAP2A as promising therapeutic targets for decidualization-related disorders such as RIF.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112016"},"PeriodicalIF":4.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695111","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}

引用次数: 0

N-glycosylation stabilized TNFAIP6 promotes ovarian cancer metastasis by activating the PI3K-AKT signaling pathway n -糖基化稳定的TNFAIP6通过激活PI3K-AKT信号通路促进卵巢癌转移。

IF 4.4 2区生物学

Cellular signalling Pub Date : 2025-07-21 DOI: 10.1016/j.cellsig.2025.112013

Xiangxiang Liu , Dongze Ji , Zhifa Wen , Qi Tang , Yajun Chen

{"title":"N-glycosylation stabilized TNFAIP6 promotes ovarian cancer metastasis by activating the PI3K-AKT signaling pathway","authors":"Xiangxiang Liu , Dongze Ji , Zhifa Wen , Qi Tang , Yajun Chen","doi":"10.1016/j.cellsig.2025.112013","DOIUrl":"10.1016/j.cellsig.2025.112013","url":null,"abstract":"<div><h3>Background</h3><div>Ovarian cancer (OC) represents the most lethal gynecological malignancy, with a dismal 5-year survival rate of ∼30 % in advanced-stage patients, largely due to metastatic dissemination and limited therapeutic options. Elucidating the molecular drivers of OC metastasis remains imperative for developing targeted interventions.</div></div><div><h3>Methods</h3><div>Integrative multi-omics analyses were performed using bulk RNA-seq and scRNA-seq data from TCGA and GEO repositories. Protein dynamics were validated via Western blot and immunofluorescence. Prognostic significance was assessed through Kaplan-Meier survival analysis with log-rank tests. Functional characterization of TNFAIP6 was achieved through lentivirus-mediated shRNA knockdown/overexpression, complemented by in vitro assays and in vivo metastasis models. The ubiquitination levels of TNFAIP6 were detected through Co-IP experiments. Immune cell infiltration was quantified via computational deconvolution algorithms.</div></div><div><h3>Results</h3><div>TNFAIP6 emerged as a metastasis-associated oncogene, with elevated expression correlating significantly with poor prognoses. Mechanistically, N-glycosylation stabilized TNFAIP6 by impeding ubiquitin-proteasomal degradation. TNFAIP6 knockdown genetically attenuated OC cell invasion, migration, and peritoneal dissemination. Pathway analyses revealed TNFAIP6-driven activation of the PI3K/AKT signaling pathway, which orchestrated epithelial-mesenchymal transition. Notably, TNFAIP6 upregulation was significantly correlated with tumor immune-suppressing microenvironment and predicted resistance to immune checkpoint inhibitors and chemotherapy.</div></div><div><h3>Conclusions</h3><div>Our study establishes TNFAIP6 as a critical regulator of OC metastasis via PI3K/AKT pathway activation and a biomarker of therapeutic resistance. Targeting TNFAIP6 may offer dual strategies to counteract metastatic progression and therapeutic resistance in OC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112013"},"PeriodicalIF":4.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697747","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}

引用次数: 0