Pub Date : 2025-11-19DOI: 10.1016/j.canlet.2025.218156
Song Tan , Yifan Chen , Yizhen Chen , Shaolin Liu , Changshun Yang , Yulong Mi , Xiaojun Lin , Houqiang Li , Hengrui Liu , Weihua Li , Shengtao Lin
Colorectal cancer (CRC) remains a significant global health challenge and is characterized by high incidence and mortality rates. Although the homeobox gene family has been implicated in oncogenic processes, the precise functional role of HOXC8 in regulating CRC proliferation and stemness remains poorly defined. Cancer cells with stem-related properties, a distinct cellular subpopulation endowed with self-renewal and differentiation capacities, play pivotal roles in tumor initiation, metastasis, and therapeutic resistance. In this study, we demonstrate that HOXC8 overexpression promotes CRC cell proliferation, enhances stemness properties, and confers chemoresistance. Mechanistically, HOXC8 transcriptionally activates TRIM22, leading to the ubiquitination and degradation of IκBα, which subsequently potentiates NF-κB signaling to drive stemness maintenance in CRC cells. These findings delineate a previously unrecognized HOXC8/TRIM22/NF-κB signaling axis that critically regulates tumor progression, offering a promising molecular target for therapeutic intervention in CRC.
{"title":"HOXC8-activated TRIM22/NF-κB pathway promotes stemness in colorectal cancer","authors":"Song Tan , Yifan Chen , Yizhen Chen , Shaolin Liu , Changshun Yang , Yulong Mi , Xiaojun Lin , Houqiang Li , Hengrui Liu , Weihua Li , Shengtao Lin","doi":"10.1016/j.canlet.2025.218156","DOIUrl":"10.1016/j.canlet.2025.218156","url":null,"abstract":"<div><div>Colorectal cancer (CRC) remains a significant global health challenge and is characterized by high incidence and mortality rates. Although the homeobox gene family has been implicated in oncogenic processes, the precise functional role of HOXC8 in regulating CRC proliferation and stemness remains poorly defined. Cancer cells with stem-related properties, a distinct cellular subpopulation endowed with self-renewal and differentiation capacities, play pivotal roles in tumor initiation, metastasis, and therapeutic resistance. In this study, we demonstrate that HOXC8 overexpression promotes CRC cell proliferation, enhances stemness properties, and confers chemoresistance. Mechanistically, HOXC8 transcriptionally activates TRIM22, leading to the ubiquitination and degradation of IκBα, which subsequently potentiates NF-κB signaling to drive stemness maintenance in CRC cells. These findings delineate a previously unrecognized HOXC8/TRIM22/NF-κB signaling axis that critically regulates tumor progression, offering a promising molecular target for therapeutic intervention in CRC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"638 ","pages":"Article 218156"},"PeriodicalIF":10.1,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562986","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}
Pub Date : 2025-11-17DOI: 10.1016/j.canlet.2025.218042
Liangjie Sun , Xiaolei Gao , Meng Wang , Yixin Zhang , Ruiqing Sun , Yang Chen , Yan Bai , Yi Li , Lan Luo , Chong Ding , Yixiang Wang
{"title":"Corrigendum to “Gobal crotonylome reveals that HNRNPC and its crotonylation promote p53-deficient tumor growth by stabilizing CCND1 and MCM3 mRNAs” [Cancer Lett. 628 (2025) 217854]","authors":"Liangjie Sun , Xiaolei Gao , Meng Wang , Yixin Zhang , Ruiqing Sun , Yang Chen , Yan Bai , Yi Li , Lan Luo , Chong Ding , Yixiang Wang","doi":"10.1016/j.canlet.2025.218042","DOIUrl":"10.1016/j.canlet.2025.218042","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"636 ","pages":"Article 218042"},"PeriodicalIF":10.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145548181","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}
Pub Date : 2025-11-17DOI: 10.1016/j.canlet.2025.218150
Zhiping Chen , Zhenxing Liang , Tanxing Cai , Xin Yang , Haiqing Jie , Wei Xiao , Xiaobin Zheng , Huashan Liu , Liang Huang , Li Xiong , Guolin Li , Liang Kang
Distant metastasis constitutes the predominant determinant of adverse prognosis and mortality in colorectal cancer (CRC), with hepatic dissemination representing the most prevalent metastatic pattern and primary contributor to CRC-related deaths. The pathogenesis of colorectal liver metastases (CRLM) involves a multistep cascade modulated by intricate tumor-host interactions, yet the molecular drivers remain incompletely elucidated. Through comparative transcriptomic profiling of matched primary tumors (PT) and liver metastases (LM) in CRC patients, we identified angiopoietin-like protein 3 (ANGPTL3) as a metastasis-associated molecular signature showing significant upregulation in LM tissues correlating with aggressive clinicopathological features. Functional characterization revealed that ANGPTL3 overexpression orchestrated pro-metastatic reprogramming, potentiating in vitro proliferation, migration, and invasion capacities, while concurrently driving subcutaneous tumorigenesis and hepatic colonization in vivo. Conversely, ANGPTL3 silencing markedly attenuated these malignant phenotypes. Mechanistic investigations revealed that ANGPTL3 binds to integrin αVβ3 via its FLD domain, inducing ITGB3 phosphorylation at Y773 and activating the downstream FAK/Src-JAK2/STAT3 axis. This cascade culminates in the transcriptional upregulation of the core extracellular matrix (ECM) component COL1A2, resulting in aberrant collagen deposition and ECM remodeling. The remodeled microenvironment in turn facilitates epithelial-mesenchymal transition (EMT) and angiogenesis, thereby promoting CRC progression and metastasis. Our findings thus delineate the ANGPTL3-integrin αVβ3-STAT3-COL1A2 axis as a central driver of CRC metastasis, nominating ANGPTL3 as both prognostic biomarker for metastatic risk stratification and therapeutic target amenable to molecular intervention in CRC management.
{"title":"ANGPTL3 promotes colorectal carcinoma progression and metastasis through regulating COL1A2 transcription via interacting with integrin αVβ3","authors":"Zhiping Chen , Zhenxing Liang , Tanxing Cai , Xin Yang , Haiqing Jie , Wei Xiao , Xiaobin Zheng , Huashan Liu , Liang Huang , Li Xiong , Guolin Li , Liang Kang","doi":"10.1016/j.canlet.2025.218150","DOIUrl":"10.1016/j.canlet.2025.218150","url":null,"abstract":"<div><div>Distant metastasis constitutes the predominant determinant of adverse prognosis and mortality in colorectal cancer (CRC), with hepatic dissemination representing the most prevalent metastatic pattern and primary contributor to CRC-related deaths. The pathogenesis of colorectal liver metastases (CRLM) involves a multistep cascade modulated by intricate tumor-host interactions, yet the molecular drivers remain incompletely elucidated. Through comparative transcriptomic profiling of matched primary tumors (PT) and liver metastases (LM) in CRC patients, we identified angiopoietin-like protein 3 (ANGPTL3) as a metastasis-associated molecular signature showing significant upregulation in LM tissues correlating with aggressive clinicopathological features. Functional characterization revealed that ANGPTL3 overexpression orchestrated pro-metastatic reprogramming, potentiating in vitro proliferation, migration, and invasion capacities, while concurrently driving subcutaneous tumorigenesis and hepatic colonization in vivo. Conversely, ANGPTL3 silencing markedly attenuated these malignant phenotypes. Mechanistic investigations revealed that ANGPTL3 binds to integrin αVβ3 via its FLD domain, inducing ITGB3 phosphorylation at Y773 and activating the downstream FAK/Src-JAK2/STAT3 axis. This cascade culminates in the transcriptional upregulation of the core extracellular matrix (ECM) component COL1A2, resulting in aberrant collagen deposition and ECM remodeling. The remodeled microenvironment in turn facilitates epithelial-mesenchymal transition (EMT) and angiogenesis, thereby promoting CRC progression and metastasis. Our findings thus delineate the ANGPTL3-integrin αVβ3-STAT3-COL1A2 axis as a central driver of CRC metastasis, nominating ANGPTL3 as both prognostic biomarker for metastatic risk stratification and therapeutic target amenable to molecular intervention in CRC management.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"638 ","pages":"Article 218150"},"PeriodicalIF":10.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556352","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}
Pub Date : 2025-11-17DOI: 10.1016/j.canlet.2025.218153
Yanghong Ni , Xiaoting Zhou , Yan Tang , Wenyan Ren , Xiao Liang , Yi Lin , Houhui Shi , Furong Qing , Aqu Alu , Ruyu Pi , Jian Liu , Xia Zhao , Min Luo , Xiawei Wei
Radiotherapy resistance is a major contributor to therapeutic failure in cervical cancer, largely due to the immunosuppressive tumor microenvironment (TME). Increasing clinical and experimental evidence underscores the role of neutrophils infiltration in reducing the efficacy of radiation therapy. Additionally, the CXCR2/CXCL signaling axis has been identified as a key regulator of neutrophils recruitment.
Our study demonstrates that radiotherapy significantly enhances neutrophils infiltration by activating CXCR2-CXCL signaling and drives their polarization toward a pro-tumor N2-like phenotype through TGF-β signaling in cervical cancer. Further investigation revealed that CXCR2 antagonist SB225002 exerts a synergistic effect with radiotherapy and concurrent chemoradiotherapy in cervical cancer, primarily via inhibiting neutrophils infiltration and alleviating the immunosuppressive TME. Meanwhile, SB225002 exerts direct antitumor activity and enhances the radiosensitivity of cervical cancer cells by facilitating DNA double-strand breaks, promoting G2/M phase cell cycle arrest, and inducing apoptosis.
In summary, our findings highlight neutrophils inhibition via CXCR2 antagonist as a promising therapeutic strategy to enhance cervical cancer responsiveness to radiotherapy.
{"title":"SB225002 enhances radiosensitivity in cervical cancer via direct neutrophil inhibition and tumor cell suppression","authors":"Yanghong Ni , Xiaoting Zhou , Yan Tang , Wenyan Ren , Xiao Liang , Yi Lin , Houhui Shi , Furong Qing , Aqu Alu , Ruyu Pi , Jian Liu , Xia Zhao , Min Luo , Xiawei Wei","doi":"10.1016/j.canlet.2025.218153","DOIUrl":"10.1016/j.canlet.2025.218153","url":null,"abstract":"<div><div>Radiotherapy resistance is a major contributor to therapeutic failure in cervical cancer, largely due to the immunosuppressive tumor microenvironment (TME). Increasing clinical and experimental evidence underscores the role of neutrophils infiltration in reducing the efficacy of radiation therapy. Additionally, the CXCR2/CXCL signaling axis has been identified as a key regulator of neutrophils recruitment.</div><div>Our study demonstrates that radiotherapy significantly enhances neutrophils infiltration by activating CXCR2-CXCL signaling and drives their polarization toward a pro-tumor N2-like phenotype through TGF-β signaling in cervical cancer. Further investigation revealed that CXCR2 antagonist SB225002 exerts a synergistic effect with radiotherapy and concurrent chemoradiotherapy in cervical cancer, primarily via inhibiting neutrophils infiltration and alleviating the immunosuppressive TME. Meanwhile, SB225002 exerts direct antitumor activity and enhances the radiosensitivity of cervical cancer cells by facilitating DNA double-strand breaks, promoting G2/M phase cell cycle arrest, and inducing apoptosis.</div><div>In summary, our findings highlight neutrophils inhibition via CXCR2 antagonist as a promising therapeutic strategy to enhance cervical cancer responsiveness to radiotherapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"638 ","pages":"Article 218153"},"PeriodicalIF":10.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556304","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}
Pub Date : 2025-11-17DOI: 10.1016/j.canlet.2025.218154
Tiance Wang , Zijian Lv , Runjia Fan , Jiejie Liu , Yan Zhang , Chunmeng Wang , Qianyi Ming , Meixia Chen , Yulin Jia , Qingming Yang , Zhengfan Jiang , Qian Mei , Weidong Han
Abscopal effect remains rare and clinically unpredictable because of immunosuppressive mechanisms and inadequate immune activation. This phenomenon may stem from cyclic GMP-AMP synthase (cGAS) sequestration within the nucleus, where high-affinity nucleosome-DNA interactions potently suppress cGAS activation. Our study elucidates the capacity of manganese (Mn2+) to overcome this limitation through cytoplasmic relocalization and potentiation of cGAS activity, thereby enabling abscopal responses. We demonstrated that Mn2+ disrupts nucleosomal constraints on cGAS, permitting robust double-stranded DNA (dsDNA) sensing and activation. This molecular reprogramming amplifies cytosolic cGAS-STING signaling cascades and IFN-I production in irradiated tumors, potentiating systemic antitumor immunity. Notably, Mn2+ exerts direct immunostimulatory effects on adaptive immunity by activating T cells, creating synergistic therapeutic benefits. Preliminary clinical observations in advanced metastatic malignancies have demonstrated that Mn2+ augments abscopal responses during radiotherapy. These findings mechanistically delineate the dual role of Mn2+ in modulating tumor-intrinsic cGAS-STING activation and immune effector functions, supporting its therapeutic application in combination with radioimmunotherapy regimens to overcome tumor microenvironment immunosuppression and induce abscopal effect.
{"title":"Manganese mediates nucleoplasm distribution of cGAS to enhance systemic antitumor immunity and drive abscopal effect","authors":"Tiance Wang , Zijian Lv , Runjia Fan , Jiejie Liu , Yan Zhang , Chunmeng Wang , Qianyi Ming , Meixia Chen , Yulin Jia , Qingming Yang , Zhengfan Jiang , Qian Mei , Weidong Han","doi":"10.1016/j.canlet.2025.218154","DOIUrl":"10.1016/j.canlet.2025.218154","url":null,"abstract":"<div><div>Abscopal effect remains rare and clinically unpredictable because of immunosuppressive mechanisms and inadequate immune activation. This phenomenon may stem from cyclic GMP-AMP synthase (cGAS) sequestration within the nucleus, where high-affinity nucleosome-DNA interactions potently suppress cGAS activation. Our study elucidates the capacity of manganese (Mn<sup>2+</sup>) to overcome this limitation through cytoplasmic relocalization and potentiation of cGAS activity, thereby enabling abscopal responses. We demonstrated that Mn<sup>2+</sup> disrupts nucleosomal constraints on cGAS, permitting robust double-stranded DNA (dsDNA) sensing and activation. This molecular reprogramming amplifies cytosolic cGAS-STING signaling cascades and IFN-I production in irradiated tumors, potentiating systemic antitumor immunity. Notably, Mn<sup>2+</sup> exerts direct immunostimulatory effects on adaptive immunity by activating T cells, creating synergistic therapeutic benefits. Preliminary clinical observations in advanced metastatic malignancies have demonstrated that Mn<sup>2+</sup> augments abscopal responses during radiotherapy. These findings mechanistically delineate the dual role of Mn<sup>2+</sup> in modulating tumor-intrinsic cGAS-STING activation and immune effector functions, supporting its therapeutic application in combination with radioimmunotherapy regimens to overcome tumor microenvironment immunosuppression and induce abscopal effect.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"637 ","pages":"Article 218154"},"PeriodicalIF":10.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556326","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}
Pub Date : 2025-11-17DOI: 10.1016/j.canlet.2025.218155
Guoqing Li , Yuxuan Wan , Gaoyuan Cui , Ke Jiang , Jiaoao Su , Saili Duan , Shi Chang
Circadian rhythm, a biological clock-regulated physiological phenomenon with a periodicity of approximately 24 h, is controlled by multiple core molecules, including BMAL1, CLOCK, PERs, and CRYs. Multiple lines of evidence demonstrates that circadian rhythm disruption can influence the metastatic cascade by modulating epithelial-mesenchymal transition, cancer stem cells, circulating tumor cells, the tumor microenvironment, and immune surveillance. Mechanistically, clock dysregulation drives extracellular matrix remodeling and alters matrix stiffness, fostering a pro-metastatic niche. It also disrupts immune homeostasis by inducing T cell exhaustion, promoting NK cell senescence, and reprogramming macrophage polarization toward tumor-supportive phenotypes. Therapeutically, targeting core circadian molecules and implementing chronotherapy have shown significant clinical potential. This review highlights the role of circadian rhythm disruption in promoting various stages of the metastatic cascade across cancers and explores the therapeutic potential of circadian-targeted agents and chronotherapy in controlling cancer metastasis. By synthesizing current evidence, we propose a novel conceptual framework that positions circadian rhythm disruption as a temporal gatekeeper of metastatic plasticity, offering a pan-cancer unifying model and new insights into the development of chronotherapeutic strategies aimed at controlling metastasis.
{"title":"Cancer metastasis mediated by circadian rhythm disruption: Molecular mechanisms to clinical significance and implications","authors":"Guoqing Li , Yuxuan Wan , Gaoyuan Cui , Ke Jiang , Jiaoao Su , Saili Duan , Shi Chang","doi":"10.1016/j.canlet.2025.218155","DOIUrl":"10.1016/j.canlet.2025.218155","url":null,"abstract":"<div><div>Circadian rhythm, a biological clock-regulated physiological phenomenon with a periodicity of approximately 24 h, is controlled by multiple core molecules, including BMAL1, CLOCK, PERs, and CRYs. Multiple lines of evidence demonstrates that circadian rhythm disruption can influence the metastatic cascade by modulating epithelial-mesenchymal transition, cancer stem cells, circulating tumor cells, the tumor microenvironment, and immune surveillance. Mechanistically, clock dysregulation drives extracellular matrix remodeling and alters matrix stiffness, fostering a pro-metastatic niche. It also disrupts immune homeostasis by inducing T cell exhaustion, promoting NK cell senescence, and reprogramming macrophage polarization toward tumor-supportive phenotypes. Therapeutically, targeting core circadian molecules and implementing chronotherapy have shown significant clinical potential. This review highlights the role of circadian rhythm disruption in promoting various stages of the metastatic cascade across cancers and explores the therapeutic potential of circadian-targeted agents and chronotherapy in controlling cancer metastasis. By synthesizing current evidence, we propose a novel conceptual framework that positions circadian rhythm disruption as a temporal gatekeeper of metastatic plasticity, offering a pan-cancer unifying model and new insights into the development of chronotherapeutic strategies aimed at controlling metastasis.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"638 ","pages":"Article 218155"},"PeriodicalIF":10.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556374","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}
Pub Date : 2025-11-17DOI: 10.1016/j.canlet.2025.218124
Paula Groza , Kanchan Kumari , Margalida Esteva-Socias , Johanna Schott , Devi Prasad Bhattarai , Joanna J. Sajkowska , Rubin Dasgupta , Carlos Peula , Eliana Destefanis , Chloe Williams , Virginie Marchand , Pernilla Wikström , Rebecca Wiberg , Ana Bosch Campos , Jonathan D. Gilthorpe , Bogdan Pop , Andre Mateus , Yuri Motorin , Erik Dassi , Katja Petzold , Francesca Aguilo
Fibrillarin (FBL), a core component of the C/D box small nucleolar ribonucleoprotein (snoRNP) complex, catalyzes the 2′-O-methylation (Nm) of the ribose 2′-hydroxyl moiety in ribosomal RNA (rRNA). Distinct Nm patterns contribute to ribosome heterogeneity, which is linked to selective translation of oncogenes. FBL dysregulation generates an aberrant Nm signature in triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype. This study investigated the role of FBL in TNBC via translation-driven mechanisms. Our findings show that FBL knockdown impairs oncogenic traits, triggers metabolic stress, and reduces the translation efficiency of oncogenes, such as metastasis-associated protein 1 (MTA1), interleukin-1 receptor-associated kinase 1 (IRAK1), and thymosin beta 10 (TMSB10). RiboMethSeq confirmed that the rRNA Nm sites exhibited differential sensitivity to FBL depletion. Additionally, FBL knockdown led to alterations in 18S ribosome structure confirmed by SHAPE and specifically reduced RPS28 incorporation into ribosomes. Notably, silencing RPS28 also disrupted both the oncogenic phenotype and downregulated MTA1, IRAK1, and TMSB10 expression. These findings reveal a complex interplay between FBL, rRNA Nm modifications, and RPS28 in shaping oncogenic protein pools and ribosomal composition in TNBC, offering promising insights into therapeutic approaches targeting this aggressive cancer subtype.
纤原蛋白（fibrarin， FBL）是C/D盒小核核核糖核蛋白（snoRNP）复合物的核心组分，可催化核糖体RNA （rRNA）中核糖2′-羟基部分的2′- o -甲基化（Nm）。不同的Nm模式有助于核糖体的异质性，这与癌基因的选择性翻译有关。FBL失调在三阴性乳腺癌（TNBC）中产生异常的Nm信号，TNBC是最具侵略性的乳腺癌亚型。本研究通过翻译驱动机制探讨了FBL在TNBC中的作用。我们的研究结果表明，FBL敲低会损害致癌性状，引发代谢应激，并降低癌基因的翻译效率，如转移相关蛋白1 （MTA1）、白细胞介素-1受体相关激酶1 （IRAK1）和胸腺酶β 10 （TMSB10）。RiboMethSeq证实，rRNA Nm位点对FBL缺失表现出不同的敏感性。此外，FBL敲低导致SHAPE证实的18S核糖体结构改变，并特异性减少RPS28与核糖体的结合。值得注意的是，沉默RPS28也破坏了致癌表型，下调了MTA1、IRAK1和TMSB10的表达。这些发现揭示了FBL、rRNA纳米修饰和RPS28在TNBC中形成致癌蛋白池和核糖体组成的复杂相互作用，为针对这种侵袭性癌症亚型的治疗方法提供了有希望的见解。
{"title":"Fibrillarin-dependent 2′-O-methylation modulates RPS28 ribosome incorporation and oncogenic translation","authors":"Paula Groza , Kanchan Kumari , Margalida Esteva-Socias , Johanna Schott , Devi Prasad Bhattarai , Joanna J. Sajkowska , Rubin Dasgupta , Carlos Peula , Eliana Destefanis , Chloe Williams , Virginie Marchand , Pernilla Wikström , Rebecca Wiberg , Ana Bosch Campos , Jonathan D. Gilthorpe , Bogdan Pop , Andre Mateus , Yuri Motorin , Erik Dassi , Katja Petzold , Francesca Aguilo","doi":"10.1016/j.canlet.2025.218124","DOIUrl":"10.1016/j.canlet.2025.218124","url":null,"abstract":"<div><div>Fibrillarin (FBL), a core component of the C/D box small nucleolar ribonucleoprotein (snoRNP) complex, catalyzes the 2′-O-methylation (Nm) of the ribose 2′-hydroxyl moiety in ribosomal RNA (rRNA). Distinct Nm patterns contribute to ribosome heterogeneity, which is linked to selective translation of oncogenes. FBL dysregulation generates an aberrant Nm signature in triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype. This study investigated the role of FBL in TNBC via translation-driven mechanisms. Our findings show that FBL knockdown impairs oncogenic traits, triggers metabolic stress, and reduces the translation efficiency of oncogenes, such as metastasis-associated protein 1 (<em>MTA1</em>), interleukin-1 receptor-associated kinase 1 (<em>IRAK1</em>), and thymosin beta 10 (<em>TMSB10</em>). RiboMethSeq confirmed that the rRNA Nm sites exhibited differential sensitivity to FBL depletion. Additionally, FBL knockdown led to alterations in 18S ribosome structure confirmed by SHAPE and specifically reduced RPS28 incorporation into ribosomes. Notably, silencing RPS28 also disrupted both the oncogenic phenotype and downregulated MTA1, IRAK1, and TMSB10 expression. These findings reveal a complex interplay between FBL, rRNA Nm modifications, and RPS28 in shaping oncogenic protein pools and ribosomal composition in TNBC, offering promising insights into therapeutic approaches targeting this aggressive cancer subtype.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218124"},"PeriodicalIF":10.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556328","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}
Pub Date : 2025-11-14DOI: 10.1016/j.canlet.2025.218129
Chenlu Hu , Jifan Chen , Xiao Liu , Yanan Zhao , Huili Pan , Xia Fang , Hua Yin , Guowei Wang , Pintong Huang
The insufficient vascular extravasation and dense extracellular matrix in pancreatic cancer jointly resist drug accumulation and penetration into tumor and lead to poor prognosis. The ligand/receptor-mediated nanocarrier has gained widespread recognition as an effective strategy for increasing the tumor targeting accumulation, but which is always impaired by protein corona pollution during circulation, as well as limited intratumor penetration. To address these problems, we have designed an E-selectin targeting cascaded ultrasonic cavitation liposome (GPGLP) that incorporates a gemcitabine prodrug (GOE), perfluoropentane, and an endogenous ligand ganglioside (GM1), which can sequentially overcome the biological barriers of tumor endothelial cells and the extracellular matrix via ligand/receptor-mediated transcytosis and ultrasonic cavitation-induced extracellular matrix loosening. The endogenous GM1 ganglioside can reduce the protein corona formation of liposome and guarantee its capability to recognize the E-selectin receptor on tumor neovascularization, initiating ligand/receptor-mediated transcytosis for efficient tumor accumulation. Upon exposure to ultrasound irradiation, GPGLP liposomes undergo a liquid-to-gas phase transition and self-assemble into smaller liposomes. The in-situ cavitation force following facilitates the extracellular matrix loosening, augmenting GPGLP deep penetration within the tumor parenchyma and releasing active gemcitabine throughout the tumor after intracellular enzymolysis. This process results in potent antitumor efficacy superior to that of clinical chemotherapeutics in pancreatic cancer treatement. This study presents an effective strategy of transcytosis cascaded ultrasonic cavitation to tackle the biological barriers in drug delivery for pancreatic cancer and other solid tumors.
{"title":"E-selectin targeting cascaded ultrasonic cavitation enables liposomes to deeply penetrate pancreatic cancer","authors":"Chenlu Hu , Jifan Chen , Xiao Liu , Yanan Zhao , Huili Pan , Xia Fang , Hua Yin , Guowei Wang , Pintong Huang","doi":"10.1016/j.canlet.2025.218129","DOIUrl":"10.1016/j.canlet.2025.218129","url":null,"abstract":"<div><div>The insufficient vascular extravasation and dense extracellular matrix in pancreatic cancer jointly resist drug accumulation and penetration into tumor and lead to poor prognosis. The ligand/receptor-mediated nanocarrier has gained widespread recognition as an effective strategy for increasing the tumor targeting accumulation, but which is always impaired by protein corona pollution during circulation, as well as limited intratumor penetration. To address these problems, we have designed an E-selectin targeting cascaded ultrasonic cavitation liposome (GPGLP) that incorporates a gemcitabine prodrug (GOE), perfluoropentane, and an endogenous ligand ganglioside (GM1), which can sequentially overcome the biological barriers of tumor endothelial cells and the extracellular matrix via ligand/receptor-mediated transcytosis and ultrasonic cavitation-induced extracellular matrix loosening. The endogenous GM1 ganglioside can reduce the protein corona formation of liposome and guarantee its capability to recognize the E-selectin receptor on tumor neovascularization, initiating ligand/receptor-mediated transcytosis for efficient tumor accumulation. Upon exposure to ultrasound irradiation, GPGLP liposomes undergo a liquid-to-gas phase transition and self-assemble into smaller liposomes. The <em>in-situ</em> cavitation force following facilitates the extracellular matrix loosening, augmenting GPGLP deep penetration within the tumor parenchyma and releasing active gemcitabine throughout the tumor after intracellular enzymolysis. This process results in potent antitumor efficacy superior to that of clinical chemotherapeutics in pancreatic cancer treatement. This study presents an effective strategy of transcytosis cascaded ultrasonic cavitation to tackle the biological barriers in drug delivery for pancreatic cancer and other solid tumors.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218129"},"PeriodicalIF":10.1,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534458","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号