Oncogene最新文献

{"title":"Par6/SOX2 interact to modulate stemness maintenance in glioma by regulating the EGFR/PI3K/AKT signaling cascade.","authors":"Ting Yang, Yan Zeng, Ya Li, Yishan Huang, Xin Meng, Chunjiao Lu, Chenchen Zhu, Pei Liu, Jing Liu, Shaocai Hao, Juanjuan Luo, Wei Cui, Xiaojun Yang","doi":"10.1038/s41388-025-03595-7","DOIUrl":"https://doi.org/10.1038/s41388-025-03595-7","url":null,"abstract":"<p><p>Glioma stem cells (GSCs) are a primary factor contributing to the failure of glioma treatment and lead to a poor prognosis for patients with glioma. However, the biological functions and mechanisms involved in regulating stemness maintenance in GSCs are not well understood. Here, we investigated the potential regulatory effects of Par6 on stemness maintenance in GSCs. Our data revealed high expression of Par6 in glioma specimens is usually accompanied by a poor prognosis. Further study indicated Par6 expression might be involved in stemness maintenance of GSCs by directly binding to SOX2 in glioma cells. In contrast, the blockade of Par6/SOX2 interaction with a specific inhibitory peptide (Par6i-P1) significantly suppressed the stemness maintenance of GSCs. Gene manipulation results showed the combination of Par6 and SOX2 promoted stemness maintenance in a complementary manner. Mechanistically, we identified PI3K/AKT signaling pathway as a downstream target of EGFR, which is also transcriptionally regulated by SOX2 in glioma cells. Moreover, a clinical study indicated the coexpression of Par6 and SOX2 predicted poor outcomes for glioma patients, suggesting the Par6/SOX2 interaction might trigger the regulation of stemness maintenance through activating EGFR/PI3K/AKT signaling pathway in glioma. Furthermore, comparing with the scrambled peptide control, the tumorigenicity assay and immunohistochemistry indicated that targeting the Par6/SOX2 interaction might effectively mitigate GSC-mediated chemotherapy resistance in temozolomide (TMZ) treatment, and improve the malignancy and prognosis in mice orthotopically transplanted with GBM. Together, these findings reveal a novel mechanism by which the Par6/SOX2 interaction contributes to the maintenance of stemness in GSCs and may serve as a promising therapeutic target for improving the prognosis of glioma patients.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275232","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":"Comprehensive single-cell analysis reveals mast cells' roles in cancer immunity.","authors":"Hao Qian, Wenbo Wang, Jiaomeng Pan, Ming Zhao, Li Gao, Jia Zeng, Hang Gong, Guangyan Zhangyuan, Zi Li, Mao Zhang, Xia Shen, Yuanchi Weng, Xiaxing Deng, Yingying Huang","doi":"10.1038/s41388-025-03590-y","DOIUrl":"https://doi.org/10.1038/s41388-025-03590-y","url":null,"abstract":"<p><p>Mast cells, traditionally known for their roles in allergic reactions and pathogen defense, have been revealed to possess significant functional diversity within the tumor microenvironment (TME). Through single-cell RNA sequencing analysis across 15 solid tumors (385 samples from 264 patients), 10 distinct mast cell states characterized by unique gene expression patterns and functional attributes were identified. Notably, the C7-HLA-DR cluster that closely linked with antigen presentation, has emerged as a key player in shaping anti-tumor immune responses. In this study, systematic analysis demonstrated that the C7-HLA-DR cluster could interact with T cells to enhance the efficacy of immunotherapy and improve patients' prognosis. On the contrary, the C1-HSPA1 cluster exhibited pro-tumor characteristics, highlighting the functional diversity of mast cells within TME. These findings illustrate the landscape of mast cell within TME and propose a new avenue to boost the efficacy of immunotherapy.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275266","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":"Correction to: Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines.","authors":"Michael J Clemens, Martin Bushell, Simon J Morley","doi":"10.1038/s41388-025-03586-8","DOIUrl":"https://doi.org/10.1038/s41388-025-03586-8","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252242","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":"Publisher Correction: RCN3 functions as a tumor promoter in colorectal cancer by modulating the GRP78-PI3K-AKT signaling pathway.","authors":"Mei Huang, Bingru Qin, Zhefan Xie, Ruling Zhou, Zhizhao Lin, Lihua Zhou, Zelong Han, Side Liu, Kangmin Zhuang","doi":"10.1038/s41388-025-03592-w","DOIUrl":"https://doi.org/10.1038/s41388-025-03592-w","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252275","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":"Atg16l1 and Xbp1 cooperatively protect from transcription-associated mutagenesis and small intestinal carcinogenesis.","authors":"Nassim Kakavand, Hang Xiang, Georg Laue, Taous Mekdoud, Lina Welz, Miguel Gomes Silva, Joana P Bernardes, Go Ito, Silke van den Bossche, Julia Kugler, Florian Tran, Alexander Ossysek, Simon Imm, Finn Hinrichsen, Moritz Jesinghaus, Arthur Kaser, Richard Blumberg, Timon E Adolph, Stefan Schreiber, Markus Tschurtschenthaler, Philip Rosenstiel, Konrad Aden","doi":"10.1038/s41388-025-03591-x","DOIUrl":"https://doi.org/10.1038/s41388-025-03591-x","url":null,"abstract":"<p><p>Atg16l1 plays a critical role in autophagy, and Xbp1 is part of the endoplasmic reticulum (ER) homeostasis. Both, Atg16l1 and Xbp1 are known risk genes for inflammatory bowel disease (IBD). Previous studies have shown that dysfunctional Atg16l1 and Xbp1 are epithelial-derived drivers of small intestinal inflammation. Despite a clear link between Crohn's disease and small intestinal adenocarcinoma, the molecular impact of autophagy and ER stress in this malignant transformation is not known. Using a model of impaired ribonucleotide excision repair (RER), a key homeostatic repair mechanism in highly proliferative cells, we investigated the impact of Atg16l1 on epithelial DNA damage responses and small intestinal carcinogenesis with and without functional ER homeostasis. We used conditional mouse models for deficient RER (Rnaseh2b^ΔIEC), bearing a co-deletion of disrupted autophagy (Atg16l1/Rnaseh2b^ΔIEC) or ER stress resolution (Xbp1/Rnaseh2b^ΔIEC), and triple-conditional knock-out mice for both, Xbp1 and Atg16l1 (Atg16l1/Xbp1/Rnaseh2b^ΔIEC). We assessed the degree of DNA damage and the incidence of small intestinal carcinoma. We report that defective epithelial RER induces autophagy, and that dysfunctional autophagy increases RER-induced DNA damage and causes the loss of RER-induced proliferative arrest but no spontaneous carcinogenesis in the gut. We demonstrate that dysfunctional Atg16l1 drastically increases the incidence of spontaneous intestinal adenocarcinomas in mice with defective epithelial RER and impaired ER homeostasis. We provide experimental evidence that the same epithelial mechanisms suppressing gut inflammation also critically protect from small intestinal carcinogenesis. Our findings set a molecular framework for the increased risk of intestinal carcinogenesis in patients with IBD, which links perturbations of ER homeostasis and autophagy defects with accumulating DNA damage. In a model of transcription-associated mutagenesis, deficiency of the IBD risk gene Atg16l1 does not induce small intestinal cancer. In contrast, double deficiency of Xbp1 and Atg16l1 drives spontaneous tumor formation highlighting a cooperative role of Xbp1 and Atg16l1 in tumor suppression.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244769","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":"Targeting SREBP-dependent lipogenesis potentiates the anti-tumor activity of docetaxel by increasing membrane permeability and intracellular drug accumulation.","authors":"Jiaqi Chen, Mu-En Wang, Alyssa R Bawcom, Yi Lu, John M Asara, Lei Li, Ming Chen","doi":"10.1038/s41388-025-03588-6","DOIUrl":"https://doi.org/10.1038/s41388-025-03588-6","url":null,"abstract":"<p><p>Lipid metabolism is among the most frequently dysregulated metabolic processes in human cancer, yet how cellular lipids, the end products of lipogenesis, and their composition are altered to support various aspects of cancer remains poorly understood. Here, we show that targeting SREBP-dependent lipogenesis via FGH10019, an orally available SREBP inhibitor, enhances docetaxel-induced cytotoxicity in human prostate cancer cells in vitro and in vivo. Mechanistically, suppression of lipid biosynthesis leads to a shift in cellular lipid composition toward polyunsaturated lipids, resulting in increased membrane permeability and intracellular docetaxel accumulation. Thus, our findings reveal a critical role of de novo lipogenesis in protecting cancer cells from chemotherapeutics and suggest that treatment with lipogenesis inhibitors could improve the efficacy of chemotherapy against human prostate cancer.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228268","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":"Mast cells interact directly with colorectal cancer cells to promote epithelial-to-mesenchymal transition.","authors":"Rosie Lanzloth, Nicole L Harris, Anthony M Cannon, Mark H Kaplan, Heather M O'Hagan","doi":"10.1038/s41388-025-03589-5","DOIUrl":"10.1038/s41388-025-03589-5","url":null,"abstract":"<p><p>Mast cells (MCs), a type of granulocytic immune cell, can be both pro- and anti-tumorigenic in colorectal cancer (CRC). We hypothesized that these contrasting findings may be in part due to differential interactions of MCs with CRC subtypes. BRAF mutant CRC uniquely contains intestinal secretory cell types. In this study, we demonstrated that MCs are enriched in BRAF mutant CRC, likely because they are recruited by factors released from cancer secretory cells. To investigate the functional consequences of MC-CRC cell interactions, we performed direct coculture experiments. We demonstrated that MCs promote epithelial-to-mesenchymal transition (EMT) in CRC cells in a calcium- and contact-dependent fashion. Furthermore, inhibiting LFA-1 and ICAM1 integrin binding reduced the coculture-induced EMT-related marker expression in CRC cells. The MC-CRC cell interaction facilitates the transfer of biological materials, including mRNA molecules, from MCs to CRC cells. This study is the first to report a contact-dependent, pro-tumorigenic role of MCs in CRC, as well as the transfer of molecules encoded by MCs to CRC cells. These findings enhance our comprehension of cell-cell communication between immune and cancer cells. Furthermore, this work suggests that targeting MC-CRC interactions, particularly through modulating integrin pathways, could offer new therapeutic strategies for aggressive CRC subtypes.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213318","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":"C1QBP forms a positive feedback loop with the PAICS/FAK/C-MYC axis to promote cancer cell proliferation.","authors":"Xiang Cheng, Mengmeng Wang, Wei Li, Bingzhang Tian, Jing Zhang, Chen Zhang, Pian Liu","doi":"10.1038/s41388-025-03568-w","DOIUrl":"https://doi.org/10.1038/s41388-025-03568-w","url":null,"abstract":"<p><p>The cell membrane, as the boundary of the cellular system, plays an extremely important role in the regulation of cellular metabolism, substance transport, information exchange and cellular immunity. Complement component 1q subcomponent binding protein (C1QBP) is a ubiquitously expressed cellular protein, and although multiple studies have suggested that C1QBP may play an important role in cancer, the functions and mechanisms of C1QBP in the progression of many tumors remain unknown. We performed bioinformatics analysis and found that C1QBP was significantly overexpressed in a variety of tumor tissues and that high C1QBP expression correlates strongly with poor prognosis in tumor patients. Further validation in cholangiocarcinoma(CCA) revealed that C1QBP is the most upregulated membrane protein in CCA, where it is involved in energy metabolism, DNA repair, and tolerance to platinum-based chemotherapeutic agents. It also correlates strongly with CCA proliferation and poor prognosis, while silencing of C1QBP significantly inhibits CCA growth in mice. Mechanistic studies further demonstrated that c-MYC can upregulate C1QBP expression at the transcriptional level, subsequently influencing PAICS/FAK expression and promoting CCA growth. Interestingly, C1QBP also regulates c-MYC expression by increasing FAK phosphorylation, establishing a positive feedback loop that drives tumor progression. Additionally, we developed a novel siRNA delivery system, HA gel-siC1QBP, by encapsulating siC1QBP within hyaluronic acid-dopamine hydrogel-coated liposomes. In vivo experiments confirmed its ability to provide prolonged and stable C1QBP inhibition along with enhanced antitumor efficacy. In conclusion, our study suggests that C1QBP may serve as a valuable biomarker for tumour prognosis and that silencing C1QBP using HA gel-siC1QBP -either alone or combined with targeted/ immunotherapies -represents a promising therapeutic strategy against tumors.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200495","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":"Targeting JMJD6/PPARγ/GPX4 axis overcomes ferroptosis resistance and enhances therapeutic efficacy in hepatocellular carcinoma.","authors":"Jie Li, Shengwei Mao, Shiguang Yang, Yunwei Lou, Xuhui Zhao, Jiafeng Chen, Yichao Bu, Bei Lv, Qing Shi, Yunjie Zhang, Xingxing Zhang, Zhijie Yu, Yuan Fang, Jinglin Xia","doi":"10.1038/s41388-025-03581-z","DOIUrl":"https://doi.org/10.1038/s41388-025-03581-z","url":null,"abstract":"<p><p>Despite ferroptosis induction being a promising strategy for hepatocellular carcinoma (HCC), its clinical application is limited by intrinsic resistance mechanisms. Through CRISPR-Cas9 screening of epigenetic regulators, we identified JMJD6 as a critical mediator of ferroptosis resistance in HCC. JMJD6 knockdown or pharmacological inhibition (iJMJD6) enhanced ferroptosis induced by ferroptosis inducers (erastin and RSL3), as indicated by decreased cell viability, reduced intracellular glutathione levels, increased lipid peroxidation, and disrupted mitochondrial cristae morphology, thereby promoting the susceptibility of HCC to ferroptosis. Clinically, JMJD6 was highly expressed in HCC, and its elevated expression was correlated with a poor prognosis in HCC. Mechanistically, JMJD6 interacts with BRD4, forming a transcriptional complex that binds to the PPARγ promoter. Through its demethylase activity, JMJD6 reduces H4R3me2s levels at the promoter, thereby promoting PPARγ transcription, activating the PPARγ-GPX4 axis to enhance lipid peroxidation scavenging and ferroptosis resistance. Given the role of ferroptosis in resistance mechanisms of molecular-targeted therapies, we combined iJMJD6 with sorafenib or lenvatinib, demonstrating enhanced ferroptosis and potent suppression of HCC proliferation in vitro and in vivo. Our findings revealed the JMJD6/PPARγ/GPX4 axis as a key driver of ferroptosis resistance and established JMJD6 targeting as a novel strategy to improve ferroptosis-based HCC therapies.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200492","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":"Targeting ZNRF2-mediated SLC3A2 plasma membrane translocation enhances ferroptosis in lung adenocarcinoma.","authors":"Weijie Zhang, Jianjun Li, Jian Zhao, Di Lu, Mengzhu Zhang, Chenkang Ma, Yang Yang, Lei Gu, Jianjie Zhu, Yuanyuan Zeng, Jian-An Huang, Zeyi Liu","doi":"10.1038/s41388-025-03585-9","DOIUrl":"https://doi.org/10.1038/s41388-025-03585-9","url":null,"abstract":"<p><p>Zinc And Ring Finger 2 (ZNRF2), an important protein related to E3 ligases activity, known for its support of cell viability of lung adenocarcinoma (LUAD), remains a functional mystery as its mechanism of action remains largely unknown. SLC3A2, a cell surface transmembrane protein, which regulates intracellular calcium levels and transports L-type amino acids, also has unclear mechanisms, particularly involving its expression and localization. In the present study, we addressed the role of ZNRF2-mediated SLC3A2 plasma membrane translocation, which influences ferroptosis in LUAD. We found that ZNRF2 exhibited ubiquitous expression in LUAD, and supported cell viability via ferroptosis inhibition. Mechanistically, ZNRF2 impacted SLC3A2 membrane localization and ferroptosis by fine-tuning K147-mediated ubiquitination. We subsequently synthesized Peptide K147 to block transportation of the SLC3A2 protein to the plasma membrane, which consequently attenuated the inhibitory effect of ZNRF2 on ferroptosis, thereby preventing tumor cell proliferation both in vitro and in vivo. Finally, we revealed that the ZNRF2- mediated SLC3A2 plasma membrane transport enhanced LUAD chemoresistance, whereas, Peptide K147 facilitated LUAD chemosensitization. Our results demonstrated that ZNRF2-mediated SLC3A2 plasma membrane translocation potentially contributes to the malignant progression and therapeutic resistance in LUAD. This knowledge is beneficial to the future design of advanced cancer therapy.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150409","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}