Cancer gene therapy最新文献

{"title":"Combined downregulation of TGF-β1 and GRP78 is responsible for overcoming acquired sorafenib resistance, which is initiated by rewiring the cell surface CD44-GRP78-IGF-1R signaling circuit.","authors":"Shengji Li, Geun-Hyeok Oh, Jeong A Hong, Soojin Choi, Minseo Kim, Hyeji Kwon, Seung-Kyun Ko, Sun Jun Park, Hee Kyung Kim, Hye Jin Choi, Jae J Song","doi":"10.1038/s41417-025-00937-1","DOIUrl":"https://doi.org/10.1038/s41417-025-00937-1","url":null,"abstract":"<p><p>Previously, we showed that the downregulation of both HSP27 and TGF-β1 decreased the survival of various tumor types. However, we found that HSP27/TGF-β1 downregulation was less effective in acquired sorafenib-resistant HCC cell lines. As an alternative to HSP27/TGF-β1 downregulation to induce acute cell death in sorafenib-resistant cancer, we substituted shGRP78 for shHSP27 as a complement to shTGF-β1. The combination of shTGF-β1/shGRP78 was shown to overcome sorafenib resistance in HCC cell lines. Notably, both GRP78 and CD44 accumulate at the cell surface during sorafenib treatment and are accompanied by IRE1α activation; this effect is responsible for triggering and maintaining sorafenib resistance. These results revealed that sorafenib-induced acquired resistance in cancer cells is the result of receptor tyrosine kinase (RTK) feedback activation via the CD44-linked GRP78 signaling pathway with efficient rewiring of the GRP78-IGF1R-PI3K-Akt signaling cascade, which provides strong survival potential as well as a continuous positive feedback loop, resulting in sustained strong sorafenib resistance. In summary, CD44-GRP78 functions as both a sensor of sorafenib-induced ER stress and a mediator of sorafenib resistance.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599533","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":"SLC34A2 inhibits tumorigenesis and progression via upregulating LRRK2/TTF-1/SELENBP1 axis in lung adenocarcinoma.","authors":"Ying Zhu, Ning An, Qiongyin Zhang, Yang Liu, Peiling Gu, Jinzhu Zhao, Wuliang Pan, Qiang Pu, Zhu Wen","doi":"10.1038/s41417-025-00928-2","DOIUrl":"https://doi.org/10.1038/s41417-025-00928-2","url":null,"abstract":"<p><p>Alveolar type II epithelial (AT2) cells have the properties of stem cells, abnormal AT2 cells serve as one of the original cells in lung adenocarcinoma (LUAD). However, the abnormal genes expression of AT2 cells during their malignant transformation into LUAD cells remain poorly understood. Importantly, SLC34A2 is a specific gene in AT2 cells of the lung. Our previous researches have reported that overexpression of SLC34A2 significantly inhibited proliferation, migration and invasion of LUAD cells. But, the underlying mechanisms of SLC34A2 in LUAD are largely unknown until now. Here, the present study discovered that the protein expression of Napi2b (SLC34A2), SELENBP1, TTF-1 and LRRK2 were all located in human AT2 cells of adjacent non-tumor tissues. However, the expression level of SLC34A2, SELENBP1, TTF-1 and LRRK2 were significantly decreased in LUAD tissues, and the expression of SLC34A2 was obviously positive correlation with the expression of SELENBP1, TTF-1 and LRRK2, respectively. Mechanistically, our study elucidated that overexpression of SLC34A2 could inhibit the activation of MEK/ERK signaling pathway through up-regulating the expression of LRRK2, and subsequently suppressed the expression of p-TTF-1(Ser327), which upregulated the expression of SELENBP1 by enhancing TTF-1 transcriptional activity. Ultimately, overexpression of SLC34A2 depressed the activation of PI3K/AKT/mTOR signaling pathway via up-regulating the expression of SELENBP1, which significantly inhibited the malignant characteristics of LUAD. In summary, our current research revealed a novel SLC34A2/LRRK2/TTF-1/SELENBP1 axis and its involvement in inhibiting the malignant characteristics of LUAD cells for the first time, which made contribution to further exploring the clinical application of SLC34A2. Furthermore, it also might offer novel insights into understanding how AT2 cells undergo malignant transformation into LUAD cells in the future.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552328","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":"Old versus new: upstream and downstream of promyelocytic leukemia zinc finger protein.","authors":"Kai Wang, Deyu Guo, Shijie Sun, Kang Tian, Hongchang Shen, Jiajun Du","doi":"10.1038/s41417-025-00912-w","DOIUrl":"10.1038/s41417-025-00912-w","url":null,"abstract":"<p><p>Promyelocytic leukemia zinc finger (PLZF) is a member of the zinc finger protein family and has been extensively studied due to its crucial role in influencing stem cell self-renewal, spermatogenesis, T cell differentiation, tumorigenesis, and development. Its function is regulated by multidimensional and multilevel regulation. Recent studies have explored the mechanism of action of PLZF in different diseases and related treatment strategies. This study aimed to summarize the regulatory mechanisms underlying PLZF expression and function, and update the latest PLZF regulatory targets and interacting molecules. We also summarized the mechanism by which PLZF promoted the transcriptional activation of target genes, besides its role as a transcriptional repressor. This study revealed a more detailed upstream and downstream regulatory mechanism of PLZF, providing directions for future research.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"750-761"},"PeriodicalIF":4.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973920","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":"Platelet activation: a barrier to effective antitumor immunity.","authors":"Daolin Tang, Rui Kang","doi":"10.1038/s41417-025-00915-7","DOIUrl":"10.1038/s41417-025-00915-7","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"741-743"},"PeriodicalIF":4.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157047","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":"Identification of an immunomodulatory lncRNA signature associated with immune cell reprogramming in high-grade glioma.","authors":"Alessandro Canella, Prajwal Rajappa","doi":"10.1038/s41417-025-00919-3","DOIUrl":"10.1038/s41417-025-00919-3","url":null,"abstract":"<p><p>High-grade gliomas (HGGs) are among the most aggressive brain tumors in pediatric, adolescent, and young adult (AYA) cancer patients, with a median survival of 12-15 months post-diagnosis. Their poor prognosis is driven by a highly immunosuppressive tumor immune microenvironment (TIME), which inhibits cytotoxic immune infiltration and anti-tumor response. This study investigated the involvement of long non-coding RNAs (lncRNAs) in shaping the immune phenotype of HGGs using two murine models: RCAS-PDGFb representing an immunosuppressive TME, and RCAS-BRAF V600E characterized by a signature more consistent with a pro-inflammatory TME. Transcriptomic analysis of tumor-infiltrating immune cells identified distinct lncRNA signatures associated with immunosuppressive and pro-inflammatory TMEs. Single-cell RNA sequencing and spatial transcriptomics supported context-dependent expression of these lncRNAs in high-grade glioma-associated immune cells, such as myeloid, T, and NK cells, and revealed their spatial distribution within the glioblastoma (GBM) TME. Several lncRNAs were enriched at the tumor edge and within necrotic regions in GBM patient samples, correlating with immunosuppression reprogramming and immune evasion mechanisms. These findings highlight specific immunomodulatory lncRNAs as potential players in the immunosuppressive glioma TME, and likely candidates for future studies aimed at developing novel therapeutic strategies to overcome immune suppression and improve clinical outcomes.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"778-784"},"PeriodicalIF":4.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315929","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":"Blocking the functional domain of cancer cell surface TIP1 upregulates Midkine via the β-catenin/Wnt signaling pathway.","authors":"Minakshi Saikia, Harendra Kumar Shah, Dennis E Hallahan, Abhay Kumar Singh, Vaishali Kapoor","doi":"10.1038/s41417-025-00922-8","DOIUrl":"10.1038/s41417-025-00922-8","url":null,"abstract":"<p><p>Drug resistance exhibited by cancer cells remains one of the primary reasons for the failure of therapeutic approaches to increase the survival of cancer patients. Marginal improvement in therapeutic efficacy with current treatment approaches for non-small cell lung cancer (NSCLC) mandates new treatment strategies. Tax interacting Protein-1 (TIP1) is a radiation-inducible molecular target involved in various cancer pathways. TIP1 expression correlates with poor survival in NSCLC patients. Antibody blocking the functional domain of TIP1 reduced cell proliferation and sensitized cancer cells to radiation. A ten-fold increase in Midkine (MDK) was observed in the proteomic analysis of cells treated with anti-TIP1 antibody. Wnt signaling activation led to MDK upregulation at the mRNA and protein levels following TIP1 blockade. Genetic silencing of β-catenin abrogated the induction of MDK following anti-TIP1 antibody treatment. Inhibiting TIP1 along with MDK showed a reduction in the colony-forming capability of the cells, indicating that MDK upregulation might be a strategy employed by cancer cells to combat the anti-proliferative capabilities of the anti-TIP1 antibody. Co-targeting cell surface TIP1 and MDK may be an effective therapeutic strategy for NSCLC patients.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"785-792"},"PeriodicalIF":4.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324592","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":"Hemorrhagic and ischemic risks of anti-VEGF therapies in glioblastoma.","authors":"Ozal Beylerli, Ilgiz Gareev, Andrey Kaprin, Aamir Ahmad, Vladimir Chekhonin, Shanshan Yang, Guang Yang","doi":"10.1038/s41417-025-00914-8","DOIUrl":"10.1038/s41417-025-00914-8","url":null,"abstract":"<p><p>Glioblastoma (GBM) is one of the most aggressive primary brain tumors, characterized by extensive neovascularization and a highly infiltrative phenotype. Anti-vascular endothelial growth factor (VEGF) therapies, such as bevacizumab, have emerged as significant adjunct treatments for recurrent and high-grade GBM by targeting abnormal tumor vasculature. Despite demonstrated benefits in slowing tumor progression and alleviating peritumoral edema, these agents are associated with notable vascular complications, including hemorrhagic and ischemic events. Hemorrhagic complications range from minor intracranial microbleeds to life-threatening intracranial hemorrhages (ICH). Mechanistically, VEGF inhibition disrupts endothelial function and decreases vascular integrity, making already fragile tumor vessels prone to rupture. Glioma-associated vascular abnormalities, including disorganized vessel networks and compromised blood-brain barrier, further exacerbate bleeding risks. Concurrent use of anticoagulants, hypertension, and genetic predispositions also significantly elevate hemorrhagic risk. In addition to bleeding complications, ischemic events are increasingly recognized in patients receiving anti-VEGF therapy. Reduced vascular endothelial cells (ECs) survival and diminished microvascular density can lead to regional hypoperfusion and potentially precipitate cerebrovascular ischemia. Impaired vasoreactivity and increased vascular resistance, often accompanied by endothelial dysfunction and microvascular rarefaction, contribute to elevated stroke and arterial thrombotic risk. This review synthesizes current evidence on hemorrhagic and ischemic complications arising from anti-VEGF therapy in GBM. We discuss underlying pathophysiological mechanisms, risk factors, and clinically relevant biomarkers, as well as prevention strategies-such as rigorous blood pressure (BP) control and close monitoring of coagulation parameters. We further highlight emerging avenues in precision medicine, including pharmacogenomic profiling and targeted adjunct agents that protect vascular integrity, aimed at mitigating adverse vascular events while preserving therapeutic efficacy. The goal is to optimize outcomes for GBM patients by balancing the benefits of anti-VEGF therapy with vigilant management of its inherent vascular risks. In addition, this study analyzes existing clinical trials of the use of anti-VEGF drugs in the treatment of gliomas using data from the clinicaltirals.gov website.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"762-777"},"PeriodicalIF":4.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109967","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":"Oleuropein regulates ubiquitination-mediated Mcl-1 turnover and exhibits antitumor activity.","authors":"Wen Liu, Song Peng, Jinzhuang Liao, Ruirui Wang, Pengfei Guo, Wei Li","doi":"10.1038/s41417-025-00921-9","DOIUrl":"10.1038/s41417-025-00921-9","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) represents the most common type of malignant oral tumor, with a high prevalence globally. Despite continual advancements in OSCC treatment, the 5-year survival rate remains around 50%, highlighting an urgent need for the development of new and effective therapeutic strategies. Here, we focused on myeloid leukemia 1 (Mcl-1), a well-known oncogenic driver in various human cancers, and systematically explored the therapeutic potential of oleuropein (Ole) through in vitro and in vivo analyses. Our findings demonstrated that Ole suppressed OSCC cell viability dose-dependently. Mechanistically, Ole facilitated β-TRCP-mediated ubiquitination of Mcl-1 by inhibiting the Akt-GSK3β-Mcl-1 pathway and enhancing the collaboration between β-TRCP and Mcl-1, ultimately leading to Mcl-1 degradation. Furthermore, the knockdown of β-TRCP mitigated the inhibitory effects of Ole on OSCC cells. In agreement with our cell-based experiments, animal studies showed that Ole treatment significantly delayed tumor growth without causing toxicity to vital organs. Additionally, whether used alone or combined with radiation, Ole effectively overcame radioresistance in OSCC cells. Our results suggest that Ole is a promising anti-tumor agent capable of treating OSCC by targeting Mcl-1.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"793-805"},"PeriodicalIF":4.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282453","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":"ARL6IP5 in cancers: bidirectional function and therapeutic value.","authors":"Zenan Hu, Hanxun Yue, Liang Qiao","doi":"10.1038/s41417-025-00903-x","DOIUrl":"10.1038/s41417-025-00903-x","url":null,"abstract":"<p><p>ARL6IP5 (ADP-ribosylation-like factor 6 interacting protein 5) plays an important role in a variety of physiological or pathological processes, including in cancers. However, the biological roles of ARL6IP5 in cancers are controversial. In this mini-review, we summarized the current understanding on the role of ARL6IP5 in cancers, particularly in the progression of chronic hepatitis virus-related hepatocellular carcinoma, as well as the potential values of ARL6IP5 in cancer therapy.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":"744-749"},"PeriodicalIF":4.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964946","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":"Enhancer hijacking drives FAM20C expression to promote papillary thyroid cancer progression.","authors":"Xianhui Ruan, Wei Zhang, Xiukun Hou, Guiming Fu, Weike Ma, Jianfeng Huang, Yuyang Qian, Mengran Tian, Nan Qin, Yupeng Chen, Ming Gao, Dapeng Li, Xiangqian Zheng","doi":"10.1038/s41417-025-00930-8","DOIUrl":"https://doi.org/10.1038/s41417-025-00930-8","url":null,"abstract":"<p><p>Papillary thyroid cancer (PTC) is the most common endocrine cancer, with a good prognosis in most cases. However, aggressive PTC can metastasise or reoccur and become refractory disease. Therefore, it's urgent to uncover new biomarkers for aggressive PTC. Accumulating evidence suggests that aberrant enhancers and targeted gene transcription drive the progression of PTC. To identify the cancer-specific enhancers and their downstream genes in PTC, we profiled the transcriptomes (RNA-seq) and enhancer-based epigenomic reorganisation (ChIP-seq) of cancer tissues and matched normal tissues from three PTC patients. Importantly, six candidate genes (RHBDF1, FAM20C, PHLDA2, TMPRSS6, LAD1, and BGN) were identified to be consistently upregulated by enhancers in PTC and correlated with prognosis. Further experiments verified the function of enhancers governing FAM20C in regulating PTC tumorigenesis, thereby unveiling a FAM20C-governed oncogenic mechanism for suppressing two cytokines (TNF-α and TGF-β) in PTC. Additionally, we demonstrated that a FAM20C inhibitor (3r) suppressed the proliferation and invasion of thyroid cancer cells in vitro and vivo. Moreover, FAM20C is driven by KLF12 through its enhancer. Collectively, our study uncovers the potential correlations between the aberrant activation of cancer-specific enhancers and PTC tumorigenesis and identifies FAM20C as a novel target for PTC.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526526","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}