Pub Date : 2026-01-30DOI: 10.1016/j.canlet.2026.218282
Kai Yu, Jiazhu Sun, Jiawei Zhang, Yuchen Shi, Junyan Wang, Yuqing Wu, Dingheng Lu, Xinyang Niu, Yuxiao Li, Suyuelin Huang, Jihuan Yuan, Zhixiang Qi, Fenghao Zhang, Jiangfeng Li, Hong Chen, Ben Liu
Acquired resistance to cisplatin remains a major therapeutic challenge in muscle-invasive bladder cancer. Here, we demonstrate for the first time that lactate accumulation induces AARS2-dependent lactylation of the m6A reader YTHDF3, establishing lactylation as a previously unrecognized regulatory layer of this epitranscriptomic factor. YTHDF3 lactylation stabilizes the protein by antagonizing ubiquitin-mediated degradation. Importantly, a lactylation-deficient YTHDF3 mutant fails to confer cisplatin resistance, underscoring the functional importance of this modification. Mechanistically, lactylated YTHDF3 enhances its m6A-dependent recognition and decay of KDM6B RNA. The resulting downregulation of KDM6B suppresses CDKN1A transcription through impaired H3K27me3 demethylation, representing an epigenetic mechanism that weakens the DNA damage response and promotes chemoresistance. Functional assays further demonstrate that YTHDF3 knockdown enhances cisplatin sensitivity in bladder cancer cells and xenograft tumors, whereas enforced expression of KDM6B or CDKN1A phenocopies the cisplatin-sensitizing effect of YTHDF3 knockdown. Collectively, our findings define a lactate-AARS2-YTHDF3-KDM6B-CDKN1A axis that integrates metabolic reprogramming, m6A-dependent epitranscriptomic regulation, and epigenetic chromatin remodeling to drive cisplatin resistance in bladder cancer.
{"title":"Lactylation enhances YTHDF3 stability to promote cisplatin resistance via m6A-dependent KDM6B decay in bladder cancer.","authors":"Kai Yu, Jiazhu Sun, Jiawei Zhang, Yuchen Shi, Junyan Wang, Yuqing Wu, Dingheng Lu, Xinyang Niu, Yuxiao Li, Suyuelin Huang, Jihuan Yuan, Zhixiang Qi, Fenghao Zhang, Jiangfeng Li, Hong Chen, Ben Liu","doi":"10.1016/j.canlet.2026.218282","DOIUrl":"10.1016/j.canlet.2026.218282","url":null,"abstract":"<p><p>Acquired resistance to cisplatin remains a major therapeutic challenge in muscle-invasive bladder cancer. Here, we demonstrate for the first time that lactate accumulation induces AARS2-dependent lactylation of the m6A reader YTHDF3, establishing lactylation as a previously unrecognized regulatory layer of this epitranscriptomic factor. YTHDF3 lactylation stabilizes the protein by antagonizing ubiquitin-mediated degradation. Importantly, a lactylation-deficient YTHDF3 mutant fails to confer cisplatin resistance, underscoring the functional importance of this modification. Mechanistically, lactylated YTHDF3 enhances its m6A-dependent recognition and decay of KDM6B RNA. The resulting downregulation of KDM6B suppresses CDKN1A transcription through impaired H3K27me3 demethylation, representing an epigenetic mechanism that weakens the DNA damage response and promotes chemoresistance. Functional assays further demonstrate that YTHDF3 knockdown enhances cisplatin sensitivity in bladder cancer cells and xenograft tumors, whereas enforced expression of KDM6B or CDKN1A phenocopies the cisplatin-sensitizing effect of YTHDF3 knockdown. Collectively, our findings define a lactate-AARS2-YTHDF3-KDM6B-CDKN1A axis that integrates metabolic reprogramming, m6A-dependent epitranscriptomic regulation, and epigenetic chromatin remodeling to drive cisplatin resistance in bladder cancer.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218282"},"PeriodicalIF":10.1,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099886","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}
The most widely accepted hypothesis for glioblastoma development posits that glioblastoma stem-like cells (GSCs) play a central role in tumor initiation, recurrence, and resistance to both chemotherapy and radiotherapy. We and others previously showed the importance of Mesenchyme Homeobox 2 (MEOX2) in supporting GSC survival and metabolism. In the present work, we demonstrate that MEOX2 also promotes DNA damage repair and contributes to resistance against genotoxic therapies in GSCs. Using a GLICO (GLioblastoma Cerebral Organoid) model, we show that MEOX2 knockdown impairs tumor growth and increases sensitivity to temozolomide (TMZ). Mechanistically, we find that MEOX2 depletion in 2D culture systems compromises genomic stability and impairs DNA repair. Co-immunoprecipitation and mass spectrometry analyses identified poly ADP-ribose polymerase 1 (PARP1) as a novel MEOX2 interactor. Consistent with this, MEOX2-depleted cells exhibit reduced PARylation levels and increased sensitivity to the PARP1 inhibitor Talazoparib, highlighting a potential therapeutic vulnerability.
Altogether, our findings reveal a previously unrecognized role for MEOX2 in the DNA damage response of GSCs, particularly in promoting survival and recovery after chemotherapy and ionizing radiation. These results also suggest that MEOX2 functions as a partner of PARP1 and may represent a promising therapeutic target in GBM.
{"title":"MEOX2 enhances DNA repair and therapy resistance in Glioblastoma stem-like cells via PARP1 interaction","authors":"Monia Russo , Elvia Valentini , Vincenza Aliperti , Federico Copparoni , Amanda Linkous , Claudia Montaldo , Silvia Soddu , Jean-Maxime Besson , Marie Lopez , Manuela Helmer Citterich , Alessandro Michienzi , Marco Tripodi , Silvia Anna Ciafrè , Silvia Galardi","doi":"10.1016/j.canlet.2026.218284","DOIUrl":"10.1016/j.canlet.2026.218284","url":null,"abstract":"<div><div>The most widely accepted hypothesis for glioblastoma development posits that glioblastoma stem-like cells (GSCs) play a central role in tumor initiation, recurrence, and resistance to both chemotherapy and radiotherapy. We and others previously showed the importance of Mesenchyme Homeobox 2 (MEOX2) in supporting GSC survival and metabolism. In the present work, we demonstrate that MEOX2 also promotes DNA damage repair and contributes to resistance against genotoxic therapies in GSCs. Using a GLICO (GLioblastoma Cerebral Organoid) model, we show that MEOX2 knockdown impairs tumor growth and increases sensitivity to temozolomide (TMZ). Mechanistically, we find that MEOX2 depletion in 2D culture systems compromises genomic stability and impairs DNA repair. Co-immunoprecipitation and mass spectrometry analyses identified poly ADP-ribose polymerase 1 (PARP1) as a novel MEOX2 interactor. Consistent with this, MEOX2-depleted cells exhibit reduced PARylation levels and increased sensitivity to the PARP1 inhibitor Talazoparib, highlighting a potential therapeutic vulnerability.</div><div>Altogether, our findings reveal a previously unrecognized role for MEOX2 in the DNA damage response of GSCs, particularly in promoting survival and recovery after chemotherapy and ionizing radiation. These results also suggest that MEOX2 functions as a partner of PARP1 and may represent a promising therapeutic target in GBM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218284"},"PeriodicalIF":10.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090229","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 : 2026-01-29DOI: 10.1016/j.canlet.2026.218288
Qian Zhao, Yao Yao, Ting Liang, Mengjie Chen, Minhui Zeng, Peixi Li, Shiyi Zhang, Tingting Yao
Platinum resistance continues to be a major therapeutic challenge in ovarian cancer, driving disease recurrence and limiting patient survival. In this study, we identify a significant enrichment of neutrophil extracellular traps (NETs) within the tumor microenvironment of platinum-resistant ovarian tumors. These NETs actively contribute to malignant progression by promoting epithelial-mesenchymal transition and fostering chemotherapy resistance. Mechanistically, we demonstrate that NETs drive chemoresistance through the unexpected activation of SHP-1. Although traditionally recognized as a tumor suppressor, SHP-1 assumes an oncogenic function in this context. Specifically, NETs trigger TGF-β signaling, resulting in Smad2 phosphorylation, which subsequently promotes both the enzymatic activation and nuclear translocation of SHP-1. Once in the nucleus, SHP-1 enhances RNA polymerase II-mediated transcription and nucleotide excision repair, ultimately enabling cancer cells to evade cisplatin-induced cytotoxicity. Our in vivo experiments corroborate these findings that elevated NETs levels exhibit poor response to cisplatin, while pharmacological inhibition of NETs effectively restores drug sensitivity. This study not only advances our understanding of microenvironment-driven drug resistance but also highlights the therapeutic potential of targeting the NETs/SHP-1 axis to overcome platinum resistance in ovarian cancer.
{"title":"Neutrophil Extracellular Traps Enhance Platinum Resistance in Ovarian Cancer via SHP-1 Activation.","authors":"Qian Zhao, Yao Yao, Ting Liang, Mengjie Chen, Minhui Zeng, Peixi Li, Shiyi Zhang, Tingting Yao","doi":"10.1016/j.canlet.2026.218288","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218288","url":null,"abstract":"<p><p>Platinum resistance continues to be a major therapeutic challenge in ovarian cancer, driving disease recurrence and limiting patient survival. In this study, we identify a significant enrichment of neutrophil extracellular traps (NETs) within the tumor microenvironment of platinum-resistant ovarian tumors. These NETs actively contribute to malignant progression by promoting epithelial-mesenchymal transition and fostering chemotherapy resistance. Mechanistically, we demonstrate that NETs drive chemoresistance through the unexpected activation of SHP-1. Although traditionally recognized as a tumor suppressor, SHP-1 assumes an oncogenic function in this context. Specifically, NETs trigger TGF-β signaling, resulting in Smad2 phosphorylation, which subsequently promotes both the enzymatic activation and nuclear translocation of SHP-1. Once in the nucleus, SHP-1 enhances RNA polymerase II-mediated transcription and nucleotide excision repair, ultimately enabling cancer cells to evade cisplatin-induced cytotoxicity. Our in vivo experiments corroborate these findings that elevated NETs levels exhibit poor response to cisplatin, while pharmacological inhibition of NETs effectively restores drug sensitivity. This study not only advances our understanding of microenvironment-driven drug resistance but also highlights the therapeutic potential of targeting the NETs/SHP-1 axis to overcome platinum resistance in ovarian cancer.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218288"},"PeriodicalIF":10.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096785","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 : 2026-01-27DOI: 10.1016/j.canlet.2026.218286
Meiwen Yuan , Yuting Hong , Yushu Feng , Jiaqi Sun , Xuelian Zhao , Shangying Hu , Fanghui Zhao
In China, cervical cancer incidence and mortality have continued to increase despite more than 15 years of nationwide organized screening, raising questions about the population-level impact of screening. Using national cancer registry data from 2004 to 2018, we analyzed temporal trends in age-standardized incidence rates (ASIRs) and mortality rates (ASMRs), as well as age-specific rates, using Joinpoint regression, and assessed their correlations with age-specific screening coverage.
From 2004 to 2018, ASIR increased from 6.06 to 11.81 per 100,000, but the annual growth rate slowed markedly after 2007, declining from 12.5 % (95 % CI: 9.7 ∼ 15.5 %) to 3.1 % (95 % CI: 2.7 ∼ 3.4 %). Among women aged 35–44 years, incidence trends shifted from a sharp rise to a sustained decline. By contrast, ASMR rose steadily from 2.07 to 3.44 per 100,000, with an average annual increase of 4.1 % (95 % CI: 3.4 ∼ 4.8 %). Notably, mortality stabilized after a rapid early rise among women aged 40–44 years, the group with the highest screening coverage. Correlation analysis revealed strong positive associations between higher screening coverage and the deceleration of incidence (ρ = 0.85, p < 0.001) and mortality trends (ρ = 0.69, p = 0.014).
These findings suggest that increased screening coverage may already be moderating incidence and mortality trends in specific age groups, particularly women aged 35–44 years. However, nationwide declines have yet to emerge, especially in rural populations where screening coverage remains low and disease burden is high. Expanding access and improving screening quality are critical to accelerate progress toward cervical cancer control in China.
{"title":"Cervical Cancer Incidence and Mortality Trends in China: The Role of Screening","authors":"Meiwen Yuan , Yuting Hong , Yushu Feng , Jiaqi Sun , Xuelian Zhao , Shangying Hu , Fanghui Zhao","doi":"10.1016/j.canlet.2026.218286","DOIUrl":"10.1016/j.canlet.2026.218286","url":null,"abstract":"<div><div>In China, cervical cancer incidence and mortality have continued to increase despite more than 15 years of nationwide organized screening, raising questions about the population-level impact of screening. Using national cancer registry data from 2004 to 2018, we analyzed temporal trends in age-standardized incidence rates (ASIRs) and mortality rates (ASMRs), as well as age-specific rates, using Joinpoint regression, and assessed their correlations with age-specific screening coverage.</div><div>From 2004 to 2018, ASIR increased from 6.06 to 11.81 per 100,000, but the annual growth rate slowed markedly after 2007, declining from 12.5 % (95 % CI: 9.7 ∼ 15.5 %) to 3.1 % (95 % CI: 2.7 ∼ 3.4 %). Among women aged 35–44 years, incidence trends shifted from a sharp rise to a sustained decline. By contrast, ASMR rose steadily from 2.07 to 3.44 per 100,000, with an average annual increase of 4.1 % (95 % CI: 3.4 ∼ 4.8 %). Notably, mortality stabilized after a rapid early rise among women aged 40–44 years, the group with the highest screening coverage. Correlation analysis revealed strong positive associations between higher screening coverage and the deceleration of incidence (ρ = 0.85, p < 0.001) and mortality trends (ρ = 0.69, p = 0.014).</div><div>These findings suggest that increased screening coverage may already be moderating incidence and mortality trends in specific age groups, particularly women aged 35–44 years. However, nationwide declines have yet to emerge, especially in rural populations where screening coverage remains low and disease burden is high. Expanding access and improving screening quality are critical to accelerate progress toward cervical cancer control in China.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218286"},"PeriodicalIF":10.1,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146084430","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 : 2026-01-27DOI: 10.1016/j.canlet.2026.218285
Senjie Dai , Wuhu Zhang , Heli Gao , Yan Wang , Junfeng Xu , Xiaowu Xu , Xianjun Yu , Shunrong Ji
Pancreatic neuroendocrine tumors (PNETs) are relatively rare and highly heterogeneous tumors. Early diagnosis is a critical step in improving patient prognosis, but there is still a lack of circulating biomarkers with both high specificity and high sensitivity. The development of liquid biopsy technologies (such as CTCs and NETest) has opened new avenues for the early diagnosis of PNETs. Considerable heterogeneity among PNETs represents a major challenge to their effective clinical management. Radiomics, however, has demonstrated significant potential in predicting the malignant behavior of these tumors. For PNETs patients after radical resection, accurate postoperative risk stratification is a key basis for formulating individualized follow-up strategies and selecting adjuvant therapies. Molecular feature-based classification systems will be a major research focus in this field in the future. In the treatment of advanced PNETs, therapeutic strategies have become increasingly diverse. Advances in targeted therapy and immunotherapy have expanded the range of available treatment options for PNETs. However, numerous challenges remain, including limited efficacy, susceptibility to drug resistance, and the lack of standardized treatment sequences. Moreover, in response to these clinical difficulties, significant progress has been made in developing preclinical models that simulate the development and progression of PNETs. Therefore, this review systematically summarized the latest research advances in the diagnosis, treatment, and research models of PNETs.
{"title":"Recent advances in the management of pancreatic neuroendocrine tumors: From diagnosis, treatment to biology","authors":"Senjie Dai , Wuhu Zhang , Heli Gao , Yan Wang , Junfeng Xu , Xiaowu Xu , Xianjun Yu , Shunrong Ji","doi":"10.1016/j.canlet.2026.218285","DOIUrl":"10.1016/j.canlet.2026.218285","url":null,"abstract":"<div><div>Pancreatic neuroendocrine tumors (PNETs) are relatively rare and highly heterogeneous tumors. Early diagnosis is a critical step in improving patient prognosis, but there is still a lack of circulating biomarkers with both high specificity and high sensitivity. The development of liquid biopsy technologies (such as CTCs and NETest) has opened new avenues for the early diagnosis of PNETs. Considerable heterogeneity among PNETs represents a major challenge to their effective clinical management. Radiomics, however, has demonstrated significant potential in predicting the malignant behavior of these tumors. For PNETs patients after radical resection, accurate postoperative risk stratification is a key basis for formulating individualized follow-up strategies and selecting adjuvant therapies. Molecular feature-based classification systems will be a major research focus in this field in the future. In the treatment of advanced PNETs, therapeutic strategies have become increasingly diverse. Advances in targeted therapy and immunotherapy have expanded the range of available treatment options for PNETs. However, numerous challenges remain, including limited efficacy, susceptibility to drug resistance, and the lack of standardized treatment sequences. Moreover, in response to these clinical difficulties, significant progress has been made in developing preclinical models that simulate the development and progression of PNETs. Therefore, this review systematically summarized the latest research advances in the diagnosis, treatment, and research models of PNETs.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218285"},"PeriodicalIF":10.1,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146084417","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 : 2026-01-23DOI: 10.1016/j.canlet.2026.218276
Palanisamy Nallasamy, Parthasarathy Seshacharyulu, Sanchita Rauth, Ashu Shah, Saravanakumar Marimuthu, Venkatesh Varadharaj, Madhulatha Bommideni, Kavita Mallya, Zahraa Wajih Alsafwani, Subodh M Lele, Venu Raman, Surinder K Batra, Moorthy P Ponnusamy
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that has a poor survival rate of ∼13% with limited options for effective therapies. DDX3 is a member of the DEAD-box RNA helicase enzyme family. It acts as an adapter protein that interacts with several transcription factors, enhancing their binding ability to the promoters of genes involved in cancer progression. Previously, we demonstrated that PAF1, a component of the RNA polymerase II-associated factor 1 complex, interacts with DDX3 to promote PDAC stemness. Here, we investigated the therapeutic efficacy of RK-33, a small molecule inhibitor targeting DDX3, in combination with gemcitabine (GEM) and 5-fluorouracil (5FU), which enhances the therapeutic efficacy in KRAS-driven PDAC. DDX3 and PAF1 exhibit progressively increased expression in various stages and correlate well with poor survival of PDAC. Targeting DDX3/PAF1 significantly mitigated clonogenic, EMT, and stemness phenotypes in PDAC cells. It also reduced tumor growth, proliferation, and increased apoptosis in xenograft and PDAC organoid models. Finally, MXRA5, EDIL3, COL13A1, and SLC16A2 were identified as top downstream response genes upon RK-33 treatment, which have been considered potential new targets to mitigate extracellular matrix remodeling, angiogenesis, cell migration, and cell cycle progression, thereby enhancing the therapeutic efficacy of GEM and 5FU. Overall, our data indicate that RK-33 enhances the therapeutic efficacy of GEM and 5FU in mitigating the aggressiveness of PDAC. Consequently, these findings open new avenues for developing efficacious therapeutic adjuvants to treat advanced pancreatic cancer.
{"title":"Targeting the DDX3/PAF1 Axis Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma.","authors":"Palanisamy Nallasamy, Parthasarathy Seshacharyulu, Sanchita Rauth, Ashu Shah, Saravanakumar Marimuthu, Venkatesh Varadharaj, Madhulatha Bommideni, Kavita Mallya, Zahraa Wajih Alsafwani, Subodh M Lele, Venu Raman, Surinder K Batra, Moorthy P Ponnusamy","doi":"10.1016/j.canlet.2026.218276","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218276","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that has a poor survival rate of ∼13% with limited options for effective therapies. DDX3 is a member of the DEAD-box RNA helicase enzyme family. It acts as an adapter protein that interacts with several transcription factors, enhancing their binding ability to the promoters of genes involved in cancer progression. Previously, we demonstrated that PAF1, a component of the RNA polymerase II-associated factor 1 complex, interacts with DDX3 to promote PDAC stemness. Here, we investigated the therapeutic efficacy of RK-33, a small molecule inhibitor targeting DDX3, in combination with gemcitabine (GEM) and 5-fluorouracil (5FU), which enhances the therapeutic efficacy in KRAS-driven PDAC. DDX3 and PAF1 exhibit progressively increased expression in various stages and correlate well with poor survival of PDAC. Targeting DDX3/PAF1 significantly mitigated clonogenic, EMT, and stemness phenotypes in PDAC cells. It also reduced tumor growth, proliferation, and increased apoptosis in xenograft and PDAC organoid models. Finally, MXRA5, EDIL3, COL13A1, and SLC16A2 were identified as top downstream response genes upon RK-33 treatment, which have been considered potential new targets to mitigate extracellular matrix remodeling, angiogenesis, cell migration, and cell cycle progression, thereby enhancing the therapeutic efficacy of GEM and 5FU. Overall, our data indicate that RK-33 enhances the therapeutic efficacy of GEM and 5FU in mitigating the aggressiveness of PDAC. Consequently, these findings open new avenues for developing efficacious therapeutic adjuvants to treat advanced pancreatic cancer.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218276"},"PeriodicalIF":10.1,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046135","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}
Introduction: Assessing progress in cancer control at the national level is crucial, as it offers key insights into the overall effectiveness of the health system. Here, we aimed to describe 20-year trends in stage distribution, treatment patterns, and survival for gastric cancer in China, and to estimate stage- and treatment-specific 1-, 3-, 5-, and 10-year overall survival (OS) at the national level.
Methods: In this study, we included data from 40,158 patients diagnosed with gastric cancer between 1998 and 2022, derived from nine tertiary grade-A hospitals located across all four major regions of China. The characteristics, treatment modalities, and survival outcomes were analyzed across four predefined time periods: period 1 (1998-2005), period 2 (2006-2010), period 3 (2011-2015), and period 4 (2016-2022). Stage- and treatment-specific survival with 95 % confidence intervals (CIs) was estimated using the Kaplan-Meier method; differences were assessed by log-rank test.
Results: During the study period, there was an increasing proportion of patients with early stage gastric cancer from 9.8 % in 1998 to 19.5 % in 2022, while patients with metastatic disease remained stable. For early gastric cancer classified as cT1aN0, the proportion of patients undergoing endoscopic resection increased from 0.0 % in period 1-30.4 % in period 4. Among patients with locally advanced gastric cancer, the proportion receiving neoadjuvant therapy increased from 0.8 % to 17.3 %. Regarding survival outcomes, the 5-year OS rate of gastric cancer cohort increased from 38.2 % in period 1-46.1 % in period 4. Stage-specific 5-year OS rates were 90.0 % (stage I), 69.0 % (stage II), 37.0 % (stage III), and 13.7 % (stage IV). Compared with Japan, gastric cancer patients with stage IA in China exhibited higher 5-year OS rate (91.9 % vs. 89.6 %) but a much lower proportion (16.9 % vs. 43.6 %). Survival for stage IIIA-IIIC was poorer in China (48.5 % vs. 59.3 %, 34.7 % vs. 45.6 %, 21.8 % vs. 29.9 %; respectively).
Conclusions: From 1998 to 2022, the proportion of patients diagnosed with early-stage gastric cancer in China gradually increased, and treatment strategies changed substantially over time, accompanied by a modest improvement in the 5-year OS rate. The disparities in stage distribution and survival outcomes between China and Japan highlight the need to further improve early detection of gastric cancer and to develop more effective treatment modalities for patients with stage III disease in China.
{"title":"Changing landscape in stage, treatment and survival of gastric cancer in China 1998-2022: Insights of 40,158 patients from the National Gastric Cancer Cohort.","authors":"Lulu Zhao, Zhihao Chen, Fan Zhang, Fengzhu Zhang, Xianchun Gao, Xiang Wang, Xiadong Zhou, Shun Zhang, Xue Han, Zerong Wang, Xiaoyi Luan, Penghui Niu, Wanqing Wang, Zhiming Fu, Huang Huang, Ranran Qie, Weili Han, Rong Zheng, Ling Chen, Likun Qi, Xiaohua Jiang, Mingyan He, Baochun Wang, Yongzhan Nie, Quanlin Guan, Yumin Li, Junjiang Wang, Fanghui Zhao, Dongbing Zhao, Yawei Zhang, Yingtai Chen","doi":"10.1016/j.canlet.2026.218261","DOIUrl":"10.1016/j.canlet.2026.218261","url":null,"abstract":"<p><strong>Introduction: </strong>Assessing progress in cancer control at the national level is crucial, as it offers key insights into the overall effectiveness of the health system. Here, we aimed to describe 20-year trends in stage distribution, treatment patterns, and survival for gastric cancer in China, and to estimate stage- and treatment-specific 1-, 3-, 5-, and 10-year overall survival (OS) at the national level.</p><p><strong>Methods: </strong>In this study, we included data from 40,158 patients diagnosed with gastric cancer between 1998 and 2022, derived from nine tertiary grade-A hospitals located across all four major regions of China. The characteristics, treatment modalities, and survival outcomes were analyzed across four predefined time periods: period 1 (1998-2005), period 2 (2006-2010), period 3 (2011-2015), and period 4 (2016-2022). Stage- and treatment-specific survival with 95 % confidence intervals (CIs) was estimated using the Kaplan-Meier method; differences were assessed by log-rank test.</p><p><strong>Results: </strong>During the study period, there was an increasing proportion of patients with early stage gastric cancer from 9.8 % in 1998 to 19.5 % in 2022, while patients with metastatic disease remained stable. For early gastric cancer classified as cT1aN0, the proportion of patients undergoing endoscopic resection increased from 0.0 % in period 1-30.4 % in period 4. Among patients with locally advanced gastric cancer, the proportion receiving neoadjuvant therapy increased from 0.8 % to 17.3 %. Regarding survival outcomes, the 5-year OS rate of gastric cancer cohort increased from 38.2 % in period 1-46.1 % in period 4. Stage-specific 5-year OS rates were 90.0 % (stage I), 69.0 % (stage II), 37.0 % (stage III), and 13.7 % (stage IV). Compared with Japan, gastric cancer patients with stage IA in China exhibited higher 5-year OS rate (91.9 % vs. 89.6 %) but a much lower proportion (16.9 % vs. 43.6 %). Survival for stage IIIA-IIIC was poorer in China (48.5 % vs. 59.3 %, 34.7 % vs. 45.6 %, 21.8 % vs. 29.9 %; respectively).</p><p><strong>Conclusions: </strong>From 1998 to 2022, the proportion of patients diagnosed with early-stage gastric cancer in China gradually increased, and treatment strategies changed substantially over time, accompanied by a modest improvement in the 5-year OS rate. The disparities in stage distribution and survival outcomes between China and Japan highlight the need to further improve early detection of gastric cancer and to develop more effective treatment modalities for patients with stage III disease in China.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218261"},"PeriodicalIF":10.1,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046114","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 : 2026-01-22DOI: 10.1016/j.canlet.2026.218279
Yujuan Jiang , Zitong Zhao , Liying Ma , Xinxin Shao , Peng Wang , Yongmei Song , Yantao Tian
Gastric signet-ring cell carcinoma (GSRCC) exhibits a poor prognosis because of its aggressive behavior and chemoresistance, which is strongly associated with dysregulated cholesterol metabolism. This study investigated the role of circUBR5 in GSRCC progression. CircUBR5 was identified by transcriptome sequencing of gastric cancer tissues and validated. CircUBR5 was upregulated in GSRCC and correlated with advanced stage, metastasis, and poor survival. Functionally, circUBR5 promoted the proliferation, metastasis, and cisplatin resistance of GSRCC cells in vitro and in vivo. Mechanistically, cytoplasmic circUBR5 functions as a sponge for miR-1208, thereby relieving miR-1208-mediated suppression of CYP19A1, a key estrogen synthesis-related enzyme, and activating estrogen signaling. Concurrently, circUBR5 directly binds to the cholesterol esterification enzyme ACAT1 and recruits the deubiquitinase PSMD14 to stabilize it, promoting cholesterol metabolic reprogramming. CircUBR5 can also be packaged into exosomes, which mediates chemoresistance transfer to recipient gastric adenocarcinoma cells. Notably, combining circUBR5-targeting antisense oligonucleotides with cisplatin synergistically inhibited tumor growth and reversed chemoresistance in vivo. Thus, circUBR5 promotes GSRCC progression through dual pathways coordinating estrogen signaling and cholesterol metabolism, and its exosomal dissemination facilitates chemoresistance induction within the tumor microenvironment, highlighting its potential as a prognostic biomarker and therapeutic target.
{"title":"Exosomal circUBR5 drives metastasis and chemoresistance in gastric signet-ring cell carcinoma by reprogramming cholesterol metabolism through the hsa-miR-1208/CYP19A1 axis and ACAT1 upregulation","authors":"Yujuan Jiang , Zitong Zhao , Liying Ma , Xinxin Shao , Peng Wang , Yongmei Song , Yantao Tian","doi":"10.1016/j.canlet.2026.218279","DOIUrl":"10.1016/j.canlet.2026.218279","url":null,"abstract":"<div><div>Gastric signet-ring cell carcinoma (GSRCC) exhibits a poor prognosis because of its aggressive behavior and chemoresistance, which is strongly associated with dysregulated cholesterol metabolism. This study investigated the role of circUBR5 in GSRCC progression. CircUBR5 was identified by transcriptome sequencing of gastric cancer tissues and validated. CircUBR5 was upregulated in GSRCC and correlated with advanced stage, metastasis, and poor survival. Functionally, circUBR5 promoted the proliferation, metastasis, and cisplatin resistance of GSRCC cells <em>in vitro and in vivo.</em> Mechanistically, cytoplasmic circUBR5 functions as a sponge for miR-1208, thereby relieving miR-1208-mediated suppression of CYP19A1, a key estrogen synthesis-related enzyme, and activating estrogen signaling. Concurrently, circUBR5 directly binds to the cholesterol esterification enzyme ACAT1 and recruits the deubiquitinase PSMD14 to stabilize it, promoting cholesterol metabolic reprogramming. CircUBR5 can also be packaged into exosomes, which mediates chemoresistance transfer to recipient gastric adenocarcinoma cells. Notably, combining circUBR5-targeting antisense oligonucleotides with cisplatin synergistically inhibited tumor growth and reversed chemoresistance <em>in vivo.</em> Thus, circUBR5 promotes GSRCC progression through dual pathways coordinating estrogen signaling and cholesterol metabolism, and its exosomal dissemination facilitates chemoresistance induction within the tumor microenvironment, highlighting its potential as a prognostic biomarker and therapeutic target.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218279"},"PeriodicalIF":10.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043601","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 : 2026-01-22DOI: 10.1016/j.canlet.2026.218280
Jiao Cai, Cheng-Hui Liang, Li-Ping Han, Hong-Ying Jiang, Jiang-Jie Duan, Fu Li, Jia Liu, Cai Liang, Lei Gao, Shi-Cang Yu
Dysfunction of the retinoic acid (RA) signaling pathway, which is mediated by the formation of the PML-RARA fusion gene, plays a central role in the pathogenesis of acute promyelocytic leukemia (APL). The activation of this pathway depends on the binding of the ligand RA to RA receptors (RARs). Members of aldehyde dehydrogenase (ALDH) family are key enzymes responsible for the biosynthesis of endogenous RA and are highly enriched in various cancer stem cell subpopulations; however, their specific contributions to APL pathogenesis remain poorly understood. In this study, we demonstrate that the expression of aldehyde dehydrogenase family member 1A3 (ALDH1A3) is negatively correlated with APL progression. Through DNA pull-down assays, liquid chromatography-tandem mass spectrometry (LC‒MS/MS) analysis, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays and electrophoretic mobility shift assay (EMSA), we show that ALDH1A3 cooperates with the transcription factor Myc-associated zinc finger protein (MAZ) to transcriptionally repress PML-RARα expression. Furthermore, EMSA and methylated DNA immunoprecipitation (MeDIP) analyses reveal that PML-RARα increases methylation of the ALDH1A3 promoter, thereby suppressing its expression in APL patients. This reciprocal inhibitory relationship is correlated with clinical remission in APL. Integrated RNA sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) analyses indicate that ALDH1A3 overexpression is associated with increased chromatin accessibility and the upregulation of genes involved in cellular differentiation. Notably, demethylation therapy induced sustained complete remission in patients with refractory and recurrent APL during experimental treatment. Our findings underscore the critical role of ALDH1A3 in leukemogenesis and highlight its potential as a therapeutic target in APL.
{"title":"Dysregulation of the ALDH1A3/PML-RARα axis promotes the progression of acute promyelocytic leukemia.","authors":"Jiao Cai, Cheng-Hui Liang, Li-Ping Han, Hong-Ying Jiang, Jiang-Jie Duan, Fu Li, Jia Liu, Cai Liang, Lei Gao, Shi-Cang Yu","doi":"10.1016/j.canlet.2026.218280","DOIUrl":"10.1016/j.canlet.2026.218280","url":null,"abstract":"<p><p>Dysfunction of the retinoic acid (RA) signaling pathway, which is mediated by the formation of the PML-RARA fusion gene, plays a central role in the pathogenesis of acute promyelocytic leukemia (APL). The activation of this pathway depends on the binding of the ligand RA to RA receptors (RARs). Members of aldehyde dehydrogenase (ALDH) family are key enzymes responsible for the biosynthesis of endogenous RA and are highly enriched in various cancer stem cell subpopulations; however, their specific contributions to APL pathogenesis remain poorly understood. In this study, we demonstrate that the expression of aldehyde dehydrogenase family member 1A3 (ALDH1A3) is negatively correlated with APL progression. Through DNA pull-down assays, liquid chromatography-tandem mass spectrometry (LC‒MS/MS) analysis, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays and electrophoretic mobility shift assay (EMSA), we show that ALDH1A3 cooperates with the transcription factor Myc-associated zinc finger protein (MAZ) to transcriptionally repress PML-RARα expression. Furthermore, EMSA and methylated DNA immunoprecipitation (MeDIP) analyses reveal that PML-RARα increases methylation of the ALDH1A3 promoter, thereby suppressing its expression in APL patients. This reciprocal inhibitory relationship is correlated with clinical remission in APL. Integrated RNA sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) analyses indicate that ALDH1A3 overexpression is associated with increased chromatin accessibility and the upregulation of genes involved in cellular differentiation. Notably, demethylation therapy induced sustained complete remission in patients with refractory and recurrent APL during experimental treatment. Our findings underscore the critical role of ALDH1A3 in leukemogenesis and highlight its potential as a therapeutic target in APL.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218280"},"PeriodicalIF":10.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043574","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 : 2026-01-22DOI: 10.1016/j.canlet.2026.218281
Devon Heroux , Xu Xin Sun , Sijie Zhang , Maryam Sharifiaghdam , Ada WY. Leung , Saeid Farzaneh , Katy Milne , Trevor MacFarlane , Chantal Di Vito , Brad H. Nelson , Charles Walsby , Marcel B. Bally
Copper-binding agents can trigger immunogenic cell death (ICD) and modulate responses to immune checkpoint inhibitors (ICIs), but how tumor copper biology, agent chemistry, and tumor microenvironment shape these effects is unclear. We evaluated diethyldithiocarbamate [Cu(DDC)2] and clioquinol [Cu(CQ)2] in two syngeneic colorectal cancer models with distinct copper handling. In vitro transcriptomic and cytokine profiling showed compound-specific activation of cuproptosis and immune pathways. In vivo, copper accumulation and isotopic fractionation correlated with immune features of the tumor microenvironment, including immune cell infiltration and calreticulin exposure. In CT26 tumors, Cu(CQ)2 transiently enhanced programmed cell death protein 1 (PD-1) blockade, then promoted immune suppression with prolonged dosing. In MC38 tumors, combination therapy showed sustained antagonism or no added benefit. These data indicate that tumor-intrinsic copper handling and ionophore identity jointly determine immune dynamics and therapeutic outcome, and they suggest copper isotopic metrics as candidate biomarkers warranting further evaluation in the context of copper-based strategies with ICIs.
{"title":"Copper ionophores drive divergent responses to immune checkpoint inhibition across colorectal tumor models","authors":"Devon Heroux , Xu Xin Sun , Sijie Zhang , Maryam Sharifiaghdam , Ada WY. Leung , Saeid Farzaneh , Katy Milne , Trevor MacFarlane , Chantal Di Vito , Brad H. Nelson , Charles Walsby , Marcel B. Bally","doi":"10.1016/j.canlet.2026.218281","DOIUrl":"10.1016/j.canlet.2026.218281","url":null,"abstract":"<div><div>Copper-binding agents can trigger immunogenic cell death (ICD) and modulate responses to immune checkpoint inhibitors (ICIs), but how tumor copper biology, agent chemistry, and tumor microenvironment shape these effects is unclear. We evaluated diethyldithiocarbamate [Cu(DDC)<sub>2</sub>] and clioquinol [Cu(CQ)<sub>2</sub>] in two syngeneic colorectal cancer models with distinct copper handling. In vitro transcriptomic and cytokine profiling showed compound-specific activation of cuproptosis and immune pathways. In vivo, copper accumulation and isotopic fractionation correlated with immune features of the tumor microenvironment, including immune cell infiltration and calreticulin exposure. In CT26 tumors, Cu(CQ)<sub>2</sub> transiently enhanced programmed cell death protein 1 (PD-1) blockade, then promoted immune suppression with prolonged dosing. In MC38 tumors, combination therapy showed sustained antagonism or no added benefit. These data indicate that tumor-intrinsic copper handling and ionophore identity jointly determine immune dynamics and therapeutic outcome, and they suggest copper isotopic metrics as candidate biomarkers warranting further evaluation in the context of copper-based strategies with ICIs.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218281"},"PeriodicalIF":10.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037429","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}
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