Cancer letters最新文献

{"title":"Fibrinogen-like 2 in tumor-associated macrophage-derived extracellular vesicles shapes an immunosuppressive microenvironment in colorectal liver metastases by promoting tumor stemness and neutrophil extracellular traps formation","authors":"Menghua Zhou ,&nbsp;Bingjie Guan ,&nbsp;Youdong Liu ,&nbsp;Qi Gu ,&nbsp;Weiwei Chen ,&nbsp;Bowen Xie ,&nbsp;Mantang Zhou ,&nbsp;Jianjun Xiang ,&nbsp;Senlin Zhao ,&nbsp;Qian Zhao ,&nbsp;Dongwang Yan","doi":"10.1016/j.canlet.2025.217642","DOIUrl":"10.1016/j.canlet.2025.217642","url":null,"abstract":"<div><div>Investigating the mechanisms underlying the development of an immunosuppressive microenvironment within colorectal liver metastases (CRLM) is important for identifying synergistic targets for immunotherapy. The regulatory role of tumor-associated macrophage-derived extracellular vesicles (TAM-EVs) in the immune microenvironment of CRLM has not yet been fully explored. Here, we found that TAM-EVs shaped the immunosuppressive microenvironment at the invasive front in murine CRLM models, thus dampening anti-PD-1 immunotherapy. This environment is characterized by an increased tumor stemness potential and abundant neutrophil extracellular traps (NETs) formation. Mechanistically, TAM-EVs-derived fibrinogen-like 2 (FGL2) interacts with the FCGR2B receptor in tumor cells, which further activates a p-STAT3/IL-1β positive feedback loop to increase the stemness potential of cancer cells, whereas IL-1β mediates the communication between cancer cells and neutrophils. The use of an anti-IL-1β monoclonal antibody can reduce NETs production and synergize with anti-PD-1 immunotherapy, which offers clinical translational significance for CRLM therapy. The FGL2/p-STAT3/IL-1β loop correlates with an immunosuppressive microenvironment and poor prognosis in human patients with CRLM. Our results revealed the potential of enhancing the efficacy of immunotherapy via the targeted clearance of NETs using anti-IL-1β monoclonal antibodies, which have significant clinical translational value in the treatment of CRLM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"618 ","pages":"Article 217642"},"PeriodicalIF":9.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143644754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generating research hypotheses to overcome key challenges in the early diagnosis of colorectal cancer - Future application of AI","authors":"Lan Yao ,&nbsp;Heliang Yin ,&nbsp;Chengyuan Yang ,&nbsp;Shuyan Han ,&nbsp;Jiamin Ma ,&nbsp;J. Carolyn Graff ,&nbsp;Cong-Yi Wang ,&nbsp;Yan Jiao ,&nbsp;Jiafu Ji ,&nbsp;Weikuan Gu ,&nbsp;Gang Wang","doi":"10.1016/j.canlet.2025.217632","DOIUrl":"10.1016/j.canlet.2025.217632","url":null,"abstract":"<div><div>We intend to explore the capability of ChatGPT 4.0 in generating innovative research hypotheses to address key challenges in the early diagnosis of colorectal cancer (CRC). We asked ChatGPT to generate hypotheses focusing on three main challenges: improving screening accuracy, overcoming technological limitations, and identifying reliable biomarkers. The hypotheses were evaluated for novelty. The experimental plans provided by ChatGPT for selected hypotheses were assessed for completion and feasibility. As a result, ChatGPT generated a total of 65 hypotheses. ChatGPT rated all 65 hypotheses, with 25 hypotheses receiving the highest rating (5) and 40 hypotheses receiving a rating of 4 or lower. The research team evaluated a total of 65 hypotheses, assigning them the following grades: hypotheses were rated as excellent (Grade 5), 16 were deemed suitable (Grade 4), 31 were classified as satisfactory (Grade 3), 12 were identified as needing Improvement (Grade 2), and one was considered poor (Grade 1). Additionally, the study determined that 17 of the generated hypotheses had corresponding publications. Out of the three experimental plans assessed, one was rated excellent (5) for feasibility, while the others received good (4) and moderate (3) ratings. Predicted outcomes and alternative approaches were rated as good, with some areas requiring further improvement. Our data demonstrate that AI has the potential to revolutionize hypothesis generation in medical research, though further validation through experimental and clinical studies is needed. This study suggests that while AI can generate novel hypotheses, human expertise is essential for evaluating their practicality and relevance in scientific research.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"620 ","pages":"Article 217632"},"PeriodicalIF":9.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircRUNX1 enhances the Warburg effect and immune evasion in non-small cell lung cancer through the miR-145/HK2 pathway","authors":"Jinyou Li ,&nbsp;Shiwei Xu ,&nbsp;Yangyang Zhan ,&nbsp;Xinyi Lv ,&nbsp;Zhenyu Sun ,&nbsp;Li Man ,&nbsp;Donghua Yang ,&nbsp;Yahong Sun ,&nbsp;Shengguang Ding","doi":"10.1016/j.canlet.2025.217639","DOIUrl":"10.1016/j.canlet.2025.217639","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) is acknowledged as the primary subtype of lung cancer. The Warburg effect, marked by elevated glucose consumption and lactate fermentation, is a prevalent characteristic of NSCLC. The mechanisms by which circRNA mediates the regulation of the Warburg effect and immune evasion in NSCLC remain unclear. This study found an elevated circRNA, circRUNX1, whiche promotes glycolysis and lactate generation, resulting in the infiltration of regulatory T cell (Treg) in NSCLC. circRUNX1 acts as a miR-145 sponge, inhibiting its negative regulation of the target gene HK2, therefore facilitating glycolysis and lactate generation. The accumulation of lactic acid in the tumor microenvironment promotes Treg cell proliferation and aids immune evasion. Functionally, the suppression of circRUNX1 significantly impedes tumor development both in vitro and in vivo. These findings collectively clarity a previously unexamined mechanism linking the circRUNX1/miR-145/HK2 axis in regulation of the Warburg effect and immune evasion in NSCLC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"620 ","pages":"Article 217639"},"PeriodicalIF":9.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial distribution and activation changes of T cells in pancreatic tumors according to KRAS mutation subtype","authors":"Ji Hye Jeong ,&nbsp;Dakyum Shin ,&nbsp;Sang-Yeob Kim ,&nbsp;Dong-Jun Bae ,&nbsp;Young Hoon Sung ,&nbsp;Eun-Young Koh ,&nbsp;Jinju Kim ,&nbsp;Chong Jai Kim ,&nbsp;Jae Soon Park ,&nbsp;Jung Kyoon Choi ,&nbsp;Song Cheol Kim ,&nbsp;Eunsung Jun","doi":"10.1016/j.canlet.2025.217641","DOIUrl":"10.1016/j.canlet.2025.217641","url":null,"abstract":"<div><div>To enhance immunotherapy efficacy in pancreatic cancer, it is crucial to characterize its immune landscape and identify key factors driving immune alterations. To achieve this, we quantitatively analyzed the immune microenvironment using multiplex immunohistochemistry, assessing the spatial relationships between immune and tumor cells to correlate with patient survival rates and oncological factors. Additionally, through Whole Exome Sequencing analysis based on public data, we explored genetic mutations that could drive these compositions. Finally, we validated T cell (Tc) migration mechanisms using patient-derived tumor organoids with induced KRAS mutation subtypes. Through this approach, we obtained the following meaningful results<strong>.</strong> First, immune cells in pancreatic cancer are denser in stromal regions than near tumor cells, with higher Tc distribution linked to increased patient survival rates. Second, the distance between tumor and Tc was within 100 μm, with higher Tc density found within 15–30 μm of the tumor cells. Third, while increasing CAF levels correspond to higher Tc density, higher ECM density tends to decrease Tc presence. Fourth, compared to KRAS G12D, KRAS G12V mutation increases various immune cells, notably Tc, which is closely linked to a dramatic rise in vascular cells. Finally, Tc migration was enhanced in tumor organoids with the G12V mutation, attributed to a reduction in the secretion of immunosuppressive cytokines. Our results indicate that KRAS mutation subtypes influence immune cell composition and function in the pancreatic cancer microenvironment, leading to varied immunotherapy responses. This underscores the need for personalized immune therapeutics and research models specific to KRAS mutations.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"618 ","pages":"Article 217641"},"PeriodicalIF":9.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pentose phosphate recycling driven by Gli1 contributes to chemotherapy resistance in cancer cells","authors":"Qiangsheng Hu ,&nbsp;Cong Jiang ,&nbsp;Yi Qin ,&nbsp;Borui Li ,&nbsp;Jingyi Wang ,&nbsp;Ting Wang ,&nbsp;Shunrong Ji ,&nbsp;Zeng Ye ,&nbsp;Qing Dang ,&nbsp;Mingyang Liu ,&nbsp;Xianjun Yu ,&nbsp;Xiaowu Xu","doi":"10.1016/j.canlet.2025.217633","DOIUrl":"10.1016/j.canlet.2025.217633","url":null,"abstract":"<div><div>The Hedgehog Signaling Pathway plays an important role in cancer development and chemotherapy resistance. However, whether the pathway functions depend on the metabolic reprogramming of cancer cells has not been well studied. In this study, we found that the expression level of Gli1, a key transcription factor downstream of the Hedgehog Signaling Pathway, is significantly increased in patients with pancreatic cancer resistant to gemcitabine neoadjuvant chemotherapy. Through metabolomics analysis, we confirmed that Gli1 can promote the transformation of cancer cells from a glycolytic-dominated metabolic pattern to a unique metabolic pattern called “Pentose Phosphate Recycling”. Transcriptome sequencing and in vitro experiments suggest that Gli1 promotes pentose phosphate recycling through transcriptional activation of key enzymes Phosphogluconate dehydrogenase (PGD) and Transketolase (TKT). The identified metabolic rerouting in oxidative and non-oxidative pentose phosphate pathway has important physiological roles in maximizing NADPH reduction and nucleotide synthesis. Therefore, the pentose phosphate cycle driven by Gli1 can resist gemcitabine-induced DNA damage by promoting pyrimidine synthesis and resist gemcitabine-induced ferroptosis by scavenging lipid Reactive Oxygen Species (Lipid ROS). Combining the Gli1 inhibitor GANT21 with gemcitabine exerts a maximal tumor suppressor effect by simultaneously promoting DNA damage and ferroptosis. Collectively, these results reveal that Gli1 drives chemotherapy resistance in cancer cells by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for reversing chemotherapy resistance.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"618 ","pages":"Article 217633"},"PeriodicalIF":9.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pediatric gliomas immunity challenges and immunotherapy advances","authors":"Eleni-Kyriaki Vetsika ,&nbsp;Maria A. Katsianou ,&nbsp;Panagiotis Sarantis ,&nbsp;Kostas Palamaris ,&nbsp;Athanasios G. Papavassiliou ,&nbsp;Christina Piperi","doi":"10.1016/j.canlet.2025.217640","DOIUrl":"10.1016/j.canlet.2025.217640","url":null,"abstract":"<div><div>Pediatric gliomas, the most frequent brain tumors in children, are characterized by heterogeneity and a unique tumor immune microenvironment. They are categorized into different subtypes, including low-grade gliomas like pilocytic astrocytomas and high-grade gliomas such as diffuse midline gliomas and diffuse intrinsic pontine gliomas, each exhibiting distinct immunological profiles. The tumor immune microenvironment in pediatric gliomas is shaped by cellular and non-cellular components, including immune cells, cytokines, and the extracellular matrix, involved in tumor progression, immune evasion, and response to therapy. While pediatric low-grade gliomas often display an immunosuppressed microenvironment, high-grade gliomas are characterized by complex immune infiltrates and intricate immunosuppressive mechanisms. The blood-brain barrier further obscures immune cell recruitment and therapeutic delivery. Despite advances in understanding adult gliomas, the immunobiology of pediatric tumors is poorly investigated, with limited data on the interactions between glioma cells and immune populations such as T and natural killer cells, as well as tumor-associated macrophages. Herein, we provide an update of the current knowledge on tumor immune microenvironment interactions in pediatric gliomas, highlighting the immunosuppressive mechanisms and emerging immunotherapeutic strategies aiming at overcoming these barriers to improve clinical outcomes for affected children.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"618 ","pages":"Article 217640"},"PeriodicalIF":9.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-treatment DNA methylome and transcriptome profiles correlate with melanoma response to anti-PD1 immunotherapy","authors":"Sultana Mehbuba Hossain ,&nbsp;Gregory Gimenez ,&nbsp;Peter Stockwell ,&nbsp;Robert Weeks ,&nbsp;Suzan Almomani ,&nbsp;Gregory T. Jones ,&nbsp;Magdalena Ratajska ,&nbsp;Mathew Shuen ,&nbsp;Basharat Bhat ,&nbsp;Janusz Ryś ,&nbsp;Bozena Cybulska-Stopa ,&nbsp;Agnieszka Harazin-Lechowska ,&nbsp;Euan Rodger ,&nbsp;Christopher Jackson ,&nbsp;Aniruddha Chatterjee ,&nbsp;Michael R. Eccles","doi":"10.1016/j.canlet.2025.217638","DOIUrl":"10.1016/j.canlet.2025.217638","url":null,"abstract":"<div><div>Successful immune checkpoint inhibitor (ICI) therapy occurs in only a fraction of melanoma patients, and yet all patients are susceptible to potentially serious ICI-related side-effects. No current biomarkers robustly predict ICI treatment response in melanoma patients. In this study we sought to identify methylome and transcriptome markers which have the potential to predict immunotherapy response in melanoma patients ahead of treatment with anti-PD1 ICI monotherapy. Using Infinium MethylationEPIC microarrays, we analysed DNA methylation profiles of &gt;850,000 CpG sites in pre-treatment melanoma tissues from patients administered anti-PD-1 monotherapy as first-line treatment. In addition, we analysed transcriptomes using RNA-seq. DNA methylation and gene expression data were then statistically compared to patient response to anti-PD1 therapy. We identified 2579 DNA hypomethylation and hypermethylation alterations correlating with melanoma response to anti-PD1 therapy. An integrative analysis of DNA methylomes and transcriptomes identified a subset of 35 loci, 13 of which were significantly differentially methylated in both initial discovery and external validation datasets. Functional enrichment analysis of hypomethylated sites (p-value &lt;0.05) in non-responders was associated with “Formation of the cornified envelope”, “Regulation of epithelial cell proliferation”, and “Purine-containing compound metabolic process”. We have identified novel integrated DNA methylation and gene expression markers, which correlate with anti-PD1 treatment response in melanoma patients. These findings suggest a relationship between tumour-associated genomic DNA methylation, gene expression patterns, and anti-PD1 ICI immunotherapy response in melanoma patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"618 ","pages":"Article 217638"},"PeriodicalIF":9.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-derived exosomal LINC01812 induces M2 macrophage polarization to promote perineural invasion in cholangiocarcinoma","authors":"Qinlei Wang ,&nbsp;Zhaowei Sun ,&nbsp;Jingyun Guo ,&nbsp;Haoran Li,&nbsp;Jingru Zhang,&nbsp;Bingyuan Zhang,&nbsp;Bin Zhou,&nbsp;Yujie Feng","doi":"10.1016/j.canlet.2025.217596","DOIUrl":"10.1016/j.canlet.2025.217596","url":null,"abstract":"<div><div>M2 macrophages play a critical role in the tumor microenvironment of invasive solid tumors. They are closely associated with perineural invasion (PNI) and are often linked to poor prognosis. In this context, tumor-derived exosomes serve as important mediators of intercellular communication. However, the relationship between tumor cell-induced M2 macrophages and PNI in cholangiocarcinoma remains unexplored. In this study, we utilized multiplex immunofluorescence and transcriptomic sequencing to demonstrate the upregulation of LINC01812 in cholangiocarcinoma tissues and its positive correlation with M2 macrophage infiltration. Exosomal lncRNA sequencing, exosome uptake experiments, RNA pull-down assays, and mass spectrometry analysis demonstrated that macrophages can internalize exosomal LINC01812 and promote the M2 phenotype in cholangiocarcinoma cells. Additionally, Transwell and in vitro cocultures with the dorsal root ganglia confirmed that the tumor microenvironment significantly enhances the nerve infiltration of cholangiocarcinoma cells via M2 macrophages. The findings of this study indicate that exosomes containing LINC01812 derived from cholangiocarcinoma can induce M2 macrophage polarization and facilitate nerve infiltration, thereby providing new potential therapeutic targets for managing PNI in cholangiocarcinoma.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"617 ","pages":"Article 217596"},"PeriodicalIF":9.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dependence on Mdm2 for Mdm4 inhibition of p53 activity.","authors":"Shunbin Xiong, Yun Zhang, Xin Zhou, Vinod Pant, Akshita Mirani, Jovanka Gencel-Augusto, Gilda Chau, M James You, Guillermina Lozano","doi":"10.1016/j.canlet.2025.217622","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217622","url":null,"abstract":"<p><p>Both Mdm2 and Mdm4 inhibit p53 activity by masking of its transcriptional activation domain. In addition, Mdm2 functions as an E3 ubiquitin ligase, targeting p53 for degradation. The Mdm4 amino terminus binds wild type and mutant p53 while its RING domain, which lacks E3 ligase activity, is required for heterodimerization with Mdm2. To determine how these domains of Mdm4 regulate p53, we generated mouse models with either a deletion of the Mdm4 RING domain (Mdm4^ΔR) or all of Mdm4 (Mdm4^─) on a hypomorphic (p53^neo) background. Mdm4^ΔR mice exhibited elevated p53 levels and activity, albeit to a lesser extent than mice with complete Mdm4 loss, indicating that the amino terminus of Mdm4 contributes to p53 inhibition. Moreover, in the absence of Mdm2, neither the deletion of the Mdm4 RING domain nor the complete loss of Mdm4 further increased p53 protein levels on a mutant p53 background, indicating that Mdm4 modulates Mdm2 in its regulation of p53 stability. Collectively, our findings suggest that Mdm4 contributes to p53 inhibition by modulating Mdm2 activity via both its amino terminus and RING domains.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217622"},"PeriodicalIF":9.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UBE2C mediates follicular thyroid carcinoma invasion and metastasis via K29-Specific vimentin ubiquitination","authors":"Lei Xu ,&nbsp;Bao Dai ,&nbsp;Lingyun Zhang ,&nbsp;Weijian Chen ,&nbsp;Shikuo Rong ,&nbsp;Jianghong Chen ,&nbsp;Muye Song ,&nbsp;Ziteng Lan ,&nbsp;Yongchen Liu ,&nbsp;Linhe Wang ,&nbsp;Jinghua Li ,&nbsp;Jian Chen ,&nbsp;Zeyu Wu","doi":"10.1016/j.canlet.2025.217624","DOIUrl":"10.1016/j.canlet.2025.217624","url":null,"abstract":"<div><div>Follicular thyroid carcinoma (FTC) poses significant clinical challenges due to its vascular invasion tendency and distant metastasis potential, leading to poorer patient outcomes compared to other thyroid carcinomas. Although ubiquitin-conjugating enzyme E2C (UBE2C) has been widely studied in various cancers, its specific role in FTC progression remains insufficiently explored. This study demonstrates UBE2C's dual functionality in FTC through clinical analysis and experimental validation. Single-cell RNA sequencing of FTC specimens revealed marked UBE2C upregulation associated with aggressive tumor behavior and unfavorable prognosis. Functional studies showed that UBE2C overexpression paradoxically enhanced cellular proliferation while suppressing migration and invasion through EMT modulation. Mechanistic investigations identified vimentin as a key substrate, where UBE2C mediated K29-linked ubiquitination leading to its degradation. Animal models yielded unexpected findings where UBE2C knockdown reduced primary tumor growth but promoted metastasis, validating its context-dependent roles. These results establish UBE2C as a molecular regulator balancing proliferation and invasion in FTC through post-translational modification of cytoskeletal components, suggesting its therapeutic potential for targeted intervention strategies.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"617 ","pages":"Article 217624"},"PeriodicalIF":9.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}