Cancer gene therapy最新文献

{"title":"Human endogenous retroviruses (HERVs) associated with glioblastoma risk and prognosis.","authors":"Harun Mazumder, Hui-Yi Lin, Melody Baddoo, Wojciech Gałan, Diana Polania-Villanueva, Chindo Hicks, David Otohinoyi, Francesca Peruzzi, Zbigniew Madeja, Victoria P Belancio, Erik K Flemington, Krzysztof Reiss, Monika Rak","doi":"10.1038/s41417-024-00868-3","DOIUrl":"10.1038/s41417-024-00868-3","url":null,"abstract":"<p><p>Emerging evidence suggests expression from human endogenous retrovirus (HERV) loci likely contributes to, or is a biomarker of, glioblastoma multiforme (GBM) disease progression. However, the relationship between HERV expression and GBM malignant phenotype is unclear. Applying several in silico analyses based on data from The Cancer Genome Atlas (TCGA), we derived a locus-specific HERV transcriptome for glioma that revealed 211 HERVs significantly dysregulated in the comparisons of GBM vs. normal brain (NB), GBM vs. low-grade glioma (LGG), and LGG vs. NB. Our analysis supported development of a unique HERV scoring algorithm that segregated GBM, LGG, and NB. Interestingly, lower HERV scores showed correlation with lower survival in GBM. However, HERV scores were less robust in predicting LGG survival or LGG progression to GBM. Functional prediction analysis linked the 211 HERV loci with 18 voltage-gated potassium channel genes. The functional link between dysregulated HERVs and specific potassium channel genes may contribute to better understanding of GBM pathogenesis, disease progression, and possibly drug resistance.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"622-632"},"PeriodicalIF":4.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of nucleotide excision repair by wild-type HRAS signaling in head and neck cancer.","authors":"Lorena Hoxhallari, Konstantinos Katsikis, Antigoni Makri, Marialena Pouliou, Zoi Kanaki, Giannis Vatsellas, Christina Sonou, Dimitrios Telios, Evangelos Giotakis, Aristeidis Giotakis, Periklis Makrythanasis, Marios Agelopoulos, Amanda Psyrri, Theodoros Rampias","doi":"10.1038/s41417-025-00902-y","DOIUrl":"10.1038/s41417-025-00902-y","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) is characterized by a high rate of locoregional or distant relapse among patients. It is well established that resistance to chemotherapeutic drugs has an important role in the emergence of the recurrent and/or metastatic type of this malignancy which is associated with poor prognosis. Therefore, understanding the molecular basis of chemoresistance in head and neck cancer is required for the development of effective therapeutic strategies. Activating mutations in the HRAS gene are driver events in human cancer. Although numerous studies have demonstrated that oncogenic HRAS mutations promote chemoresistance in HNSCC, the molecular profile of HNSCC tumors that overexpress wild-type HRAS (wtHRAS^ov) and their response to chemotherapy is poorly investigated. To gain deeper insights into the characteristics of wtHRAS^ov tumors, we conducted a gene expression analysis using transcriptome data from The Cancer Genome Atlas (TCGA). This analysis revealed a distinct signature of overexpressed nucleotide excision repair (NER) genes in wtHRAS^ov tumors, which are associated with chemoresistance. We further explored the role of these NER components in response to genotoxic stress, utilizing a diverse panel of HNSCC cell lines and patient-derived xenografts. Our findings indicate that in a specific cluster of head and neck tumors, ERK/cJun signaling activation is strongly reliant on HRAS activity. Inhibiting HRAS in these tumors results in a significant downregulation of the NER signature components, re-sensitizing cancer cells to platinum-based chemotherapy.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"662-677"},"PeriodicalIF":4.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: The role of tumor-derived exosomal LncRNA in tumor metastasis.","authors":"Zhile Yu, Jiali Fu, Vanya Mantareva, Ivica Blažević, Yusong Wu, Dianchang Wen, Tungalag Battulga, Yuqing Wang, Jianye Zhang","doi":"10.1038/s41417-025-00909-5","DOIUrl":"10.1038/s41417-025-00909-5","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"737"},"PeriodicalIF":4.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring RNA biology in pseudomyxoma peritonei uncovers splicing dysregulation as a novel, targetable molecular vulnerability.","authors":"María Trinidad Moreno-Montilla, Sergio Pedraza-Arevalo, Ana Martínez-López, Ricardo Blázquez-Encinas, Víctor García-Vioque, Lidia Rodríguez-Ortiz, Francisca Valenzuela-Molina, Blanca Rufián-Andújar, Melissa Granados-Rodríguez, Rosa Ortega-Salas, Emilia Alors-Pérez, Mari C Vázquez-Borrego, Antonio Romero-Ruiz, Justo P Castaño, Álvaro Arjona-Sánchez, Alejandro Ibáñez-Costa","doi":"10.1038/s41417-025-00911-x","DOIUrl":"10.1038/s41417-025-00911-x","url":null,"abstract":"<p><p>Pseudomyxoma peritonei (PMP) is a rare neoplasm coursing with uncontrollable mucus accumulation, with a high relapse rate. RNA biology processes have emerged as new players in cancer development and progression, nevertheless their role in PMP remains unknown. In this study, we aimed to examine RNA-regulatory machineries in PMP and their potential contribution to this disease progression. We analyzed 62 splicing-related genes, 27 RNA exosome and 21 nonsense-mediated decay genes, in a cohort of 29 patients using a microfluidic array, comparing tumor and control/reference tissues, together with external RNA-seq and proteomic data. Our results revealed a profound dysregulation of key components, which correlated to relevant clinical parameters and enabled to distinguish between tumor and control tissues. In vitro splicing inhibition using Pladienolide-B, as well as the modulation of specific splicing factors, reduced aggressiveness parameters, enhanced the effect of clinically used drugs, and revealed a strong correlation between dysregulated genes and key cancer-related genes. This inhibition also affected mucin secretion and mucin variants production. Collectively, our findings provide the first evidence for dysregulation of the genes of pivotal RNA-regulatory processes in PMP, implying that these targetable mechanisms may be functionally altered and play a role in the disease. Hence, a thorough understanding of its RNA biology could aid in the discovery of new clinically actionable vulnerabilities in this rare disease.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"721-736"},"PeriodicalIF":4.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of LncRNA-MANCR induced by HIF-1α drive the malignant progression of pancreatic cancer by targeting miRNA-494/SIRT1 signaling axis under hypoxic conditions.","authors":"Yan Jin, Hao Hu, Yitong Tian, Han Xu, Qiao Yu, Long Cheng, Xiaoyu Guo, Zongwei Wang, Xiaoxu Huang, Xiaoming Wang, Gang Wang","doi":"10.1038/s41417-025-00900-0","DOIUrl":"10.1038/s41417-025-00900-0","url":null,"abstract":"<p><p>This study revealed the prospective biological role and fundamental mechanisms of hypoxia-induced lncRNA-MANCR (MANCR), which is notably upregulated in pancreatic cancer (PC). This work uncovered the potential biological function and underlying mechanisms of hypoxia-induced MANCR, which is significantly elevated in PC. Microarray assays confirmed MANCR expression in the tissues of patients with PC and patients with chronic pancreatitis (CP), which positively correlated with sirtuin-1 (SIRT1) mRNA levels. Chromatin immunoprecipitation and luciferase assays were employed to gauge binding within the hypoxia-inducible factor-1α (HIF-1α)/MANCR/miRNA-494/SIRT1 pathway. Additionally, the association between MANCR expression and the clinical outcomes of patients with PC was confirmed. MANCR is significantly upregulated in PC cells under hypoxic conditions, which is closely linked to poor prognosis in patients with PC. Depletion of MANCR repressed in vitro proliferation, migration, and invasion of PC cells and in vivo growth of PC xenograft tumours. We further demonstrated that MANCR is localised in the cytoplasm and competitively binds miR-494, which directly targets SIRT1. Mechanically, the overexpression of SIRT1 improved the stability of the HIF-1α protein through deacetylation, leading to enhanced HIF-1α assembly. Moreover, MANCR underwent transcriptional regulation by HIF-1α in a hypoxic setting. This modulation was ascribed to HIF-1α binding to hypoxia response elements present in the MANCR promoter sequence. Data revealed the potential possibility of feedback between MANCR and HIF-1α, which may be conducive to hypoxia-induced oncogenicity and PC tumorigenesis, thereby providing a suitable therapeutic target.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"633-648"},"PeriodicalIF":4.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glioblastoma-associated macrophages in glioblastoma: from their function and mechanism to therapeutic advances.","authors":"Yuqin Zhang, Hanxing He, Xin Fu, Ganzhi Liu, Huiying Wang, Wen Zhong, Xia Xu, Bo Chen, Lin Mei","doi":"10.1038/s41417-025-00905-9","DOIUrl":"10.1038/s41417-025-00905-9","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults and has high mortality rates worldwide. GBM progression, treatment, and prognosis are influenced by the tumor microenvironment (TME), which includes immune, stromal, and tumor cells. Among them, glioblastoma-associated macrophages (GAMs) act as key regulators of GBM pathobiology. GAMs exhibit remarkable plasticity, as they can exhibit both protumor and antitumor effects. However, their function is determined by polarization and the TME. In this review, we provide a comprehensive overview of the current understanding of the biology of GAMs in GBM, including their origins, phenotypic diversity, and functional roles. We discuss the intricate crosstalk between GAMs and tumor cells, as well as other immune and stromal components, and highlight the mechanisms underlying GAM-mediated tumor progression, invasion, angiogenesis, and immune system evasion. Furthermore, we explore the therapeutic implications of targeting GAMs in GBM and discuss emerging strategies aimed at reprogramming GAMs toward an antitumorigenic phenotype or selectively depleting protumorigenic subsets. The final aim is to develop innovative therapeutic approaches that disrupt GBMs. By leveraging our increased understanding of GAM biology, we lay the foundation for transformative advances in GBM treatment to improve patient prognosis.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"595-607"},"PeriodicalIF":4.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-cancer oncogenic properties and therapeutic potential of SF3B4.","authors":"Yanmei Shi, Qimei Pan, Wenli Chen, Limin Xie, Shiru Tang, Zhizhi Yang, Man Zhang, Dong Yin, Lehang Lin, Jian-You Liao","doi":"10.1038/s41417-025-00910-y","DOIUrl":"10.1038/s41417-025-00910-y","url":null,"abstract":"<p><p>Splicing factor 3B (SF3B) subunit 4 (SF3B4), an SF3B complex component essential for spliceosome assembly and accurate splicing, plays a major role in cancer development. However, the precise mechanism through which SF3B4 contributes to tumor growth remains unclear. Here, we demonstrate that SF3B4 is strongly expressed in patients with various cancer types and correlated with their survival. By using hepatocellular carcinoma (HCC) as a model, we reveal that SF3B4's interactions with and regulatory influence on the checkpoint protein BUB1 are essential for appropriate cancer cell mitosis and proliferation. Our results thus demonstrate the roles of SF3B4 as both a cell-cycle regulator and an oncogenic factor in HCC, highlighting its potential as a pan-cancer therapeutic target and diagnostic biomarker.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"706-720"},"PeriodicalIF":4.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM).","authors":"Filipa Martins, Renata Arada, Hélio Barros, Paulo Matos, José Ramalho, Valentín Ceña, Vasco D B Bonifácio, Luís G Gonçalves, Jacinta Serpa","doi":"10.1038/s41417-025-00906-8","DOIUrl":"10.1038/s41417-025-00906-8","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly lethal disease with limited treatment options due to its infiltrative nature and the lack of efficient therapy able to cross the protective blood-brain barrier (BBB). GBMs are metabolically characterized by increased glycolysis and glutamine dependence. This study explores a novel metabolism-based therapeutic approach using a polyurea generation 4 dendrimer (PURE_G4) surface functionalized with lactate (LA) (PURE_G4-LA₂₄), to take advantage of glucose-dependent monocarboxylate transporters (MCTs) overexpression, loaded with selenium-chrysin (SeChry) and temozolomide (TMZ) or complexed with anti-glutaminase (GLS1) siRNAs to abrogate glutamine dependence. The nanoparticles (PURE_G4-LA₂₄) were efficient vehicles for cytotoxic compounds delivery, since SeChry@PURE_G4-LA₂₄ and TMZ@PURE_G4-LA₂₄ induced significant cell death in GBM cell lines, particularly in U251, which exhibits higher MCT1 expression. The anti-GLS1 siRNA-dendriplex with PURE_G4-LA₁₂ (PURE_G4-LA₁₂-anti-GLS1-siRNA) knocked down GLS1 in the GBM cell lines. In two in vitro BBB models, these dendriplexes successfully crossed the BBB, decreased GLS1 expression and altered the exometabolome of GBM cell lines, concomitantly with autophagy activation. Our findings highlight the potential of targeting glucose and glutamine pathways in GBM using dendrimer-based nanocarriers, overcoming the BBB and disrupting key metabolic processes in GBM cells. PURE_G4-LA₁₂-anti-GLS1-siRNA dendriplexes cross the blood-brain barrier (BBB) and impair glioblastoma (GBM) metabolism. The BBB is formed by a thin monolayer of specialized brain microvascular endothelial cells joined together by tight junctions that selectively control the passage of substances from the blood to the brain. It is a major obstacle in the treatment of GBM, since many chemotherapeutic drugs are unable to penetrate the brain. Therefore, we developed a strategy to overcome this obstacle: a lactate-coated polyurea dendrimer generation 4 (PURE_G4) able to cross the BBB in vitro, that act as a nanocarrier of drugs and siRNA to the GBM cells. PURE_G4-LA₁₂ are nanoparticles functionalized with lactate (LA) to target MCT1, a lactate transporter highly expressed by GBM cells. Moreover, a complex of this nanoparticle with anti-GLS1 (glutaminase) siRNA (PURE_G4-LA₁₂-anti-GLS1-siRNA) was made, to target glutamine metabolism. It efficiently knocked down GLS1. Moreover, PURE_G4-LA₂₄ loaded with SeChry led to BBB disruption.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"690-705"},"PeriodicalIF":4.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12245715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Nrf2 overexpression increases the resistance of acute myeloid leukemia to cytarabine by inhibiting replication factor C4.","authors":"Tianzhen Hu, Chengyun Pan, Tianzhuo Zhang, Ming Ni, Weili Wang, Siyu Zhang, Ying Chen, Jishi Wang, Qin Fang","doi":"10.1038/s41417-025-00913-9","DOIUrl":"10.1038/s41417-025-00913-9","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"739"},"PeriodicalIF":4.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural regulation of PLK1 activity: implications for cell cycle function and drug discovery.","authors":"Danda Chapagai, Klaus Strebhardt, Michael D Wyatt, Campbell McInnes","doi":"10.1038/s41417-025-00907-7","DOIUrl":"10.1038/s41417-025-00907-7","url":null,"abstract":"<p><p>Polo Like Kinase 1 (PLK1), a key regulator of mitosis whose overexpression is often associated with poor survival rates in cancer, continues to be widely investigated as an oncology drug target with clinical trials evaluating second and third generation inhibitors. In addition to the conserved N-terminal kinase domain (KD), a unique characteristic of the Polo-Like kinase family is the C-terminal polo-box domain (PBD). The PBD contains a phosphopeptide binding site that recognizes substrates primed by other kinases and furthermore is responsible for subcellular localization of PLK1 to specific sites in the nucleus including centrosomes and kinetochores. Another role of the PBD is its regulatory ability through domain-domain interactions with the KD to maintain an autoinhibited state of PLK1. Insights into post translational modifications and the PBD - KD domain-domain association have been obtained and show that key events in PLK1 regulation include phosphosubstrate binding, T210 phosphorylation and engagement with the Bora protein. These can induce an open and active conformation where the domain-domain inhibitory interactions no longer dominate. Further regulatory events recently described include the interchange between monomeric and dimeric forms, which can also serve to inhibit or activate PLK1 during the cell cycle. Different oligomeric forms of PLK1, existing as homodimers and heterodimers with PLK2, have been identified and likely play context dependent roles. This review provides an overview of recent information describing structural and mechanistic insights into inhibition of PLK1 and the temporal and spatial requirements of its activation and regulation. It also covers recent insights into the conformational regulation of other members of the Polo-Like kinase family. The implications of the conformational regulation of PLK1 with respect to cell cycle function and drug discovery are significant and are therefore discussed in detail.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"608-621"},"PeriodicalIF":4.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}