Cancer letters最新文献

{"title":"Cutting-edge technologies illuminate the neural landscape of cancer: Insights into tumor development","authors":"Yajing Wang ,&nbsp;Zhaojun Wang ,&nbsp;Xinyuan Mao ,&nbsp;Hongrui Zhang ,&nbsp;Lu Zhang ,&nbsp;Yufei Yang ,&nbsp;Beibei Liu ,&nbsp;Xinxu Li ,&nbsp;Feiyang Luo ,&nbsp;Haitao Sun","doi":"10.1016/j.canlet.2025.217667","DOIUrl":"10.1016/j.canlet.2025.217667","url":null,"abstract":"<div><div>Neurogenesis constitutes a pivotal facet of malignant tumors, wherein cancer and its therapeutic interventions possess the ability to reconfigure the nervous system, establishing a pathologic feedback loop that exacerbates tumor progression. Recent strides in high-resolution imaging, single-cell analysis, multi-omics technologies, and experimental models have opened unprecedented avenues in cancer neuroscience. This comprehensive review summarizes the latest advancements of these emerging technologies in elucidating the biological mechanisms underlying tumor initiation, invasion, metastasis, and the dynamic heterogeneity of the tumor microenvironment(TME), with a specific focus on neuron-glial-tumor interactions in glioblastoma(GBM) and other neurophilic cancers. Moreover, we innovatively propose target screening processes based on sequencing technologies and database frameworks. It rigorously evaluates ongoing clinical trial drugs and efficacy while spotlighting characteristic cells in the central and peripheral TME, consolidating cancer biomarkers pivotal for future targeted therapies and management strategies. By integrating these cutting-edge findings, this review aims to offer fresh insights into tumor-nervous system interactions, establishing a robust foundation for forthcoming clinical advancements.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217667"},"PeriodicalIF":9.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699299","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":"Allogeneic versus autologous hematopoietic stem cell transplantation for adult T-lymphoblastic lymphoma: a real-world multicenter analysis in China.","authors":"Yuewen Wang, Weiping Liu, Zhenyang Gu, Yu Chang, Chunli Zhang, Yang Cao, Haiyang Lu, Xiaodan Liu, Kang Lu, Jin Lu, Fengrong Wang, Luxiang Wang, Shenmiao Yang, Chuanhe Jiang, Chuan Li, Mingzhi Zhang, Xiaojun Huang, Xiaoyu Zhu, Xiaojin Wu, Xiaoxia Hu, Xiaodong Mo, Daihong Liu","doi":"10.1016/j.canlet.2025.217664","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217664","url":null,"abstract":"<p><p>Both allogeneic hematopoietic stem cell transplantation (allo-HSCT) and autologous HSCT (ASCT) are important consolidation therapies for T-lymphoblastic lymphoma (T-LBL). In this multicenter, real-world study, we aimed to compare the clinical outcomes between ASCT and allo-HSCT in adult T-LBL patients. 163 Ann Arbor stage III or IV T-LBL patients (>16 years) who achieved complete or partial response after induction chemotherapies and received HSCT across 11 transplant centers were enrolled. Patients with > 25% BM involvement or 5% lymphoma cells in the peripheral blood at diagnosis were excluded. Landmark analyses were performed to assess outcomes within 1.5 years and between 1.5 years and 3 years after transplantation. The 3-year cumulative incidence of disease progression and non-relapse mortality (NRM) was 24.3% versus 40.3% (P=0.04) and 14.6% versus 7.1% (P=0.29), respectively, for allo-HSCT and ASCT group. The 3-year probability of progression-free survival (PFS) and overall survival (OS) after transplantation was 60.5% versus 52.6% (P=0.34) and 65.8% versus 61.8% (P=0.65), respectively, for allo-HSCT and ASCT group. In landmark analysis, allo-HSCT group showed a superior PFS to ASCT group at 1.5 to 3 years follow-up (P=0.02). In conclusion, this large-scale real-world study showed that adults T-LBL patients might benefit more from allo-HSCT than ASCT.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217664"},"PeriodicalIF":9.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691343","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":"Lactate accumulation drives hepatocellular carcinoma metastasis through facilitating tumor-derived exosome biogenesis by Rab7A lactylation.","authors":"Chenhao Jiang, Xinyi He, Xialin Chen, Jianyang Huang, Yasong Liu, Jianhao Zhang, Huaxin Chen, Xin Sui, Xing Lv, Xuegang Zhao, Cuicui Xiao, Jiaqi Xiao, Jiebin Zhang, Tongyu Lu, Haitian Chen, Haibo Li, Hongmiao Wang, Guo Lv, Linsen Ye, Rong Li, Jun Zheng, Jia Yao, Yinqian Kang, Tao Wang, Hua Li, Jiancheng Wang, Yingcai Zhang, Guihua Chen, Jianye Cai, Andy Peng Xiang, Yang Yang","doi":"10.1016/j.canlet.2025.217636","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217636","url":null,"abstract":"<p><p>Previous studies have demonstrated that lactate accumulation, a common hallmark for metabolic deprivation in solid tumors, could actively drive tumor invasion and metastasis. However, whether lactate influences the biogenesis of tumor-derived exosomes (TDEs), the prerequisite for distant metastasis formation, remains unknown. Here, we demonstrated that extracellular lactate, after taken up by tumor cells via lactate transporter MCT1, drove the release of TDE mainly through facilitating multivesicular body (MVB) trafficking towards plasma membrane instead of lysosome. Mechanistically, lactate promoted p300-mediated Rab7A lactylation, which hereafter inhibited its GTPase activity and promoted MVB docking with plasma membrane. Moreover, lactate administration enriched integrin β4 and ECM remodeling-related proteins in TDE cargos, which promoted pulmonary pre-metastatic niche formation. Combinatorial inhibition of MCT1 and p300 significantly abrogated HCC metastasis in a clinical-relevant PDX model. In summary, we demonstrated that lactate promote TDE biogenesis and HCC pulmonary metastasis, and proposed a potential clinical strategy targeting TDEs to prevent HCC metastasis.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217636"},"PeriodicalIF":9.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691346","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":"Intestinal estrogen receptor beta modulates the murine colon tumor immune microenvironment.","authors":"Madeleine Birgersson, Matilda Holm, Carlos J Gallardo-Dodd, Baizhen Chen, Lina Stepanauskaitė, Linnea Hases, Claudia Kutter, Amena Archer, Cecilia Williams","doi":"10.1016/j.canlet.2025.217661","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217661","url":null,"abstract":"<p><p>Chronic inflammation contributes to the development of colorectal cancer, partly through its regulation of the microenvironment and antitumor immunity. Interestingly, women have a lower incidence of colorectal cancer, and estrogen treatment has been shown to reduce the occurrence of colorectal tumors. While intestinal estrogen receptor beta (ERβ, Esr2) can protect against colitis and colitis-induced cancer in mice, its role in shaping the tumor microenvironment remains unknown. In this study, we performed RNA sequencing to analyze the transcriptome of colonic epithelia and tumors from azoxymethane/dextran sulfate sodium-treated wild-type and intestinal ERβ knockout (ERβKO^Vil) mice and vehicle-treated controls. This revealed significant differences in gene expression and enriched biological processes influenced by sex and genotype, with immune-related responses being overrepresented. Deconvolution supported differential immune cell abundance and immunostaining showed that tumors from ERβKO^Vil mice displayed significantly increased macrophage infiltration, decreased T cell infiltration, and impaired natural killer cell infiltration. Further, ERβ mRNA levels in clinical colorectal tumors correlated with immune signaling profiles and better survival. Our findings indicate that intestinal ERβ promotes an antitumor microenvironment and could potentially affect the effectiveness of immunotherapy. These insights highlight the importance of ERβ in modulating antitumor immunity and underscore its therapeutic potential in colorectal cancer.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217661"},"PeriodicalIF":9.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691345","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":"CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling","authors":"Veronika Danek ,&nbsp;Jolana Tureckova ,&nbsp;Kerstin Huebner ,&nbsp;Katharina Erlenbach-Wuensch ,&nbsp;Petra Baranova ,&nbsp;Jan Dobes ,&nbsp;Jana Balounova ,&nbsp;Michaela Simova ,&nbsp;Vendula Novosadova ,&nbsp;Carlos Eduardo Madureira Trufen ,&nbsp;Michaela Prochazkova ,&nbsp;Pavel Talacko ,&nbsp;Karel Harant ,&nbsp;Cyril Barinka ,&nbsp;Inken M. Beck ,&nbsp;Regine Schneider-Stock ,&nbsp;Radislav Sedlacek ,&nbsp;Jan Prochazka","doi":"10.1016/j.canlet.2025.217663","DOIUrl":"10.1016/j.canlet.2025.217663","url":null,"abstract":"<div><div>Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"621 ","pages":"Article 217663"},"PeriodicalIF":9.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691344","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":"Analysis of germline-somatic mutational connections in colorectal cancer reveals differential tumorigenic patterns and a novel predictive marker for germline mutation carriers.","authors":"Mintao Li, Xuan Gao, Xiangchun Lin, Yan Zhang, Wenying Peng, Tao Sun, Weiyang Shu, Yanyan Shi, Yanfang Guan, Xuefeng Xia, Xin Yi, Yuan Li, Jinzhu Jia","doi":"10.1016/j.canlet.2025.217637","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217637","url":null,"abstract":"<p><p>Colorectal cancer (CRC) genetic testing of regions beyond clinical guidelines has revealed a substantial number of likely pathogenic germline mutations (GMs). It remains largely undetermined whether and how these GMs, typically located in non-mismatch repair (non-MMR) genes, are associated with the tumorigenesis of CRC. This study aimed to identify CRC-predisposing GMs among 93 cancer susceptibility genes and investigate their potential influences on CRC somatic mutational features. We secondarily aimed to investigate whether somatic ERBB2 amplification contributes to identifying GM carriers. This study incorporated a total of 3,240 Chinese CRC patients and 10,588 control individuals. CRC patients were subjected to paired tumor-normal sequencing with a 1,021-gene panel. A case-control analysis was conducted to profile the GM-associated CRC risk. A comprehensive germline-somatic association analysis was performed among 2,405 patients, with key findings subsequently validated in an independent 835-patient cohort and the TCGA CRC cohort. The case-control results supported CRC-predisposing effects of GMs in certain homologous recombination repair (HRR) and DNA damage checkpoint factor (CPF) genes, such as BRCA1/2, RecQ helicase genes, ATM, and CHEK2. HRR GMs were associated with an increased copy number alteration burden, more TP53 clonal mutations, and a higher probability of carrying somatic ERBB2 amplification. CPF GMs were inferred to have synergistic effects with ARID1A and KDM6A somatic mutations in CRC tumorigenesis. Among patients with onset age ≥ 55 years, stable microsatellites, and no cancer family history, ERBB2 amplification was significantly predictive of GM carriers. Our findings elucidate different germline tumorigenic patterns not driven by deficient MMR. Somatic ERBB2 amplification in CRC can serve as an indicator for germline genetic testing when traditional risk features are absent.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217637"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672960","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":"Organoid-based single cell sequencing revealed the lineage evolution during docetaxel treatment in gastric cancer","authors":"Dejun Yang ,&nbsp;Xin Zhang ,&nbsp;Zunqi Hu ,&nbsp;Qiang Sun ,&nbsp;Hongbing Fu ,&nbsp;Jun Yao ,&nbsp;Binbin Zheng ,&nbsp;Xin Zhang ,&nbsp;Weijun Wang","doi":"10.1016/j.canlet.2025.217617","DOIUrl":"10.1016/j.canlet.2025.217617","url":null,"abstract":"<div><div>Docetaxel resistance in gastric cancer poses a major therapeutic challenge. In this study, we established docetaxel-sensitive and -resistant gastric cancer organoids and performed single-cell RNA sequencing to identify cellular and molecular alterations. We observed significant shifts in cell populations, with increased secretory, immune-chemotactic, and transitional gastric cancer cells in the resistant group. Key resistance-related genes, including FOS, IFI27, and PTTG1IP, were upregulated in resistant organoids and gastric cancer patients. A pseudo-time trajectory analysis revealed that resistant cells predominantly occupied terminal differentiation stages. Knocking down FOS, IFI27, and PTTG1IP enhanced docetaxel sensitivity in both cell lines and organoids, regulating ROS production, autophagy, and apoptosis. In vivo, silencing these genes reduced tumor growth in response to docetaxel. These findings suggest that targeting FOS, IFI27, and PTTG1IP could overcome resistance and improve treatment outcomes for gastric cancer patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217617"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672878","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":"5-Year survival rate over 20 % in pancreatic ductal adenocarcinoma: A retrospective study from a Chinese high-volume center","authors":"Xiang Li ,&nbsp;Yiwen Chen ,&nbsp;Guoliang Qiao ,&nbsp;Jian Ni ,&nbsp;Tao Chen ,&nbsp;Yangyang Wang ,&nbsp;Chengyi Wu ,&nbsp;Qi Zhang ,&nbsp;Tao Ma ,&nbsp;Shunliang Gao ,&nbsp;Min Zhang ,&nbsp;Yan Shen ,&nbsp;Jian Wu ,&nbsp;Jun Yu ,&nbsp;Risheng Que ,&nbsp;Xiaochen Zhang ,&nbsp;Ke Sun ,&nbsp;Wenbo Xiao ,&nbsp;Tian'an Jiang ,&nbsp;Xueli Bai ,&nbsp;Tingbo Liang","doi":"10.1016/j.canlet.2025.217658","DOIUrl":"10.1016/j.canlet.2025.217658","url":null,"abstract":"<div><div>Standardized clinical management of pancreatic adenocarcinoma (PDAC) remains challenging and high-volume centers provide essential insights for establishing effective multimodal treatment approaches. This retrospective observational study evaluated the impact of standardized, multimodal clinical management on survival outcomes in patients with PDAC across all stages, based on NCCN guidelines resectability criteria, at a high-volume center<strong>.</strong> From 2019, 4143 patients were diagnosed with PDAC, with 3268 patients receiving further treatment, including surgical resection and/or systemic therapy. The median overall survival (OS) was 18.5 (95 %CI 17.5–19.4) months for the treated cohort and the 5-year survival rate reached 23.3 %. Patients who underwent surgical resection had significantly improved median OS compared to those who received non-surgical treatments (28.4 months vs. 13.0 months, <em>P</em> &lt; 0.001), with corresponding 5-year survival rates of 31.6 % vs. 15.0 %. Moreover, the patients who received NAT followed by surgical resection had improved survival outcomes compared to those who underwent upfront surgical resection in both resectable (median OS: 37.5 months vs. 28.9 months, P &lt; 0.01) and borderline resectable group (median OS: 31.8 months vs. 18.4 months, P &lt; 0.001). This study demonstrated a 5-year survival rate exceeding 20 % for PDAC across all stages at our center. The application of evidence-based treatment strategies through the multidisciplinary team, accompanying with standardized and comprehensive therapeutic managements, high patient adherence, have been considered as critical determinants in enhancing therapeutic efficacy and improving long-term prognosis for patients with PDAC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217658"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673389","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":"Unraveling the molecular mechanism underlying the anticancer activity of CISD2/NAF-144−67","authors":"Linda Rowland ,&nbsp;Itai Alfoni ,&nbsp;Ehud Neumann ,&nbsp;Ola Karmi ,&nbsp;Rachel Nechushtai ,&nbsp;Ron Mittler","doi":"10.1016/j.canlet.2025.217644","DOIUrl":"10.1016/j.canlet.2025.217644","url":null,"abstract":"<div><div>We recently reported on the development of a unique cancer-targeting peptide called NAF-1⁴⁴⁻⁶⁷ (derived from CISD2/NAF-1). NAF-1⁴⁴⁻⁶⁷ selectively permeates the plasma membrane (PM) of cancer cells, but not healthy cells, causing the activation of apoptotic and ferroptotic cell death pathways specifically in cancer cells. NAF-1⁴⁴⁻⁶⁷ also targets and shrinks human breast and ovarian cancer tumors in a xenograft mice model system without any apparent side effects. Although the specific permeation of NAF-1⁴⁴⁻⁶⁷ through cancer cell PMs was studied, and its cancer killing effects validated <em>in vitro</em> and <em>in vivo</em>, little is known about how NAF-1⁴⁴⁻⁶⁷ exerts its biological activity once it enters cancer cells. Here, we report that NAF-1⁴⁴⁻⁶⁷ targets the CISD2/NAF-1 protein of cancer cells and disrupts its homodimeric structure. We further reveal that a peptide derived from the same domain of the human CISD1 (mitoNEET; mNT^19-42) protein, a close family member to CISD2, has no killing activity towards cancer cells, and that dimers of NAF-1⁴⁴⁻⁶⁷ (at two different orientations) have higher anticancer activity compared to monomeric NAF-1⁴⁴⁻⁶⁷. Our findings shed new light on the biological activity of NAF-1⁴⁴⁻⁶⁷ and bring it closer to becoming a potential new anticancer drug.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217644"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672896","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":"FUT2-dependent fucosylation of LAMP1 promotes the apoptosis of colorectal cancer cells by regulating the autophagy-lysosomal pathway","authors":"Zijun Guo ,&nbsp;Lingnan He ,&nbsp;Weijun Wang ,&nbsp;Shuxin Tian ,&nbsp;Rong Lin","doi":"10.1016/j.canlet.2025.217643","DOIUrl":"10.1016/j.canlet.2025.217643","url":null,"abstract":"<div><div>Fucosyltransferase 2 (FUT2) is an enzyme that adds fucose to proteins or lipids via α-1,2-fucosylation in the intestinal mucosa. While FUT2 deficiency is linked to increased susceptibility to inflammatory bowel disease (IBD), its role in colorectal cancer (CRC) is unclear, and the molecular mechanisms involved remain largely unknown. We established an azoxymethane (AOM) and dextran sulfate sodium (DSS) model to induce CRC. FUT2 expression was assessed in human CRC tissues, AOM/DSS-induced mouse models, and CRC cell lines using qRT-PCR, western blotting, and UEA-I staining. FUT2 knockout (FUT2^△IEC) mice were treated with AOM/DSS, and FUT2-overexpressing CRC cells were created to evaluate the effects of FUT2 on apoptosis in both <em>in vitro</em> and <em>in vivo</em> settings through Western blot analyses and functional assays. N-glycoproteomics, UEA-I chromatography, and co-immunoprecipitation were utilized to identify regulatory mechanisms and target fucosylated proteins. FUT2 expression and α-1,2-fucosylation were significantly decreased in CRC. FUT2 deficiency worsened AOM/DSS-induced CRC and reduced tumor apoptosis, while FUT2 overexpression induced apoptosis and inhibited proliferation in CRC cells and xenografts. Mechanistically, FUT2 appears to suppress autophagy by impairing lysosomal function and directly targeting and fucosylating LAMP1, contributing to lysosomal dysfunction. Our study reveals a fucosylation-dependent antitumor mechanism of FUT2 in CRC, suggesting potential therapeutic strategies for CRC treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217643"},"PeriodicalIF":9.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669210","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}