Experimental cell research最新文献_第5页

GNA15 as a potential prognostic and immunological biomarker in ccRCC based on bioinformatics analysis and experimental verification 基于生物信息学分析和实验验证的GNA15作为ccRCC潜在的预后和免疫学生物标志物。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-25 DOI: 10.1016/j.yexcr.2025.114874

Xiumin Xu , Zeping Zuo , Jinhai Zhu , Jun Wu , Tao Zhang

As the most common and aggressive subtype of renal cancer, clear cell renal cell carcinoma (ccRCC) often shows poor responsiveness to current therapeutic strategies. Although GNA15, a G protein alpha subunit, has been associated with the progression of multiple tumor types, its functional significance in ccRCC remains largely undefined. Public datasets were used to profile GNA15 expression across cancers, and its links to prognosis, genomic diversity, stemness, and immune infiltration were analyzed with multiple computational tools. In ccRCC, transcriptomic and protein expression levels were validated using immunofluorescence and western blotting. Functional assays, including colony formation, transwell migration, tumor spheroid formation, and GSEA, were used to investigate the biological role of GNA15. The effects of GNA15 knockdown were assessed in renal cancer cell lines. GNA15 was aberrantly upregulated in multiple cancers and significantly elevated in ccRCC tissues and cell lines. High GNA15 expression correlated with poor overall survival and advanced clinical stage. It was also positively associated with tumor heterogeneity, stemness, and immunosuppressive microenvironment characteristics, particularly M2 macrophage and neutrophil infiltration. GSEA identified enrichment in oncogenic pathways, including JAK-STAT, Wnt, and Notch signaling. In vitro knockdown of GNA15 reduced tumor cell proliferation, migration, spheroid formation, and expression of stemness markers and PD-L1. Our results highlight GNA15 as a novel oncogenic and immune-related contributor to ccRCC progression, supporting its potential as a prognostic biomarker and therapeutic target.

作为肾癌中最常见和最具侵袭性的亚型，透明细胞肾细胞癌（ccRCC）通常对当前的治疗策略反应较差。尽管GNA15（一种G蛋白α亚基）与多种肿瘤类型的进展有关，但其在ccRCC中的功能意义仍未明确。使用公共数据集分析GNA15在癌症中的表达，并使用多种计算工具分析其与预后、基因组多样性、干性和免疫浸润的联系。在ccRCC中，使用免疫荧光和western blotting验证转录组学和蛋白质表达水平。功能分析，包括集落形成、跨井迁移、肿瘤球体形成和GSEA，用于研究GNA15的生物学作用。研究了GNA15基因敲低对肾癌细胞系的影响。GNA15在多种癌症中异常上调，在ccRCC组织和细胞系中显著升高。GNA15高表达与总生存期差、临床分期晚期相关。它还与肿瘤异质性、干性和免疫抑制微环境特征呈正相关，特别是M2巨噬细胞和中性粒细胞浸润。GSEA发现在致癌途径中富集，包括JAK-STAT、Wnt和Notch信号。体外敲除GNA15可降低肿瘤细胞的增殖、迁移、球状体的形成以及干细胞标志物和PD-L1的表达。我们的研究结果强调了GNA15作为ccRCC进展的一种新的致癌和免疫相关因子，支持其作为预后生物标志物和治疗靶点的潜力。

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引用次数: 0

Corrigendum to “m6A-mediated upregulation of miRNA-193a aggravates cardiomyocyte apoptosis and inflammatory response in sepsis-induced cardiomyopathy via the METTL3/ miRNA-193a/BCL2L2 pathway” [Exp Cell Res. 2023 Sep 1; 430(1): 113712] “m6a介导的miRNA-193a上调通过METTL3/ miRNA-193a/BCL2L2途径加重败血症诱导的心肌病心肌细胞凋亡和炎症反应”的更正[Exp Cell Res. 2023 Sep 1；430(1): 113712。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-24 DOI: 10.1016/j.yexcr.2025.114856

Lian Liang , Siqi Liu , Qingyu Wu , Ran Chen , Shanping Jiang , Zhengfei Yang

引用次数: 0

Neutrophil extracellular traps promote epithelial-mesenchymal transition in COPD via the RAGE/PI3K/AKT pathway 中性粒细胞胞外陷阱通过RAGE/PI3K/AKT通路促进COPD的上皮-间质转化。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-24 DOI: 10.1016/j.yexcr.2025.114869

Jiawei Zou , Lin Chen , Yang Yang , Zengyu Huo , Yuhong Liu , Zhijuan Luo , Siyi Ou , Cunlai Xu , Jing Bai

Neutrophil extracellular traps (NETs) play a critical role in smoking-related chronic airway inflammation. However, it remains unknown whether NETs promote COPD progression by affecting epithelial-mesenchymal transition (EMT). This study aimed to investigate the correlation between serum biomarker profiles and pulmonary function in COPD patients, elucidate the relationship between NETs formation and EMT in COPD lung tissue, and explore the effect of cigarette smoke extract (CSE)-induced NETs on EMT in bronchial epithelial cells and its molecular mechanisms. We found that COPD patients showed decreased serum DNase-I and elevated IL-6, TNF-α, dsDNA, and MPO-DNA levels. COPD lung tissues exhibited increased NETs accumulation and altered EMT-related protein expression. In vitro, CSE-NETs treatment altered the gene expression profile of BEAS-2B cells, activating the RAGE/PI3K/AKT signaling pathway and promoting EMT. Inhibition of RAGE or PI3K attenuated CSE-NETs-induced EMT. In vivo, DNase-I and CI-amidine Attenuate Emphysema and EMT in Cigarette Smoke–Induced COPD Mice by Reducing NETs. This study reveals the critical role of CSE-induced-NETs in the pathogenesis of COPD and identifies the RAGE/PI3K/AKT signaling pathway as a potential therapeutic target, providing new insights for COPD treatment.

中性粒细胞胞外陷阱（NETs）在吸烟相关的慢性气道炎症中起关键作用。然而，尚不清楚NETs是否通过影响上皮-间质转化（EMT）促进COPD进展。本研究旨在探讨COPD患者血清生物标志物谱与肺功能的相关性，阐明COPD肺组织NETs形成与EMT的关系，探讨香烟烟雾提取物（CSE）诱导的NETs对支气管上皮细胞EMT的影响及其分子机制。我们发现COPD患者血清dna - i降低，IL-6、TNF-α、dsDNA和MPO-DNA水平升高。COPD肺组织表现出NETs积累增加和emt相关蛋白表达改变。在体外，CSE-NETs处理改变了BEAS-2B细胞的基因表达谱，激活了RAGE/PI3K/AKT信号通路，促进了EMT。抑制RAGE或PI3K可减弱cse - nets诱导的EMT。在体内，dna - i和ci -脒通过减少NETs减轻香烟烟雾诱导的COPD小鼠的肺气肿和EMT。本研究揭示了cse诱导的nets在COPD发病机制中的关键作用，并确定了RAGE/PI3K/AKT信号通路作为潜在的治疗靶点，为COPD的治疗提供了新的见解。

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引用次数: 0

Targeting the Gas6-TAM-SOCS1/3 axis: CP-25 attenuates macrophage dysfunction in primary Sjögren's syndrome 靶向Gas6-TAM-SOCS1/3轴：CP-25减轻原发性Sjögren综合征中的巨噬细胞功能障碍

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-23 DOI: 10.1016/j.yexcr.2025.114871

Yun Chen , Qianwen Tian , Meng Yang , Yunxin Zhang , Fuxue Kuang , Lejie Sun , Qi Xi , Wendong Xu , Hongfei Cai , Yukang Mao , Tao Wang , Wei Wei , Huaxun Wu

The etiology of primary Sjögren's syndrome (pSS) remains largely unexplained to date, and there is a relative lack of effective clinical treatment options.This study aimed to explore the potential therapeutic mechanism of paeoniflorin-6′-O-benzenesulfonate (CP-25) for pSS, especially regarding whether it exerts its effect by regulating the Gas6/TAM signaling axis. The study assessed the expression of the Gas6/TAM axis and its association with macrophage polarization using labial gland tissues, peripheral blood samples from patients with primary Sjögren's syndrome (pSS), and an experimental Sjögren's syndrome mouse model. In vitro, RAW264.7 cells and submandibular gland epithelial cells were employed to analyze changes in the TAM-SOCS1/3 axis, JAK1-STAT1 pathway, and polarization markers (iNOS, Arg1). ELISA was used to detect Gas6 secretion by SGECs, while flow cytometry and confocal microscopy evaluated macrophage function.Both primary Sjögren's syndrome patients and experimental Sjögren's syndrome mice showed dysregulation of the Gas6/TAM signaling pathway, which was closely linked to macrophage polarization imbalance.CP-25 alleviated ESS mouse symptoms by activating the TAM-SOCS1/3 axis, inhibiting the JAK1-STAT1 pathway, and promoting M2 macrophage polarization. In vitro experiments confirmed that CP-25 stimulated salivary gland epithelial cells (SGECs) to secrete Gas6 and reduced matrix metalloproteinase-9 (MMP-9) expression. Moreover, exogenous Gas6 promoted M2 polarization via TAM receptor activation; knockdown of the Mer receptor impaired macrophage phagocytic function. The study also indicated that MMP-9 may be involved in regulating TAM receptors on macrophages.In conclusion, CP-25 treats pSS by regulating SGEC Gas6/MMP-9 secretion, targeting macrophage TAM-SOCS1/3, modulating JAK1-STAT1, and restoring macrophage function.

迄今为止，原发性Sjögren综合征（pSS）的病因在很大程度上仍未得到解释，并且相对缺乏有效的临床治疗方案。本研究旨在探讨芍药苷-6′-邻苯磺酸盐（CP-25）对pSS的潜在治疗机制，特别是其是否通过调节Gas6/TAM信号轴发挥作用。该研究通过唇腺组织、原发性Sjögren综合征（pSS）患者外周血样本和实验性Sjögren综合征小鼠模型，评估了Gas6/TAM轴的表达及其与巨噬细胞极化的关系。在体外，采用RAW264.7细胞和颌下腺上皮细胞分析TAM-SOCS1/3轴、JAK1-STAT1通路和极化标记物（iNOS, Arg1）的变化。ELISA检测sges分泌Gas6，流式细胞术和共聚焦显微镜检测巨噬细胞功能。原发性Sjögren综合征患者和实验性Sjögren综合征小鼠均出现Gas6/TAM信号通路失调，这与巨噬细胞极化失衡密切相关。CP-25通过激活TAM-SOCS1/3轴，抑制JAK1-STAT1通路，促进M2巨噬细胞极化，缓解ESS小鼠症状。体外实验证实，CP-25刺激唾液腺上皮细胞（SGECs）分泌Gas6，降低基质金属蛋白酶-9 （MMP-9）表达。此外，外源Gas6通过激活TAM受体促进M2极化；敲低Mer受体会损害巨噬细胞的吞噬功能。本研究还提示MMP-9可能参与巨噬细胞上TAM受体的调节。综上所述，CP-25通过调节SGEC Gas6/MMP-9分泌，靶向巨噬细胞TAM-SOCS1/3，调节JAK1-STAT1，恢复巨噬细胞功能来治疗pSS。

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引用次数: 0

FBXL6 drives tumorigenesis in lung adenocarcinoma through ubiquitination and proteasomal degradation of CDKN1C FBXL6通过泛素化和蛋白酶体降解CDKN1C驱动肺腺癌的肿瘤发生。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-22 DOI: 10.1016/j.yexcr.2025.114872

Guanzhong Dong, Ning Zhang, Dong Yang, Zibo Zhu, Yi He

Lung adenocarcinoma (LUAD) is a highly prevalent and lethal malignancy. Although F-box and leucine-rich repeat protein 6 (FBXL6), an E3 ubiquitin ligase, has been implicated in tumor progression across certain cancers, its functional role in LUAD remains unclear. In this study, we investigated the oncogenic potential of FBXL6 in LUAD pathogenesis. Bioinformatics analysis of GEO, TCGA, and TNM datasets revealed significant upregulation of FBXL6 in LUAD tissues. Functional studies using FBXL6-knockdown (via shRNA in PC-9 cells) and FBXL6-overexpressing (via plasmid transfection in A549 cells) demonstrated that FBXL6 depletion suppressed cell proliferation, migration, and invasion, whereas its overexpression reversed these effects. In vivo experiments further confirmed that FBXL6 knockdown in PC-9 cells inhibited tumor growth and liver metastasis in BALB/c nude mice following subcutaneous or tail vein injection. Mechanistically, FBXL6 was found to physically interact with cyclin-dependent kinase inhibitor 1C (CDKN1C/p57Kip2) and promote its polyubiquitination and proteasomal degradation, thereby destabilizing this tumor suppressor. Rescue assays validated that CDKN1C mediates the pro-tumorigenic effects of FBXL6 on LUAD cell proliferation and metastasis. Collectively, our findings reveal that FBXL6 drives LUAD progression by ubiquitinating and degrading CDKN1C, highlighting its potential as a therapeutic target for LUAD.

肺腺癌（LUAD）是一种非常普遍和致命的恶性肿瘤。虽然F-box和富亮氨酸重复蛋白6 (FBXL6)，一种E3泛素连接酶，与某些癌症的肿瘤进展有关，但其在LUAD中的功能作用尚不清楚。在本研究中，我们研究了FBXL6在LUAD发病机制中的致癌潜力。GEO、TCGA和TNM数据集的生物信息学分析显示，FBXL6在LUAD组织中显著上调。FBXL6敲低（在PC-9细胞中通过shRNA）和FBXL6过表达（在A549细胞中通过质粒转染）的功能研究表明，FBXL6缺失抑制细胞增殖、迁移和侵袭，而其过表达逆转了这些作用。体内实验进一步证实，PC-9细胞中FBXL6敲低可抑制BALB/c裸鼠皮下或尾静脉注射后的肿瘤生长和肝脏转移。在机制上，FBXL6被发现与细胞周期蛋白依赖性激酶抑制剂1C （CDKN1C/p57Kip2）物理相互作用，促进其多泛素化和蛋白酶体降解，从而破坏这种肿瘤抑制因子的稳定。救援实验证实CDKN1C介导FBXL6对LUAD细胞增殖和转移的促瘤作用。总的来说，我们的研究结果表明FBXL6通过泛素化和降解CDKN1C来驱动LUAD的进展，突出了其作为LUAD治疗靶点的潜力。

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引用次数: 0

p38 MAPK-mediated suppression of Nrf2-MPC2 axis drives metabolic reprogramming which confers imatinib resistance in blast crisis phase of chronic myeloid leukemia p38 mapk介导的Nrf2-MPC2轴抑制驱动代谢重编程，在慢性髓性白血病细胞危象期赋予伊马替尼耐药。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-19 DOI: 10.1016/j.yexcr.2025.114870

Manish Bhat , Mythreyi Narasimhan , Ashutosh Shelar , Raghavendra Patwardhan , Santosh Kumar Sandur , Rukmini Govekar

Background

Metabolic reprogramming is a hallmark of cancer and its role in tumour drug resistance is emerging. This study explored its role in resistance to tyrosine kinase inhibitors (TKIs) in the blast crisis (BC) phase of chronic myeloid leukemia (CML), which occurs despite inactivation of the oncogenic Bcr-Abl by TKIs. We previously reported that this Bcr-Abl-independent resistance is mimicked in TKI-resistant CML-BC cell line and is causally associated with p38MAPK, a known modulator of metabolism. Thus, we investigated whether p38MAPK-mediated metabolic rewiring caused resistance in CML-BC.

Methods

Imatinib sensitive and resistant CML-BC cell lines K562 and KU812 were analysed for metabolic proteins by Western blotting, metabolome by mass spectrometry, and apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) by flow cytometry. Sequence of alterations was established by inhibition and knockdown studies.

Results

TKI-resistant cells exhibited enhanced glucose uptake, increased levels of GLUT1, glycolytic enzymes, and those of pyruvate and ATP which reduced upon inhibition of GLUT1, indicative of enhanced glycolysis as contributor of energy. In contrast, the cells displayed reduced NADH/NAD ratio, MMP, mitochondrial ROS which resulted in reduction in apoptotic population. Inhibition studies revealed that suppression of hyperphosphorylated p38MAPK-mediated activation of Nrf2, caused reduced mitochondrial pyruvate carrier (MPC2) expression. MPC2 inhibition in sensitive cells recapitulated the resistant phenotype with reduced MMP and ROS levels.

Conclusion

p38MAPK-mediated suppression of Nrf2/MPC2 axis abrogates mitochondrial function and ROS-mediated cell death while enhanced glycolysis generates ATP to sustain growth. The resultant pro-survival conditions allow leukemic cell survival under drug pressure causing resistance.

背景：代谢重编程是癌症的一个标志，它在肿瘤耐药中的作用正在逐渐显现。本研究探讨了其在慢性髓性白血病（CML）细胞危化期（BC）中对酪氨酸激酶抑制剂（TKIs）耐药的作用，尽管TKIs使致癌的Bcr-Abl失活。我们之前报道过，这种bcr - abl无关的耐药在tki耐药CML-BC细胞系中被模拟，并且与p38MAPK（一种已知的代谢调节剂）有因果关系。因此，我们研究了p38mapk介导的代谢重布线是否引起CML-BC的耐药性。方法：对CML-BC细胞株K562和KU812进行伊马替尼敏感和耐药细胞株的代谢蛋白和代谢组学检测，流式细胞术检测细胞凋亡、线粒体膜电位（MMP）和活性氧（ROS）。通过抑制和敲低研究确定了改变序列。结果：tki耐药细胞表现出葡萄糖摄取增强，GLUT1、糖酵解酶水平升高，丙酮酸和ATP水平在GLUT1抑制后降低，表明糖酵解作为能量来源增强。相反，细胞表现出NADH/NAD比率、MMP、线粒体ROS降低，导致凋亡群体减少。抑制研究表明，抑制高磷酸化p38mapk介导的Nrf2激活导致线粒体丙酮酸载体（MPC2）表达降低。敏感细胞的MPC2抑制再现了耐药表型，降低了MMP和ROS水平。结论：p38mapk介导的Nrf2/MPC2轴抑制消除线粒体功能和ros介导的细胞死亡，而糖酵解增强产生ATP维持生长。由此产生的促生存条件允许白血病细胞在药物压力下存活，从而产生耐药性。

{"title":"p38 MAPK-mediated suppression of Nrf2-MPC2 axis drives metabolic reprogramming which confers imatinib resistance in blast crisis phase of chronic myeloid leukemia","authors":"Manish Bhat , Mythreyi Narasimhan , Ashutosh Shelar , Raghavendra Patwardhan , Santosh Kumar Sandur , Rukmini Govekar","doi":"10.1016/j.yexcr.2025.114870","DOIUrl":"10.1016/j.yexcr.2025.114870","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic reprogramming is a hallmark of cancer and its role in tumour drug resistance is emerging. This study explored its role in resistance to tyrosine kinase inhibitors (TKIs) in the blast crisis (BC) phase of chronic myeloid leukemia (CML), which occurs despite inactivation of the oncogenic Bcr-Abl by TKIs. We previously reported that this Bcr-Abl-independent resistance is mimicked in TKI-resistant CML-BC cell line and is causally associated with p38MAPK, a known modulator of metabolism. Thus, we investigated whether p38MAPK-mediated metabolic rewiring caused resistance in CML-BC.</div></div><div><h3>Methods</h3><div>Imatinib sensitive and resistant CML-BC cell lines K562 and KU812 were analysed for metabolic proteins by Western blotting, metabolome by mass spectrometry, and apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) by flow cytometry. Sequence of alterations was established by inhibition and knockdown studies.</div></div><div><h3>Results</h3><div>TKI-resistant cells exhibited enhanced glucose uptake, increased levels of GLUT1, glycolytic enzymes, and those of pyruvate and ATP which reduced upon inhibition of GLUT1, indicative of enhanced glycolysis as contributor of energy. In contrast, the cells displayed reduced NADH/NAD ratio, MMP, mitochondrial ROS which resulted in reduction in apoptotic population. Inhibition studies revealed that suppression of hyperphosphorylated p38MAPK-mediated activation of Nrf2, caused reduced mitochondrial pyruvate carrier (MPC2) expression. MPC2 inhibition in sensitive cells recapitulated the resistant phenotype with reduced MMP and ROS levels.</div></div><div><h3>Conclusion</h3><div>p38MAPK-mediated suppression of Nrf2/MPC2 axis abrogates mitochondrial function and ROS-mediated cell death while enhanced glycolysis generates ATP to sustain growth. The resultant pro-survival conditions allow leukemic cell survival under drug pressure causing resistance.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"455 2","pages":"Article 114870"},"PeriodicalIF":3.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Mechanistic insights into hypoxia-induced TCF7L2 upregulation and its oncogenic effects on colorectal cancer 低氧诱导的TCF7L2上调及其在结直肠癌中的致癌作用的机制研究

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-18 DOI: 10.1016/j.yexcr.2025.114868

Kang Tang , Yong Cheng , Jianping Gong , Yang Li

Hypoxia plays a crucial role in the advancement of colorectal cancer (CRC); however, the downstream mechanisms facilitated by hypoxia-inducible factor 1α (HIF-1α) remain incompletely understood. This study employed in vitro and in vivo models to investigate the role of transcription factor 7-like 2 (TCF7L2) under hypoxic conditions in CRC. Utilizing reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis, we observed an upregulation of TCF7L2 mRNA and protein expression in Caco-2 and HCT-116 CRC cell lines under hypoxia. Functional assays, including CCK-8, colony and sphere formation, Transwell, flow cytometry, and xenograft tumor models, provided evidence that the knockdown of TCF7L2 leads to the suppression of CRC cell proliferation, the induction of apoptosis, cell cycle arrest at the G0/G1 phase, and a decrease in migration and invasion capabilities. Furthermore, it inhibited epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) characteristics in vitro, while also reducing tumor growth in vivo. Mechanistically, chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (co-IP) assays have elucidated that the expression of TCF7L2 induced by hypoxia is dependent on HIF-1α, which directly binds to hypoxia response elements (HREs) within the TCF7L2 promoter. Additionally, Western blot and experiments employing the PI3K inhibitor LY294002 have demonstrated that TCF7L2 activates the PI3K/AKT signaling pathway, thereby facilitating the proliferation of CRC cells. A clinical analysis of 104 CRC specimens, utilizing immunohistochemistry (IHC) and RT-qPCR, revealed that elevated expression levels of TCF7L2 were significantly associated with advanced T stage, metastasis, and unfavorable prognosis. Spearman correlation analysis confirmed a positive relationship between the expressions of TCF7L2 and HIF-1α, while Kaplan-Meier survival analysis demonstrated that their co-expression was predictive of reduced overall survival. Collectively, these findings position TCF7L2 as a critical downstream effector of HIF-1α in hypoxic CRC, and its mechanistic role in promoting malignancy and correlation with poor prognosis provide a theoretical basis for exploring TCF7L2 as a potential therapeutic target in future studies.

缺氧在结直肠癌（CRC）的进展中起关键作用然而，缺氧诱导因子1α (HIF-1α)促进的下游机制仍不完全清楚。本研究通过体外和体内模型探讨缺氧条件下转录因子7-like 2 （TCF7L2）在CRC中的作用。利用逆转录定量聚合酶链反应（RT-qPCR）和Western blot分析，我们观察到缺氧条件下Caco-2和HCT-116 CRC细胞株中TCF7L2 mRNA和蛋白的表达上调。包括CCK-8、集落和球体形成、Transwell、流式细胞术和异种移植肿瘤模型在内的功能分析表明，TCF7L2的敲低导致CRC细胞增殖抑制，诱导凋亡，细胞周期阻滞在G0/G1期，迁移和侵袭能力下降。此外，它在体外抑制上皮-间质转化（EMT）和癌症干细胞（CSC）特征，同时在体内抑制肿瘤生长。在机制上，染色质免疫沉淀（ChIP）和共免疫沉淀（co-IP）实验已经阐明了缺氧诱导的TCF7L2的表达依赖于HIF-1α， HIF-1α直接结合TCF7L2启动子内的缺氧反应元件（HREs）。此外，Western blot和使用PI3K抑制剂LY294002的实验表明，TCF7L2激活PI3K/AKT信号通路，从而促进CRC细胞的增殖。利用免疫组织化学（IHC）和RT-qPCR对104例结直肠癌标本进行临床分析，发现TCF7L2表达水平升高与晚期T分期、转移和不良预后显著相关。Spearman相关分析证实TCF7L2与HIF-1α的表达呈正相关，Kaplan-Meier生存分析显示它们的共表达可预测总生存期降低。综上所述，这些发现表明TCF7L2在低氧CRC中是HIF-1α的关键下游效应物，其促进恶性肿瘤的机制及其与不良预后的相关性为在未来的研究中探索TCF7L2作为潜在的治疗靶点提供了理论基础。

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引用次数: 0

Metabolic adaptation in colorectal cancer microenvironment: Focus on cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) 结直肠癌微环境中的代谢适应：关注癌症相关成纤维细胞（CAFs）和肿瘤相关巨噬细胞（tam）。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-15 DOI: 10.1016/j.yexcr.2025.114867

Chou-Yi Hsu , Amr Ali Mohamed Abdelgawwad El-Sehrawy , Mirza R. Baig , Zahraa Khudhair , Saidmurodkhon Murtazaev , Pareshkumar N. Patel , Subbulakshmi Ganesan , Vimal Arora , Sandeep Kumar Shukla , Priya Priyadarshini Nayak

Metabolic reprogramming within the tumor microenvironment (TME) is a critical driver of colorectal cancer (CRC) progression, influencing tumor growth, immune evasion, and metastatic dissemination. Cancer-associated fibroblasts (CAFs) undergo adaptive shifts toward aerobic glycolysis, a process often termed the “reverse Warburg effect,” producing high levels of lactate and pyruvate that are shuttled to adjacent CRC cells to fuel oxidative phosphorylation and anabolic biosynthesis. CAFs additionally secrete cytokines and growth factors, including TGF-β, IL-6, and VEGF, which integrate metabolic and signaling networks to stimulate epithelial–mesenchymal transition (EMT), angiogenesis, and metastatic potential. Similarly, tumor-associated macrophages (TAMs) exhibit remarkable metabolic plasticity that correlates with their functional heterogeneity. Beyond the classical M1/M2 dichotomy, TAM subsets display differential reliance on oxidative phosphorylation, fatty acid oxidation, or glycolysis depending on local oxygen and nutrient availability. M2-like TAMs, for example, preferentially use oxidative phosphorylation and fatty acid metabolism to sustain survival in hypoxic niches while secreting immunosuppressive metabolites such as arginase, polyamines, and lactate, which inhibit cytotoxic T-cell function. Crosstalk between CAFs and TAMs amplifies these metabolic adaptations: CAF-derived lactate promotes M2 polarization, while TAMs enhance glycolysis and biosynthetic activity in tumor cells. This study aims to systematically investigate the metabolic reprogramming of CAFs and TAMs within the CRC tumor microenvironment. Specifically, we seek to characterize the metabolic adaptations and heterogeneity of these stromal populations, elucidate their reciprocal interactions with tumor cells, and identify potential metabolic vulnerabilities that can be therapeutically targeted to disrupt tumor growth, immune evasion, and metastatic progression.

肿瘤微环境（TME）内的代谢重编程是结直肠癌（CRC）进展的关键驱动因素，影响肿瘤生长、免疫逃避和转移性传播。癌症相关成纤维细胞（CAFs）经历向有氧糖酵解的适应性转变，这一过程通常被称为“反向Warburg效应”，产生高水平的乳酸和丙酮酸，这些乳酸和丙酮酸被转运到邻近的CRC细胞中，以促进氧化磷酸化和合成代谢生物合成。CAFs还分泌细胞因子和生长因子，包括TGF-β、IL-6和VEGF，它们整合代谢和信号网络，刺激上皮-间质转化（EMT）、血管生成和转移潜能。同样，肿瘤相关巨噬细胞（tam）也表现出与其功能异质性相关的显著代谢可塑性。除了经典的M1/M2二分法外，TAM亚群还表现出对氧化磷酸化、脂肪酸氧化或糖酵解的不同依赖，这取决于局部氧气和营养的可用性。例如，m2样tam优先利用氧化磷酸化和脂肪酸代谢来维持缺氧生态位中的生存，同时分泌免疫抑制代谢物，如精氨酸酶、多胺和乳酸，从而抑制细胞毒性t细胞功能。CAFs和tam之间的串扰放大了这些代谢适应：CAFs衍生的乳酸促进M2极化，而tam增强肿瘤细胞的糖酵解和生物合成活性。本研究旨在系统研究CRC肿瘤微环境中CAFs和tam的代谢重编程。具体来说，我们试图表征这些基质群体的代谢适应性和异质性，阐明它们与肿瘤细胞的相互作用，并确定潜在的代谢脆弱性，这些代谢脆弱性可以作为治疗目标来破坏肿瘤生长、免疫逃避和转移进展。

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引用次数: 0

Tumor cell exosome circ-0023919 promotes EMT through the miR-197-5p/ICAM5 axis and enhances the drug resistance of colorectal cancer to 5-fu 肿瘤细胞外泌体circ-0023919通过miR-197-5p/ICAM5轴促进EMT，增强结直肠癌对5-Fu的耐药性。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-13 DOI: 10.1016/j.yexcr.2025.114866

Jingjing Zhang, Yuanxiang Wu, Yaping Wang, Huihui Zeng

5-Fluorouracil (5-Fu) is a cornerstone chemotherapeutic agent in the treatment of colorectal cancer (CRC). However, its clinical efficacy is frequently hampered by the development of drug resistance, which remains a major obstacle to successful treatment. The aim of this study is to gain a comprehensive understanding of the role and mechanism of the tumor cell-derived exosomal circ-0023919 in 5-Fu resistance. High-throughput microarray technology was employed to identify differentially expressed circRNAs in 5-Fu resistance CRC cells and their derived exosomes. A CRC/5-Fu drug-resistant cell line was successfully established using the drug gradient induction method, and its resistance index was subsequently determined. We employed transmission electron microscopy, nanoparticle tracking analysis (NTA) and Western blot to characterize exosomes by detecting the exosomal markers CD63 and TSG101. The circular structure, stability, and subcellular localization of circ-0023919 were confirmed using a combination of approaches, including actinomycin D treatment, RNase R digestion, specific primer PCR amplification, Sanger sequencing and FISH. Furthermore, we systematically evaluated the regulatory role of circ-0023919 in multiple biological functions of CRC cells by assessing cell proliferation, migration, invasion, drug resistance, stemness and EMT-related markers. Our findings demonstrate that circ-0023919 promotes the migration and invasion of CRC/5-Fu cells both in vitro and in vivo, while also enhancing resistance to 5-Fu chemotherapy. Mechanistically, circ-0023919 acts as a molecular sponge for miR-197-5p, thereby upregulating the expression of ICAM5. In this scientific study, circ-0023919 is shown to enhance the resistance of CRC cells to 5-Fu by promoting EMT. Thus, circ-0023919 is considered a potential therapeutic target for CRC treatment.

5-氟尿嘧啶（5-Fu）是治疗结直肠癌（CRC）的基础化疗药物。然而，其临床疗效经常受到耐药性的影响，这仍然是成功治疗的主要障碍。本研究旨在全面了解肿瘤细胞源性外泌体circ-0023919在5-Fu耐药中的作用和机制。采用高通量微阵列技术鉴定5-Fu耐药CRC细胞及其衍生外泌体中差异表达的环状rna。采用药物梯度诱导法成功建立CRC/5-Fu耐药细胞株，并测定其耐药指数。我们通过检测外泌体标志物CD63和TSG101，采用透射电镜、纳米颗粒跟踪分析（NTA）和Western blot对外泌体进行了表征。采用放线菌素D处理、RNase R酶切、特异性引物PCR扩增、Sanger测序和FISH等综合方法对circ-0023919的圆形结构、稳定性和亚细胞定位进行了验证。此外，我们通过评估细胞增殖、迁移、侵袭、耐药、干性和emt相关标志物，系统地评估了circ-0023919在CRC细胞多种生物学功能中的调节作用。我们的研究结果表明，circ-0023919在体外和体内均能促进CRC/5-Fu细胞的迁移和侵袭，同时还能增强对5-Fu化疗的耐药性。在机制上，circ-0023919作为miR-197-5p的分子海绵，从而上调ICAM5的表达。在这项科学研究中，circ-0023919被证明通过促进EMT来增强CRC细胞对5-Fu的抗性。因此，circ-0023919被认为是CRC治疗的潜在治疗靶点。

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引用次数: 0

Migrasomes in the tumor microenvironment: Functional roles and therapeutic potential 肿瘤微环境中的偏头痛：功能角色和治疗潜力。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-13 DOI: 10.1016/j.yexcr.2025.114865

Xinxin Li , Jinshan Yang , Hao Xie , Jiahao Guo , Jiazi Cha , Jiahui Wang , Chunhua Lin

Migrasomes are large extracellular vesicles (0.5–3 μm in diameter) with a distinctive pomegranate-like structure, formed along retraction fibers during cell migration and released their content through migracytosis. Unlike other extracellular vesicles, migrasomes play unique roles in intercellular communication by transferring proteins, RNAs, and signaling molecules within the tumor microenvironment. This review summarizes recent advances in understanding migrasome biogenesis, composition, and functional roles in cancer progression. We highlight their contributions to tumor angiogenesis, extracellular matrix remodeling, and most notably immune escape, through the regulation of tumor-associated macrophages, T cells, and other immune and stromal cells. Pan-cancer evidence supports a strong correlation between migrasome abundance and immunosuppressive gene signatures, including immune checkpoint expression and tumor immune dysfunction and exclusion (TIDE) scores. We also highlight the promising diagnostic and therapeutic potential of migrasomes as novel biomarkers and targets for cancer therapy. Finally, we discuss current research challenges and outline future directions for advancing migrasome research toward clinical translation.

迁移体是一种直径0.5-3 μm的大细胞外囊泡，具有独特的石榴状结构，在细胞迁移过程中沿着收缩纤维形成，并通过迁移细胞作用释放其内容物。与其他细胞外囊泡不同，迁移小体通过在肿瘤微环境中传递蛋白质、rna和信号分子，在细胞间通讯中发挥独特的作用。本文综述了近年来对迁移小体的生物发生、组成和在癌症进展中的功能作用的研究进展。我们强调了它们通过调节肿瘤相关巨噬细胞、T细胞和其他免疫和基质细胞，对肿瘤血管生成、细胞外基质重塑和最显著的免疫逃逸的贡献。泛癌症证据支持偏头痛小体丰度与免疫抑制基因特征之间的强相关性，包括免疫检查点表达和肿瘤免疫功能障碍和排斥（TIDE）评分。我们还强调了偏头痛作为新的生物标志物和癌症治疗靶点的诊断和治疗潜力。最后，我们讨论了当前的研究挑战，并概述了未来的方向，以推进偏头痛研究的临床转化。

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