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Advanced ensemble staking model employing cfDNA fragmentation for early detection of esophageal and gastric cancer 应用cfDNA片段化的先进集合桩模型早期检测食管癌和胃癌
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-07-23 DOI: 10.1016/j.canlet.2025.217945
Shitong Cheng , Yusong Luo , Xiaolong Dong , Meng-yuan Liu , Zhaoqi Wu , Lu Xu , Honghao Yin , Xin Li , Sha Shi , Huan Zhai , Jia Li , Chuan He , Ying Xiong , Linan Bao , Siyu Li , Siyu Zhang , Xiao Sun , Qingxin Xie , Ningyou Li , Hua Bao , Hong Shang
{"title":"Advanced ensemble staking model employing cfDNA fragmentation for early detection of esophageal and gastric cancer","authors":"Shitong Cheng ,&nbsp;Yusong Luo ,&nbsp;Xiaolong Dong ,&nbsp;Meng-yuan Liu ,&nbsp;Zhaoqi Wu ,&nbsp;Lu Xu ,&nbsp;Honghao Yin ,&nbsp;Xin Li ,&nbsp;Sha Shi ,&nbsp;Huan Zhai ,&nbsp;Jia Li ,&nbsp;Chuan He ,&nbsp;Ying Xiong ,&nbsp;Linan Bao ,&nbsp;Siyu Li ,&nbsp;Siyu Zhang ,&nbsp;Xiao Sun ,&nbsp;Qingxin Xie ,&nbsp;Ningyou Li ,&nbsp;Hua Bao ,&nbsp;Hong Shang","doi":"10.1016/j.canlet.2025.217945","DOIUrl":"10.1016/j.canlet.2025.217945","url":null,"abstract":"<div><div>Esophageal and gastric cancers are aggressive malignancies with poor prognoses due to late-stage diagnosis. Our study recruited 275 healthy participants, 201 gastric cancer patients, 74 esophageal patients and 103 patients with precancerous conditions. The participants were assigned into training and validation cohorts. After processing a low-depth whole genome sequencing for all plasma samples, a stacked ensembled model was constructed, integrating three cfDNA fragmentomic features: Copy Number Variation, Fragment Size Profile, and Fragment Based Methylation. The multi-dimensional model was trained with 5-fold cross-validation, and its performance was evaluated through validation. The detection sensitivity and specificity were validated at 95 % specificity of training set. The stacked ensemble model achieved an AUC of 0.967 in the validation dataset. At a 95 % specificity threshold, the model attained a high sensitivity of 79.2 %, underscoring its clinical utility in distinguishing cancer from healthy individuals. Notably, it achieved sensitivity of 77.4 % and 68.3 % for stage I cases in training and validation cohorts, respectively. The model also identified precancerous conditions effectively, with an AUC of 0.828 and sensitivity of 53.8 % and 71.4 % for gastric and esophageal precancer lesions, while maintaining clear score distinctions in specifying benign diseases. Overall, our stacked model achieved high sensitivity in identifying esophageal and gastric cancer, offering a strong, non-invasive alternative to endoscopy. This approach supports timely intervention and improved patient outcomes by enabling earlier and more targeted treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217945"},"PeriodicalIF":9.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144696859","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}
引用次数: 0
High-fat diet driven post-operative colon cancer recurrence is dependent upon genetic susceptibility to deoxycholic acid 高脂肪饮食驱动结肠癌术后复发依赖于脱氧胆酸的遗传易感性
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-07-22 DOI: 10.1016/j.canlet.2025.217943
Ryan Morgan , Mohammad Amin Bayat Tork , Zitong Lin , Claire Wild , Luke R. Frietze , Sihao Huang , Meejeon Roh , Andrea Olivas , Colin W. Steele , Tao Pan , Benjamin D. Shogan
{"title":"High-fat diet driven post-operative colon cancer recurrence is dependent upon genetic susceptibility to deoxycholic acid","authors":"Ryan Morgan ,&nbsp;Mohammad Amin Bayat Tork ,&nbsp;Zitong Lin ,&nbsp;Claire Wild ,&nbsp;Luke R. Frietze ,&nbsp;Sihao Huang ,&nbsp;Meejeon Roh ,&nbsp;Andrea Olivas ,&nbsp;Colin W. Steele ,&nbsp;Tao Pan ,&nbsp;Benjamin D. Shogan","doi":"10.1016/j.canlet.2025.217943","DOIUrl":"10.1016/j.canlet.2025.217943","url":null,"abstract":"<div><div>The development of postoperative recurrent tumors or metastasis following surgical resection of colorectal cancer remains a major obstacle to colon cancer cure. While a high-fat diet is a risk factor for the development of recurrence, studies that examine the molecular mechanism by which diet drives postoperative tumors have been lacking. Here, using a murine model that mimics postoperative tumor formation, we show that the tumorigenic influence of a high-fat diet strongly depends on the genetic backbone of the primary tumor cells. We identify deoxycholic acid as a major contributor to the promotion of tumor recurrence only when the primary cancer cell has an APC-driving mutation. We investigate the deoxycholic acid effect on the proliferation of organoids and identify the organoid response to deoxycholic acid treatment, including the transcriptome expression and transfer RNA abundance, modification, and charging. The integrated analysis of mRNA and tRNA sequencing results reveals enhanced decoding of codons in proliferation-promoting genes. Our results provide a new understanding of how both diet and tumor genetics together lead to postoperative colorectal cancer recurrence.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217943"},"PeriodicalIF":9.1,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144696858","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}
引用次数: 0
Circulating cytokine profiling and clustering identify biomarker predicting efficacy of ICI in combination with chemotherapy 循环细胞因子分析和聚类识别预测ICI联合化疗疗效的生物标志物
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-07-22 DOI: 10.1016/j.canlet.2025.217918
Xiaotian Xu , Yiling Li , Shiran Sun , Xianlong Lin , Wenfeng Zhang , Yue Wu , Baojun Wei , Danfei Xu , Cuiling Zheng , Hezhi Fang , Wei Cui
{"title":"Circulating cytokine profiling and clustering identify biomarker predicting efficacy of ICI in combination with chemotherapy","authors":"Xiaotian Xu ,&nbsp;Yiling Li ,&nbsp;Shiran Sun ,&nbsp;Xianlong Lin ,&nbsp;Wenfeng Zhang ,&nbsp;Yue Wu ,&nbsp;Baojun Wei ,&nbsp;Danfei Xu ,&nbsp;Cuiling Zheng ,&nbsp;Hezhi Fang ,&nbsp;Wei Cui","doi":"10.1016/j.canlet.2025.217918","DOIUrl":"10.1016/j.canlet.2025.217918","url":null,"abstract":"<div><div>The combination of chemotherapy can enhance the efficacy of immune checkpoint inhibitors (ICIs), but requires precise patient stratification and biomarker screening. Cytokines influence immunotherapy outcomes, and multiplex cytokine profiling aids in identifying predictive biomarkers for ICIs. We analyzed 1331 plasma samples (1025 untreated pan-cancer patients and 306 healthy controls), including 238 receiving ICIs plus chemotherapy. Cytokine clusters were identified via non-negative matrix factorization. Cluster effected on early response and progression-free survival (PFS) were evaluated, and a Cytokine-based ICI Survival Index (CISI) was developed. The effect of specific cytokines on anti-programmed death 1 (PD1) treatment was verified in vivo. Thus, three inflammatory clusters were identified: Cluster 1 (high IFN-γ/IL-8/IL-1β, proinflammatory), Cluster 2 (high IL-6), and Cluster 3 (high IL-5/IL-17, Th2 activation). Cluster 3 showed superior PFS (HR = 2.44/3.84, p = 0.00011) and response rates (85.42 % vs. 54.33 %/61.90 %, p = 0.00075) versus Clusters 1&amp;2. High IFN-γ/IL-8 predicted poorer outcomes. The CISI model, incorporating cytokine clusters and clinical variables (treatment, IL-10, monocyte-to-lymphocyte ratio, and M stage), outperformed conventional biomarkers programmed death-ligand 1 (PD-L1) and IL-8 in predictive efficiency [Concordance indexes (C-indexes) = 0.75 vs. 0.55 and 0.56]. In vivo studies confirmed the effects on anti-PD1 efficacy by characteristic cytokines in clusters. In conclusion, our cytokine clustering based on multi-cytokine profiles and CISI model predicted prognosis and immunotherapeutic response in tumor patients, providing new insights into personalized cancer therapy strategies.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217918"},"PeriodicalIF":9.1,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144679108","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}
引用次数: 0
DOT1L inhibition reprograms innate immunity to potentiate immunomodulatory drug responses in multiple myeloma DOT1L抑制重编程先天免疫以增强多发性骨髓瘤的免疫调节药物反应
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-07-21 DOI: 10.1016/j.canlet.2025.217941
Kazuya Ishiguro , Hiroshi Kitajima , Takeshi Niinuma , Reo Maruyama , Tomohide Tsukahara , Yoshihiko Hirohashi , Akari Takaya , Kohei Kumegawa , Ayano Yoshido , Shohei Sekiguchi , Hajime Sasaki , Akira Yorozu , Mutsumi Toyota , Masahiro Kai , Toshihiko Torigoe , Hiroshi Nakase , Hiromu Suzuki
{"title":"DOT1L inhibition reprograms innate immunity to potentiate immunomodulatory drug responses in multiple myeloma","authors":"Kazuya Ishiguro ,&nbsp;Hiroshi Kitajima ,&nbsp;Takeshi Niinuma ,&nbsp;Reo Maruyama ,&nbsp;Tomohide Tsukahara ,&nbsp;Yoshihiko Hirohashi ,&nbsp;Akari Takaya ,&nbsp;Kohei Kumegawa ,&nbsp;Ayano Yoshido ,&nbsp;Shohei Sekiguchi ,&nbsp;Hajime Sasaki ,&nbsp;Akira Yorozu ,&nbsp;Mutsumi Toyota ,&nbsp;Masahiro Kai ,&nbsp;Toshihiko Torigoe ,&nbsp;Hiroshi Nakase ,&nbsp;Hiromu Suzuki","doi":"10.1016/j.canlet.2025.217941","DOIUrl":"10.1016/j.canlet.2025.217941","url":null,"abstract":"<div><div>Immunomodulatory drugs (IMiDs), such as lenalidomide, are a cornerstone of multiple myeloma (MM) treatment; however, their efficacy remains suboptimal. We previously reported that inhibition of DOT1L, a histone H3 lysine 79 methyltransferase, upregulates interferon (IFN)-regulated genes (IRGs) and exerts anti-MM effects. In this study, we aimed to further elucidate the epigenetic dependency of DOT1L in MM and the mechanism by which its inhibition induces innate immune signaling. Analysis of DepMap portal data revealed that MM cells are preferentially dependent on DOT1L, among epigenetic regulators, for survival. DOT1L inhibition activated type I IFN responses and increased expression of human leukocyte antigen (HLA) class II genes in MM cells. Notably, DOT1L inhibition was associated with induction of DNA damage responses. CRISPR/Cas9-mediated knockout of <em>STING1</em> attenuated IRG induction and diminished the anti-proliferative effects of DOT1L inhibition, suggesting that activation of STING signaling contributes to its anti-MM activity. Furthermore, DOT1L inhibition downregulated IKZF1/3 and IRF4, which was also associated with IRG induction. Finally, DOT1L inhibition enhanced the anti-MM efficacy of lenalidomide by further upregulating IRGs and suppressing IRF4-MYC signaling. These findings suggest that DOT1L is a preferential epigenetic therapeutic target in MM. Its inhibition not only activates innate immune signaling but also enhances the efficacy of lenalidomide.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217941"},"PeriodicalIF":9.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685790","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}
引用次数: 0
Microbiome and Gartynecologic Cancer. 微生物组与gartynecological Cancer。
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-07-19 DOI: 10.1016/j.canlet.2025.217940
Bingqing Liao, Liang Chen, Jinghan Ruan, Renjie Wang, Bai Hu, Rui Long, Yan Li, Guangmei Zhang, Jing Yu, Ming Zhang, Yuanzhen Zhang, Shujie Liao
{"title":"Microbiome and Gartynecologic Cancer.","authors":"Bingqing Liao, Liang Chen, Jinghan Ruan, Renjie Wang, Bai Hu, Rui Long, Yan Li, Guangmei Zhang, Jing Yu, Ming Zhang, Yuanzhen Zhang, Shujie Liao","doi":"10.1016/j.canlet.2025.217940","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217940","url":null,"abstract":"<p><p>In recent years more and more studies have pointed out that the microbiota plays an important role in the development of gynecological tumors. A healthy female reproductive tract microbiota is dominated by lactobacilli, which can produce lactic acid and other metabolites to protect the normal reproductive tract microenvironment. If the microflora is out of balance, the abnormally increased flora may contribute to inflammation and even cancer in the reproductive system by activating the immune response, regulating metabolites and hormone levels. In this review, we focus on the relationship between microbiota and three common gynecological cancers, namely cervical, endometrial and ovarian cancers, as well as the significance of microbes in the prevention, diagnosis, and treatment of these cancers, and we introduce the application of multi-omics techniques in microbes; finally, we analyze the common characteristics of microbes in gynecological cancers, and we propose the current challenges and future research directions.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217940"},"PeriodicalIF":9.1,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682090","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}
引用次数: 0
NSUN2-mediated m5C modification of KDM6B mRNA enhances osteoclast differentiation and promotes breast cancer bone metastasis. nsun2介导的m5C修饰KDM6B mRNA增强破骨细胞分化,促进乳腺癌骨转移。
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-07-19 DOI: 10.1016/j.canlet.2025.217939
Ming Zhang, Cheng Tang, Shang Li, Xinluan Jiang, Bilan Li, Yan Chen, Que Zheng, Yuting Tang, Xiaoshu Zhu, Lei Huang, Hongyan Yuan, Jue Wang, Yongmei Yin, Yucui Jin, Changyan Ma
{"title":"NSUN2-mediated m<sup>5</sup>C modification of KDM6B mRNA enhances osteoclast differentiation and promotes breast cancer bone metastasis.","authors":"Ming Zhang, Cheng Tang, Shang Li, Xinluan Jiang, Bilan Li, Yan Chen, Que Zheng, Yuting Tang, Xiaoshu Zhu, Lei Huang, Hongyan Yuan, Jue Wang, Yongmei Yin, Yucui Jin, Changyan Ma","doi":"10.1016/j.canlet.2025.217939","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217939","url":null,"abstract":"<p><p>Bone metastasis frequently occurs in advanced breast cancer (BCa) and is associated with poor prognosis. The pathogenesis of bone metastasis is driven by cross-communications within the tumor-bone microenvironment. In this study, we demonstrated that NSUN2, a 5-methylcytosine (m<sup>5</sup>C) methyltransferase, is highly expressed in BCa tissues with bone metastasis compared to non-metastatic breast tumors. Overexpression of NSUN2 promoted osteoclast differentiation and osteolytic bone metastasis, whereas knockdown of NSUN2 had the opposite effects. Mechanistically, NSUN2 facilitates the degradation of lysine demethylase 6B (KDM6B) mRNA through m<sup>5</sup>C modification in a peptidylprolyl isomerase A (PPIA)-dependent manner. Reduced KDM6B leads to hypermethylation of NUMB, disrupting its interaction with the Notch1 intracellular domain (NICD1). Consequently, the Notch signaling pathway is activated, leading to upregulated RANKL expression and accelerated osteoclast differentiation, which contributes to osteolytic bone metastasis. Strikingly, activating KDM6B expression with paricalcitol or inhibiting the Notch pathway with DAPT effectively counteracted NSUN2-induced osteolytic bone metastasis in vivo. Collectively, our findings underscore the pivotal role of the NSUN2-KDM6B-Notch axis in promoting osteoclast differentiation and bone metastasis in BCa, providing potential therapeutic targets for BCa patients with bone metastasis.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217939"},"PeriodicalIF":9.1,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682091","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}
引用次数: 0
CircFLNB upregulated by chemotherapy via alternative splicing suppresses the progression of colorectal cancer 化疗通过选择性剪接上调cirflnb抑制结直肠癌的进展。
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-07-18 DOI: 10.1016/j.canlet.2025.217932
Ying Han , Xinyue Xu , Yinghui Peng , Jiang Zhu , Yijia Tang , Wantao Wu , Yan Gao , Zhaohui Jiang , Xiangyang Zhang , Peng Zhang , Jiang Fei , Changjing Cai , Hong Shen , Shan Zeng
{"title":"CircFLNB upregulated by chemotherapy via alternative splicing suppresses the progression of colorectal cancer","authors":"Ying Han ,&nbsp;Xinyue Xu ,&nbsp;Yinghui Peng ,&nbsp;Jiang Zhu ,&nbsp;Yijia Tang ,&nbsp;Wantao Wu ,&nbsp;Yan Gao ,&nbsp;Zhaohui Jiang ,&nbsp;Xiangyang Zhang ,&nbsp;Peng Zhang ,&nbsp;Jiang Fei ,&nbsp;Changjing Cai ,&nbsp;Hong Shen ,&nbsp;Shan Zeng","doi":"10.1016/j.canlet.2025.217932","DOIUrl":"10.1016/j.canlet.2025.217932","url":null,"abstract":"<div><div>Alternative splicing (AS) is a tightly regulated process that gives rise to proteins with distinct or even opposing functions. But cancer-specific alternative splicing of circRNA formation is less likely to be identified. We identified circFLNB by a circRNA microarray and validated it by quantitative reverse transcription PCR. The role of circFLNB in CRC progression was assessed both in vitro and in vivo, and its downstream target genes were identified and validated in CRC cells by bioinformatics analysis and confirmed by luciferase reporter assays. The dysregulated alternative splicing events and splicing factors in chemotherapy-induced CRC tissues were identified using RNA-seq and rMATS analysis. The clinical implications of circFLNB were assessed in CRC tissue using the nomogram algorithm. We found that circFLNB was weakly expressed in colorectal cancer tissues and cells and its expression was increased by chemotherapy. Functionally, circFLNB repressed the proliferation and invasion of CRC cells in vitro, as well as inhibited the growth of CRC xenografts in mice in vivo. Mechanistically, circFLNB inhibited the proliferation of CRC in vivo and in vitro by targeting the miR-3127-3p/MOB1B/Hippo pathway. Furthermore, our investigation indicated that splicing factors QKI and CELF4 are essential and sufficient for the circFLNB biogenesis through chemotherapy-regulated alternative splicing. A patient prognosis model based on circFLNB expression levels can effectively predict the prognosis of CRC patients. Our research demonstrated that QKI- and CELF4- dependent alternative splicing induced by chemotherapy promotes circFLNB biogenesis, which inhibits CRC tumorigenesis via binding with miR-3127-3p to regulate the MOB1B/Hippo pathway.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217932"},"PeriodicalIF":9.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673965","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}
引用次数: 0
PAF signaling axis functions as biomarker or target for esophageal squamous cell carcinoma diagnosis or treatment PAF信号轴可作为食管癌诊断或治疗的生物标志物或靶点
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-07-18 DOI: 10.1016/j.canlet.2025.217937
Yanmeng Zhu , Fenglong Wang , Yuheng Zhu , Jingyuan Pang , Qingnan Wu , Yan Wang , Qimin Zhan , Jie Chen
{"title":"PAF signaling axis functions as biomarker or target for esophageal squamous cell carcinoma diagnosis or treatment","authors":"Yanmeng Zhu ,&nbsp;Fenglong Wang ,&nbsp;Yuheng Zhu ,&nbsp;Jingyuan Pang ,&nbsp;Qingnan Wu ,&nbsp;Yan Wang ,&nbsp;Qimin Zhan ,&nbsp;Jie Chen","doi":"10.1016/j.canlet.2025.217937","DOIUrl":"10.1016/j.canlet.2025.217937","url":null,"abstract":"<div><div>Dysregulated lipid metabolism is one of the most extinguishing metabolic hallmarks, and contributes to tumorigenesis and tumor malignancy. Platelet-activating factor (PAF), the lipid metabolite, serves as an inflammatory stimulator to induce the aggressive progression of esophageal squamous cell carcinoma (ESCC). However, whether PAF and its downstream signaling axis can function as biomarker or therapeutic target for ESCC diagnosis or treatment are still unclear. In this study, we found that plasma PAF level can reflect the lymph node (LN) metastasis status of ESCC patients. Importantly, results from Olink assay showed that several cytokines in plasma, such as interleukin-8 (IL-8), C-X-C motif chemokine ligand 1 (CXCL1), CXCL5, or CXCL11 were positively related with the LN metastasis status of ESCC patients, the expression of these cytokines was also tightly correlated with that of PAF in the plasma from LN metastatic ESCC patients. Results from RNA-seq in ESCC cell lines and immunohistochemistry (IHC) in clinical ESCC samples showed that PAF signaling effectively induced the expression of these cytokines and some tumor-promoting molecules in ESCC. Therapeutically, ginkgetin, a natural biflavonoid isolated from <em>Ginkgo biloba</em> L, inhibited the PAF-mediated Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) activation, the expression of downstream inflammatory cytokines, glycolysis- and tumor-progression related molecules, and the malignancy of tumor cells both <em>in vitro</em> and <em>in vivo</em>, but generated barely significant toxicity towards the normal tissues of xenografted animals. Present study has illustrated that PAF can serve as biomarker for evaluation of ESCC LN metastasis, and ginkgetin could exert excellent antitumor effect on ESCC cells via suppressing PAF axis-controlled signaling pathways.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217937"},"PeriodicalIF":9.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665512","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}
引用次数: 0
SMARCA1-NPFF axis inhibits colorectal cancer metastasis by blocking epithelial-mesenchymal transition and macrophage-dependent immune reprogramming SMARCA1-NPFF轴通过阻断上皮-间质转化和巨噬细胞依赖性免疫重编程抑制结直肠癌转移。
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-07-18 DOI: 10.1016/j.canlet.2025.217933
Haojia Wang , Shuya Du , Songtao Ji , Ge Miao , Jianing Yu , Mingzhen Zhou , Yuanci Zhang , Xuemei Li , Wanqi Ma , Ang Li , Xiaohua Yang , Yun Zhou , Junshu Wang , Xiaoyu Huang , Xin Wang , Zhenxiong Liu , Xue Bai , Yuanyuan Lu , Xiaodi Zhao
{"title":"SMARCA1-NPFF axis inhibits colorectal cancer metastasis by blocking epithelial-mesenchymal transition and macrophage-dependent immune reprogramming","authors":"Haojia Wang ,&nbsp;Shuya Du ,&nbsp;Songtao Ji ,&nbsp;Ge Miao ,&nbsp;Jianing Yu ,&nbsp;Mingzhen Zhou ,&nbsp;Yuanci Zhang ,&nbsp;Xuemei Li ,&nbsp;Wanqi Ma ,&nbsp;Ang Li ,&nbsp;Xiaohua Yang ,&nbsp;Yun Zhou ,&nbsp;Junshu Wang ,&nbsp;Xiaoyu Huang ,&nbsp;Xin Wang ,&nbsp;Zhenxiong Liu ,&nbsp;Xue Bai ,&nbsp;Yuanyuan Lu ,&nbsp;Xiaodi Zhao","doi":"10.1016/j.canlet.2025.217933","DOIUrl":"10.1016/j.canlet.2025.217933","url":null,"abstract":"<div><div>Dysregulation of chromatin remodeling represents an essential driving factor for cancer development and progression. Our previous work demonstrated that increased inclusion of exon 13 during alternative splicing functionally inactivates SMARCA1, the catalytic subunit of the ISWI chromatin remodeling complex, to promote colorectal cancer (CRC) metastasis, but the precise mechanism underlying SMARCA1-mediated metastasis suppression remains elusive. In this study, through ATAC-seq and RNA-seq analyses, we established an inverse correlation between SMARCA1 activity and neuropeptide FF (NPFF) transcriptional output in CRC cell lines and clinical specimens. Ectopic NPFF expression significantly enhanced CRC cell migration, invasion and metastatic potential, effectively counteracting the antimetastatic function mediated by SMARCA1. Mechanistically, SMARCA1 attenuates NPFF transcription by impairing the DNA-binding capacity of the ETS-family transcription factor SPIB at the NPFF promoter. SMARCA1-deficient CRC cells exhibit increased NPFF secretion, which drives epithelial‒mesenchymal transition (EMT) through autocrine activation of the JAK2/STAT5 signaling axis, subsequently increasing the expression of EMT-related transcription factors. Notably, the oncogenic activity of NPFF was also dependent on immune microenvironment modulation, as NPFF orchestrated the polarization of tumor-associated macrophages toward the M2-like phenotype while upregulating protumorigenic genes, which encode growth factors, chemokines, and matrix metalloproteinases, in macrophages. Our study reveals the SMARCA1–NPFF axis as a dual regulator of metastatic progression and immune microenvironment reprogramming in CRC, identifying the NPFF as a novel therapeutic vulnerability factor for the management of metastatic CRC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217933"},"PeriodicalIF":9.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673977","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}
引用次数: 0
Corrigendum to "Sublethal heat treatment of hepatocellular carcinoma promotes intrahepatic metastasis and stemness in a VEGFR1-dependent manner" [Cancer Lett. (460), 28 September 2019, Pages 29-40]. “肝细胞癌的亚致死热处理以vegfr1依赖的方式促进肝内转移和干细胞”的更正[Cancer Lett]。(460), 2019年9月28日,页29-40]。
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-07-18 DOI: 10.1016/j.canlet.2025.217893
Li Tan, Shuling Chen, Guangyan Wei, Yue Li, Junbin Liao, Huilin Jin, Ying Zou, Manling Huang, Zhenwei Peng, Yu Guo, Sui Peng, Lixia Xu, Ming Kuang
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