Cancer letters最新文献

{"title":"The nuclear condensates of ESE3/EHF induce cellular senescence without the associated inflammatory secretory phenotype in pancreatic ductal adenocarcinoma.","authors":"Tianxing Zhou, Jingrui Yan, Bohang Xu, Yu Zhang, Guohua Mao, Yongjie Xie, Qingxiao Fang, Bin Wang, Ziyun Liu, Yiping Zou, Zhaoyu Zhang, Yifei Wang, Xiuchao Wang, Tiansuo Zhao, Hongwei Wang, Chongbiao Huang, Yukuan Feng, Chao Yang, Song Gao, Jun Yu, Jihui Hao","doi":"10.1016/j.canlet.2024.217408","DOIUrl":"10.1016/j.canlet.2024.217408","url":null,"abstract":"<p><p>Senescent cells are in a stable state of cell cycle arrest, leading to a natural barrier to tumorigenesis. Senescent cells secrete a pool of molecules, including cytokines, chemokines, proteases, and growth factors, termed the senescence-associated secretory phenotype (SASP), paradoxically contributing to pro-tumorigenic processes. However, the mechanism for regulating senescence and SASP in tumor cells remains unclear. Here, SPiDER senescence probe-based CRISPR/Cas9 library screening has identified ETS homologous factor (EHF) could effectively induce cellular senescence but without SASP, which could further significantly inhibit PDAC progression. Mechanically, tumoral EHF could form liquid-like condensates and further transcriptionally repress the expression of telomerase reverse transcriptase (TERT) and associated inflammatory factors, such as IL-6, CXCL12, etc. The reduction of TERT led to the telomere shortening and dysfunction of cancer cells, which further drove cellular senescence in PDAC. Moreover, EHF-mediated repression of inflammatory factors effectively declined the infiltration of immunosuppressive cells including MDSCs, Tregs, neutrophils, and promoted the accumulation of CD8⁺T cells and NK cells, which enhanced tumor immune surveillance. Furthermore, high throughput drug screening identified that Bilobetin could effectively promote the phase separation of EHF, which could further induce tumoral senescence but without SASP. In vivo, preclinical translational research uncovered that Bilobetin could ameliorate immunosuppressive tumor microenvironment (TME) and sensitize PDAC to anti-PD-1 therapy. Overall, our study revealed EHF as a potential candidate to overcome the paradoxical function of cellular senescence and elucidated the effects of its phase separation state on gene regulation, which provided new insights and strategies for PDAC treatment.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217408"},"PeriodicalIF":9.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-derived exosomes: Unravelling the pathogenesis of pancreatic cancer with liver metastases and exploring the potential for clinical translation.","authors":"Dongqi Li, Xiangyu Chu, Yongsu Ma, Fusheng Zhang, Xiaodong Tian, Yanlian Yang, Yinmo Yang","doi":"10.1016/j.canlet.2024.217403","DOIUrl":"10.1016/j.canlet.2024.217403","url":null,"abstract":"<p><p>Pancreatic cancer (PC) is one of the most malignant solid cancers, and PC metastasis, particularly liver metastasis, is a major cause of cancer mortality. A key event in tumor metastasis is the formation of pre-metastatic niche (PMN), which provides a microenvironment conducive to tumor cells colonization and progression. Various molecules loaded in tumor-derived exosomes (TDEs) contribute to PMN formation and distant tumor metastasis, by regulating immune and stromal cell function, inducing angiogenesis, and promoting metabolic reprogramming. Therefore, therapies targeting PMN may offer novel advantages to prevent tumor metastasis at an earlier stage. In this review, we summarize multifaceted mechanisms underlying hepatic PMN formation, with a focus on how PC TDEs participate in angiogenesis and vascular permeability, create immune suppressive microenvironment, remodel the extracellular matrix, and regulate metabolic reprogramming. In addition, we highlight the promise of TDEs for early diagnosis and effective therapy of PC liver metastases.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217403"},"PeriodicalIF":9.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-acetylcysteine prevents cisplatin-induced cognitive impairments in an ovarian cancer rat model.","authors":"Naomi Lomeli, Diana C Pearre, Javier Lepe, Donovan A Argueta, Mya A Arellano, Joni L Ricks-Oddie, Kalpna Gupta, Daniela A Bota","doi":"10.1016/j.canlet.2024.217405","DOIUrl":"10.1016/j.canlet.2024.217405","url":null,"abstract":"<p><p>Cancer-related cognitive impairment (CRCI) is prevalent among cancer patients. A critical disparity in the CRCI field is that most pre-clinical studies have been conducted on young cancer-free male rodents, although CRCI predominantly affects breast cancer and ovarian cancer women survivors. Since oxidative stress is widely implicated in the development of CRCI, we developed an ovarian cancer xenograft rat model of CRCI in Cr:NIH-RNU female rats to examine whether administration of the antioxidant N-acetylcysteine (NAC) prevents cisplatin-induced CRCI without altering its anti-cancer efficacy. In vitro, delayed treatment with NAC (10 h) following cisplatin treatment in the human ovarian cancer cell line SKOV3.ip1 did not decrease cisplatin's anti-cancer efficacy while mitigating hippocampal dendritic branching damage and neuronal apoptosis. Rats received subcutaneous and intraperitoneal implantation of SKOV3.ip1 cells. Rats received one cisplatin (5 mg/kg) injection every two weeks for a total of four cycles, with or without NAC (250 mg/kg/day), given for five consecutive days during cisplatin treatment. NAC was administered 10 h after cisplatin, based on our in vitro data. Cognitive testing was performed six to seven weeks after treatment cessation. In vivo, cognitive impairments were observed in tumor-bearing rats in the vehicle and cisplatin-treatment groups, while delayed NAC prevented cognitive impairments. Delayed NAC administration did not affect cisplatin-induced tumor volume reduction. Our study supports using NAC to mitigate cisplatin-induced CRCI through the novel development of an ovarian cancer rodent model. This study highlights the importance of developing clinically relevant tumor-bearing models to elucidate the underlying mechanisms associated with CRCI, which will aid in identifying potential therapeutic agents for preventing CRCI.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217405"},"PeriodicalIF":9.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A human-like glutaminase-free asparaginase is highly efficacious in ASNS^low leukemia and solid cancer mouse xenograft models.","authors":"Maaike Van Trimpont, Amanda M Schalk, Kenneth Hofkens, Evelien Peeters, Sara T'Sas, Katrien Vandemeulebroecke, Ying Su, Ashley De Loera, Alyssa Garcia, Hui Chen, Tim Lammens, Pieter Van Vlierberghe, Steven Goossens, Arnon Lavie","doi":"10.1016/j.canlet.2024.217404","DOIUrl":"10.1016/j.canlet.2024.217404","url":null,"abstract":"<p><p>L-asparaginase (L-ASNase) is crucial in treating pediatric acute lymphoblastic leukemia (ALL), but its use is hampered by side effects from the immunogenicity and L-glutaminase (L-GLNase) co-activity of FDA-approved bacterial L-ASNases, often leading to treatment discontinuation and poor outcomes. The toxicity of these L-ASNases makes them especially challenging to use in adult cancer patients. To overcome these issues, we developed EBD-200, a humanized guinea pig L-ASNase with low Km and no L-GLNase activity, eliminating glutamine-related toxicity. EBD-200 showed comparable anti-cancer effects to PEGylated L-ASNase in ASNS^low ALL, melanoma and liver cancer models, with improved tolerability. Its potent anti-cancer efficacy and enhanced safety profile suggest that EBD-200 could benefit ALL patients and broaden treatment options for ASNS^low solid cancers.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217404"},"PeriodicalIF":9.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA FIRRE drives gastric cancer progression via ZFP64-mediated TUBB3 promoter activation.","authors":"Jingwen Yuan, Jiatong Lu, Jie Zhu, Fangfang Chen, Zhi Zeng, Junfeng Yan, Qiang Li, Rui Zhou, Qiang Tong","doi":"10.1016/j.canlet.2024.217398","DOIUrl":"10.1016/j.canlet.2024.217398","url":null,"abstract":"<p><p>Gastric cancer is a common global malignancy that requires detailed study of its development mechanisms. Although LncRNA FIRRE is known to play a crucial role in the progression and treatment resistance of several cancers, its effect on gastric cancer is not well understood. This study confirms the impact of FIRRE on the malignant behavior of gastric cancer. Using RNA-sequencing, dual luciferase reporter assay, RIP and CHIP, we identified transcription factors and target genes linked to FIRRE. Elevated FIRRE expression in gastric cancer correlates with worse patient prognosis and promotes gastric cancer proliferation, migration, and invasion both in vitro and in vivo. FIRRE regulates the TUBB3 gene, facilitating gastric cancer progression by activating the TUBB3 promoter in vitro. ZFP64 is the transcription factor for TUBB3, activating its promoter and binding specifically with FIRRE. Reducing ZFP64 disrupts FIRRE's positive regulation of TUBB3 in vitro and in vivo. This study shows FIRRE promotes gastric cancer progression by binding to ZFP64 and activating the TUBB3 promoter.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217398"},"PeriodicalIF":9.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASPH dysregulates cell death and induces chemoresistance in hepatocellular carcinoma.","authors":"Jingtao Li, Guocai Zhong, Fengli Hu, Yingnan Zhang, Xiaohang Ren, Zongwen Wang, Shuoheng Ma, Qiankun Zhu, Junwei Li, Shicong Zeng, Yao Zhang, Ting Wang, Qiushi Lin, Xiaoqun Dong, Bo Zhai","doi":"10.1016/j.canlet.2024.217396","DOIUrl":"10.1016/j.canlet.2024.217396","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is resistant to multiple conventional drugs including sorafenib, leading to poor prognosis. Inducing cell death has been inextricably pursued in therapeutics, although targeted therapy and immunotherapy have made very limited progress. ASPH (Aspartate β-hydroxylase) can be breakthrough in meeting this unmet clinical need. In HCC, high expression of ASPH enhanced proliferation, migration and invasion. High levels of ASPH predicted worse clinical outcomes of sorafenib-treated HCC patients. Mechanistically, ASPH upregulated SQSTM1/P62 and SLC7A11-GPX4 axis, thereby promoting tumor cell autophagy but blocking ferroptosis. Sorafenib-induced enhancement of autophagy was attenuated by knockout (KO) of ASPH, resulting in sensitization of tumor cells to sorafenib. By silencing ASPH combined with sorafenib, senescence, apoptosis and ferroptosis were mediated, whereas proliferation, migration, invasion, tube formation and stemness were inhibited. As validated by in vivo murine models of HCC, ASPH promoted tumor growth, distant metastasis, and resistance to sorafenib. By contrast, KO ASPH combined with sorafenib effectively inhibited tumor development and progression, including intrahepatic, pulmonary, and splenic metastases. Targeting ASPH generated antitumor efficacy will pave the way for HCC therapy.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217396"},"PeriodicalIF":9.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Super-enhancer-associated circPVT1 promotes malignancy of hepatocellular carcinoma via YBX1-mediated RRM2 activation.","authors":"Yunhao Chen, Chengli Du, Jie Tang, Yanchun Zhao, Haiyang Xie, Shusen Zheng, Zhengliang Tu","doi":"10.1016/j.canlet.2024.217395","DOIUrl":"10.1016/j.canlet.2024.217395","url":null,"abstract":"<p><p>Circular RNAs (circRNAs), the essential members of epigenetic reprogramming, are emerging as an appealing layer in hepatocellular carcinoma (HCC). Super-enhancers (SEs) are large clusters of transcriptional enhancers with the tremendous gene activation potential and are extensively investigated in cancer research. The present study explores and uncovers an SE-related circRNA circPVT1, identifying its biological functions and downstream mechanisms in HCC. CircPVT1 is upregulated in HCC, serving as an independent prognostic factor for patients with HCC. Enrichment of H3K27ac and H3K4me1 modifications has been confirmed at the genomic loci of circPVT1's host gene, and the expression of circPVT1 is triggered by SEs. Functionally, circPVT1 enhances cell propagation and mobility capabilities in vitro, and facilitates tumour growth and metastasis in vivo. Mechanistically, circPVT1 recruits YBX1 into the cell nucleus, promoting the transcription of RRM2. Dysregulation of the circPVT1-RRM2 axis advances HCC malignancy, while inhibition of RRM2 or SE alleviates the effects of circPVT1 overexpression. In conclusion, our work demonstrates that circPVT1 is driven by super-enhancers. CircPVT1 promotes HCC progression via YBX1-mediated transcriptional activation of RRM2. These findings provide constructive insights into exploring the pathogenesis of HCC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217395"},"PeriodicalIF":9.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elaiophylin targets EIF4B to suppress the growth of esophageal squamous cell carcinoma via the PI3K/AKT signaling pathway.","authors":"Hu Qiu, Lijuan Gao, Wei Shi, Jing Wang, Bin Li, Shaobo Ke, Jiamei Chen, Yi Gong, Yong Wu, Wensi Zhao, Yongshun Chen","doi":"10.1016/j.canlet.2024.217401","DOIUrl":"10.1016/j.canlet.2024.217401","url":null,"abstract":"<p><p>Elaiophylin is known to exert antitumor effects through certain signaling pathways; however, no reports regarding its effects on esophageal cancer are available. This study explored the effects of elaiophylin in esophageal squamous cell carcinoma (ESCC) cells. Transwell and immunofluorescence assays confirmed that elaiophylin inhibited the migration and proliferation of ESCC cells, and western blotting assays showed that it affected apoptosis-related gene expression in ESCC cells. Based on RNA-seq analyses, Single-cell RNA-seq, a human cancer pathway phosphorylation antibody array, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomics analyses, we found that elaiophylin was related to low expression of EIF4B and activation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. In both in vitro and in vivo experiments, ESCC cells treated with elaiophylin showed low EIF4B expression, which inhibited their proliferation and promoted apoptosis by activating the PI3K/AKT signaling pathway; EIF4B overexpression could reverse these effects of elaiophylin on ESCC cells. Therefore, our results indicate that elaiophylin targets EIF4B to inhibit ESCC cell proliferation via the PI3K/AKT signaling pathway. Targeting elaiophylin or the EIF4B/PI3K/AKT signaling pathway may produce new methods for ESCC treatment.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217401"},"PeriodicalIF":9.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polo-like kinase 4 accelerates glioma malignant progression and vasculogenic mimicry by phosphorylating EphA2.","authors":"Bo Wang, Run-Ze Yu, Xiao-Yang Zhang, Yu Ren, Ying-Wei Zhen, Lei Han","doi":"10.1016/j.canlet.2024.217397","DOIUrl":"10.1016/j.canlet.2024.217397","url":null,"abstract":"<p><p>Vasculogenic mimicry (VM), which involved the formation of vascular-like structures by highly invasive tumor cells, had been identified as one of the mechanisms contributing to resistance against anti-angiogenic therapy in patients with glioblastoma (GBM). Therefore, inhibition of VM formation may serve as an effective therapeutic strategy against angiogenesis resistance. Polo-like kinase 4 (PLK4), a protein kinase, had been linked to the progression of glioblastoma and was associated with an unfavorable prognosis. The integration of proteomics and phosphoproteomics revealed that PLK4 directly activated the PI3K-Akt and MAPK signaling cascades by phosphorylating the Ser901 and Ser897 of EphA2. In addition, EphA2 Ser901 phosphorylating catalyzed by PLK4 significantly enhanced the phosphorylation of its own Ser897 site, which is a hallmark of EphA2 activation. The PI3K-Akt signaling was intricately associated with the progression of VM. Thus, PLK4 influenced malignant progression and VM formation via stimulation of the EphA2 signal transduction. Moreover, the expression level of PLK4 protein positively correlated with the level of EphA2 phosphorylation in glioma tissues. These results highlighted the crucial significance of PLK4 phosphorylating EphA2 in the malignant progression and VM formation in GBM.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217397"},"PeriodicalIF":9.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPDPF promotes esophageal squamous cell carcinoma progression by blocking PCCA binding to PCCB and inhibiting methionine catabolism.","authors":"Mengwei Li, Yi Zhang, Zhexin Wang, Kai Wang, Jie Gao, Haiyong Gu, Zimei Zeng, Haoyao Jiang, Qi Fan, Yuxue Zhang, Xudong Hu, Lingling Cui, Yuezhen Deng, Yifeng Sun","doi":"10.1016/j.canlet.2024.217402","DOIUrl":"10.1016/j.canlet.2024.217402","url":null,"abstract":"<p><p>While metabolic reprogramming and remodeling of tumor microenvironment play important roles in the development of esophageal squamous cell carcinoma (ESCC), the mechanisms remain unclear. In this study, we found that pancreatic progenitor cell differentiation and proliferation factor (PPDPF) is upregulated in ESCC and its expression level is associated with lymph node metastasis. PPDPF was found to promote tumorigenesis, lymph node metastasis and distal metastasis of ESCC cells. Furthermore, the results of mass spectrometry analysis revealed that PPDPF interacts with PCCA, the subunit of the PCC, a key enzyme involved in the catabolism of methionine by the C-Vomit pathway. In addition, PPDPF increases methionine and SAM levels. Additionally, knockdown of PPDPF decreases the levels of methionine and SAM in vivo, and promotes the infiltration of CD8⁺ T cells in ESCC. Taken together, the results of this study suggest that PPDPF inhibits the interaction between PCCA and PCCB to downregulate methionine catabolism via the C-Vomit pathway, providing a new target for the treatment of ESCC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217402"},"PeriodicalIF":9.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853126","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}