Cancer gene therapy最新文献

{"title":"Therapeutic potential of synthetic microRNA mimics based on the miR-15/107 consensus sequence","authors":"Glen Reid, Marissa Williams, Yuen Yee Cheng, Kadir Sarun, Patrick Winata, Michaela B. Kirschner, Nancy Mugridge, Jocelyn Weiss, Mark Molloy, Himanshu Brahmbhatt, Jennifer MacDiarmid, Nico van Zandwijk","doi":"10.1038/s41417-025-00885-w","DOIUrl":"10.1038/s41417-025-00885-w","url":null,"abstract":"MicroRNA expression is frequently suppressed in cancer, and previously we demonstrated coordinate downregulation of multiple related microRNAs of the miR-15/107 group in malignant pleural mesothelioma (PM). From an alignment of the miR-15 family and the related miR-103/107, we derived a consensus sequence and used this to generate synthetic mimics. The synthetic mimics displayed tumour suppressor activity in PM cells in vitro, which was greater than that of a mimic based on the native miR-16 sequence. These mimics were also growth inhibitory in cells from non-small cell lung (NSCLC), prostate, breast and colorectal cancer, and sensitised all cell lines to the chemotherapeutic drug gemcitabine. The increased activity corresponded to enhanced inhibition of the expression of target genes and was associated with an increase in predicted binding to target sites, and proteomic analysis revealed a strong effect on proteins involved in RNA and DNA processes. Applying the novel consensus mimics to xenograft models of PM and NSCLC in vivo using EGFR-targeted nanocells loaded with mimic led to tumour growth inhibition. These results suggest that mimics based on the consensus sequence of the miR-15/107 group have therapeutic potential in a range of cancer types.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"486-496"},"PeriodicalIF":4.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00885-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691168","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":"Pbx3-mediated suppression of type I interferon response contributes to leukemia progression driven by MLL-AF9","authors":"Li Tang, Meng Lu, Yulong Du, Jianlong Sun","doi":"10.1038/s41417-025-00888-7","DOIUrl":"10.1038/s41417-025-00888-7","url":null,"abstract":"Cell-intrinsic repression of inflammatory signaling supports the survival of acute myeloid leukemia blasts. However, how the cell-intrinsic inflammation status changes during AML progression remains elusive. Here, we used CRISPR-mediated genome editing to create a murine AML model driven by a chromosomal translocation between the mixed-lineage leukemia (Mll) gene and the Mllt3/Af9 gene. The resulting MLL-AF9 (MA9) fusion protein is sufficient to immortalize hematopoietic stem and progenitor cells (HSPCs) in vitro but insufficient to induce an overt leukemia phenotype in vivo rapidly. Leukemia progression in vivo is associated with a downregulation of type I interferon response genes, and this process depends on the upregulation of MA9 transcriptional target Pbx3 in the progenitor cell compartment. Accordingly, enhancing interferon response by interferon-α (IFNα) administration induces leukemic cell differentiation, and inhibiting MA9 transcriptional activity on top of the enhanced IFN signaling further delays leukemia progression. Our study underscores the importance of Pbx3-mediated suppression of interferon response genes in the progression of MA9-induced AML and highlights the potential application of type I interferon for its treatment.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"475-485"},"PeriodicalIF":4.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662575","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":"BAIAP2L2 facilitates hepatocellular carcinoma progression and immune evasion of via targeting JAK1-mediated pathway and PD-L1 expression","authors":"Zhiyue Xie, Yanxia Wu, Nan Peng, Jing Wang, Hui Wang, Liang Zhao","doi":"10.1038/s41417-025-00890-z","DOIUrl":"10.1038/s41417-025-00890-z","url":null,"abstract":"Hepatocellular carcinoma (HCC) poses a serious threat to human health due to its high mortality rate. Recently, breakthrough progress has been made in immunotherapy field. However, the mechanisms underlying HCC progression and immune escape are still unclear. This study aimed to investigate the impact of brain-specific angiogenesis inhibitor 1-associated protein 2-like 2 (BAIAP2L2) in HCC and elucidate its potential mechanisms in this context. Clinical data revealed that the overexpression of BAIAP2L2 correlated with tumor progression and poor prognosis in HCC patients. Functional assays demonstrated that BAIAP2L2 facilitates HCC proliferation, metastasis, invasion, and PD-L1-mediated immune evasion both in vitro and in vivo. Mechanistically, we observed co-localization and interaction between BAIAP2L2 and JAK1 within HCC cells, in turn enhancing the activation of the JAK1/STAT3 signaling pathway. Utilizing the JAK1 inhibitor Ruxolitinib effectively reversed BAIAP2L2-induced cellular processes such as proliferation, migration, invasion, and PD-L1 upregulation. Overall, our results emphasize that BAIAP2L2 plays a crucial role in driving tumor progression and immune evasion in HCC through the JAK1-mediated signaling pathway, thus proposing BAIAP2L2 as a promising therapeutic target for HCC treatment.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"464-474"},"PeriodicalIF":4.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646904","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":"IER3: exploring its dual function as an oncogene and tumor suppressor","authors":"Meena Kanduri, Santhilal Subhash, Rossana Putino, Sagar Mahale, Chandrasekhar Kanduri","doi":"10.1038/s41417-025-00891-y","DOIUrl":"10.1038/s41417-025-00891-y","url":null,"abstract":"The IER3 gene has a complex role in cancer biology, acting either as a tumor suppressor or an oncogene, depending on the cancer type. This duality underscores the complexity and importance of molecular pathways in modulating cancer behavior. Despite its significance in cancer development, there is a dearth of studies elucidating the exact mechanisms underlying IER3’s involvement in modulating cancer behavior. Here, utilizing cervical carcinoma and neuroblastoma (NB) cell lines as model systems we characterized the pathways that mediate the functional switch between the oncogenic and tumor suppressor roles of IER3. In HeLa cells, IER3 expression promotes an oncogenic program that includes immediate early response pathway genes such as EGR2, FOS, and JUN. However, in NB cells, IER3 suppresses the EGR2-dependent oncogenic program. This differential regulation of EGR2 by IER3 involves epigenetic modulation of the EGR2 promoter. IER3 dependent tumor suppressor pathway in NB cells relies on ADAM19 gene. Thus, our findings uncover the molecular pathways that dictate the context-dependent roles of IER3 in cancer, providing insights into its dual functionality in different cancer types.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"450-463"},"PeriodicalIF":4.8,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00891-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647095","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":"Targeted inactivation of EWSR1 : : FLI1 gene in Ewing sarcoma via CRISPR/Cas9 driven by an Ewing-specific GGAA promoter","authors":"Saint T. Cervera, Selene Martínez, María Iranzo-Martínez, Laura Notario, Raquel M. Melero-Fernández de Mera, Javier Alonso","doi":"10.1038/s41417-025-00887-8","DOIUrl":"10.1038/s41417-025-00887-8","url":null,"abstract":"We have recently demonstrated that genetic inactivation of EWSR1 : : FLI1 by CRISPR/Cas9, successfully blocks cell proliferation in a cell model of Ewing sarcoma. However, CRISPR/Cas9-mediated gene editing can exhibit off-target effects, and thus, precise regulation of Cas9 expression in target cells is essential to develop gene-editing strategies to inactivate EWSR1 : : FLI1 in Ewing sarcoma cells. In this study, we demonstrate that Cas9 can be specifically expressed in Ewing sarcoma cells when located downstream a promoter consisting of GGAA repeats and a consensus TATA box (GGAAprom). Under these conditions, Cas9 is selectively expressed in Ewing sarcoma cells that express EWSR1 : : FLI1 oncoproteins, but not in cells expressing wild-type FLI1. Consequently, Ewing sarcoma cells infected with GGAAprom>Cas9 and a specific gRNA designed to inactivate EWSR1 : : FLI1, showed successful EWSR1 : : FLI1 inactivation and the subsequent blockade of cell proliferation. Notably, GGAAprom>Cas9 can be efficiently delivered to Ewing sarcoma cells via adenoviral vectors both in vitro and in vivo, highlighting the potential of this approach for Ewing sarcoma treatment. Our results demonstrate that the CRISPR/Cas9 machinery is safe and specific for Ewing sarcoma cells when driven under a GGAAprom, paving the way for the development of cancer gene therapies based on the selective expression of genes with therapeutic potential.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"437-449"},"PeriodicalIF":4.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00887-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633571","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":"Suppression of FOXO1 activity by SIRT1-mediated deacetylation weakening the intratumoral androgen autocrine function in glioblastoma","authors":"Yuanchi Cheng, Zhijun Xiao, Weijia Cai, Ting Zhou, Zhen Yang","doi":"10.1038/s41417-025-00880-1","DOIUrl":"10.1038/s41417-025-00880-1","url":null,"abstract":"Elevated levels of androgens in the brain accelerate tumor progression in patients with glioblastoma (GBM). Despite current research efforts concentrating on decreasing peripheral androgens to improve GBM prognosis, results have not met expectations. Herein, we aim to elucidate the source of increased androgen levels in the brains of GBM patients and investigate whether lowering it can improve the prognosis of GBM patients. The Elisa was employed to measure androgen levels. The effects of androgens on U87 cells were evaluated using CCK-8 assays, clone formation assays, wound healing assays, and migration/invasion assays. RNA sequencing, RT-qPCR and Western blotting were performed to assess the expression levels of steroid enzymes, tumor drug resistance, Sirt1, FOXO1genes and proteins. Co-immunoprecipitation (Co-IP) assays were conducted to investigate the interactions and acetylation levels between Sirt1 and FOXO1. Lentiviral transfection was utilized to establish stable cell lines. Furthermore, an in vivo murine subcutaneous tumor model was established to further confirm the role of Sirt1 in tumor progression. We found androgen levels in the cerebrospinal fluid of GBM patients were higher than in the periphery, contrasting with healthy individuals. Additionally, the steroid enzymes in GBM cells were upregulated. Reducing peripheral androgens compensatorily enhances GBM androgen synthesis capacity (CYP17A1, CYP11A1, SRD5A2) and chemo-resistance (ABCB11, BIRC3, FGF2, NRG1), while the levels of androgens in the brain remain consistently high. The above results indicate that the increased androgens in the brain of GBM patients are self-secreted. Further investigations demonstrate that the transcription factor FOXO1 in GBM is regulated by silent information regulator 1 (Sirt1) through deacetylation, leading to enhanced androgen synthesis capacity in vivo and in vitro. Overexpressing Sirt1 significantly lowers brain androgen levels and delays tumor progression in mouse models. Compared to conventional finasteran therapy, the targeted-Sirt1 results in lower brain androgen levels and smaller tumor volumes. Our findings provide evidence that the elevated androgens in the brain of GBM patients came from tumor autocrine. Overexpression of Sirt1 reduces FOXO1 acetylation, lowers androgen synthesis enzyme levels, and effectively decreases brain androgen levels, thereby delaying tumor progression.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 3","pages":"343-354"},"PeriodicalIF":4.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00880-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613402","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":"Emerging roles of prohibitins in cancer: an update","authors":"Yunliang Gao, Yuanyuan Tang","doi":"10.1038/s41417-025-00883-y","DOIUrl":"10.1038/s41417-025-00883-y","url":null,"abstract":"The prohibitin (PHB) family, including PHB1 and its homolog PHB2, is ubiquitously located in different cellular compartments and plays roles in fundamental cellular processes such as proliferation, differentiation, and apoptosis. Accumulating evidence has indicated that this family contributes to the development of numerous diseases in particular cancers. Aberrant expressions of PHBs can been observed in diverse types of human cancer. Depending on their cell compartment-specific attributes and interacting proteins, PHBs are tightly linked to almost all aspects of cancer biology and have distinct bidirectional functions of tumor-suppression or tumor-promotion. However, the roles of PHBs in cancer have yet to be fully characterized and understood. This review provides an updated overview of the pleiotropic effects of PHBs and emphasizes their characteristic roles in each cancer respectively, with the great expectation to identify potential targets for therapeutic approaches and promising molecular biomarkers for cancer diagnosis and prognostic monitor.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"357-370"},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584674","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":"Chimeric Ad5/35 oncolytic adenovirus overcome preexisting neutralizing antibodies and enhance tumor targeting efficiency","authors":"Zhoutong Dai, Yao Si, Shengfeng Xiong, Ying Li, Jiaqi Ye, Qinglei Gao, Ding Ma, Xin Jin, Fei Li","doi":"10.1038/s41417-025-00884-x","DOIUrl":"10.1038/s41417-025-00884-x","url":null,"abstract":"KD01, a third-generation conditionally replicating adenovirus serotype 5 developed by our team, has approved by the China Center for Drug Evaluation (CDE) for Phase I clinical trials (NCT06552598). However, 60% seroprevalence of anti-Ad5 neutralizing antibodies is a major hurdle for Ad5-based oncolytic viruses. To address this issue, we developed oAd5/35-HF, a fourth-generation oncolytic adenovirus vector designed to enhance infection efficiency and evade pre-existing neutralizing antibodies (NABs). To achieve this, we introduced targeted capsid modifications, replacing hexon hypervariable regions (HVRs) 1 and 5 with those from adenovirus serotype 35 (Ad35), along with alterations to the fiber region. These combined modifications significantly improved infection efficiency, maintained high viral titers, and enabled the virus to resist NABs. This is the first report of replacing both the Ad5 hexon HVRs and fiber regions with those from Ad35 in an oncolytic adenovirus, resulting in potent antitumor activity across multiple cancer types, even in the presence of high NAB levels. The oAd5/35-HF backbone provides a versatile platform for developing new chimera oncolytic adenovirus and adenovirus vector-based vaccine.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"418-436"},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584183","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":"Ferroptosis enhances the therapeutic potential of oncolytic adenoviruses KD01 against cancer","authors":"Wenhuan Li, Teng Ji, Jiaqi Ye, Shengfeng Xiong, Yao Si, Xiaohui Sun, Fei Li, Zhoutong Dai","doi":"10.1038/s41417-025-00882-z","DOIUrl":"10.1038/s41417-025-00882-z","url":null,"abstract":"Oncolytic virotherapy has emerged as a promising strategy for cancer treatment by selectively targeting and lysing tumor cells. However, its efficacy is often limited in certain tumor types due to multiple factors. This study explores the combination of oncolytic adenoviruses with Erastin, a potent ferroptosis inducer, to enhance antitumor efficacy in oncolytic virus-insensitive cancer cell lines. In vitro experiments demonstrated that Erastin significantly increased the cytotoxicity of oncolytic virotherapy, leading to greater inhibition of cell proliferation and elevated rates of cell death compared to monotherapies. The combination treatment further promoted ferroptosis, as evidenced by increased reactive oxygen species (ROS) levels, enhanced lipid peroxidation, and disrupted redox homeostasis. RNA sequencing identified the downregulation of Dickkopf-1 (DKK1) as a key mediator of the enhanced ferroptotic effect. Restoring the expression of DKK1 partially mitigated the cytotoxic effects of the combination therapy, highlighting its crucial role in mediating the enhanced ferroptosis-induced oncolytic virotherapy efficacy. In vivo studies further validated these findings, demonstrating that the combined treatment significantly reduced tumor growth without inducing notable toxicity. This novel therapeutic approach has great potential to enhance the efficacy of oncolytic virotherapy in cancers resistant to oncolytic viruses by inducing ferroptosis. Further investigation in clinically relevant models is warranted to fully elucidate the underlying mechanisms and to optimize this combination strategy for potential clinical applications.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"403-417"},"PeriodicalIF":4.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-025-00882-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540160","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":"Therapeutic targeting of the tryptophan-kynurenine-aryl hydrocarbon receptor pathway with apigenin in MED12-mutant leiomyoma cells","authors":"Takashi Iizuka, Azna Zuberi, Helen Wei, John S. Coon V, Melania Lidia Anton, Kadir Buyukcelebi, Mazhar Adli, Serdar E. Bulun, Ping Yin","doi":"10.1038/s41417-025-00881-0","DOIUrl":"10.1038/s41417-025-00881-0","url":null,"abstract":"Approximately 77.4% of uterine leiomyomas carry MED12 gene mutations (mut-MED12), which are specifically associated with strikingly upregulated expression and activity of the tryptophan 2,3-dioxygenase (TDO2) enzyme, leading to increased conversion of tryptophan to kynureine. Kynurenine increases leiomyoma cell survival by activating the aryl hydrocarbon receptor (AHR). We used a leiomyoma-relevant model, in which a MED12 Gly44 mutation was knocked in by CRISPR in a human uterine myometrial smooth muscle (UtSM) cell line, in addition to primary leiomyoma cells from 26 patients to ascertain the mechanisms responsible for therapeutic effects of apigenin, a natural compound. Apigenin treatment significantly decreased cell viability, inhibited cell cycle progression, and induced apoptosis preferentially in mut-MED12 versus wild-type primary leiomyoma and UtSM cells. Apigenin not only blocked AHR action but also decreased TDO2 expression and kynurenine production, preferentially in mut-MED12 cells. Apigenin did not alter TDO2 enzyme activity. TNF and IL-1β, cytokines upregulated in leiomyoma, strikingly induced TDO2 expression levels via activating the NF-κB and JNK pathways, which were abolished by apigenin. Apigenin or a TDO2 inhibitor decreased UtSM cell viability induced by TNF/IL-1β. We provide proof-of-principle evidence that apigenin is a potential therapeutic agent for mut-MED12 leiomyomas.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 4","pages":"393-402"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536449","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}