Oncogene最新文献

{"title":"Wnt target IQGAP3 promotes Wnt signaling via disrupting Axin1-CK1α interaction","authors":"Muhammad Bakhait Rahmat, Aashiq Hussain, Yu Xuan Teh, Bibek Dutta, Sumedha Pundrik, Dennis Kappei, Yoshiaki Ito","doi":"10.1038/s41388-025-03512-y","DOIUrl":"10.1038/s41388-025-03512-y","url":null,"abstract":"The scaffold protein IQGAP3 is highly upregulated in most epithelial cancers. While recent studies have highlighted its pivotal roles in cancer cell proliferation and metastasis, a deeper mechanistic understanding of IQGAP3 is currently lacking. We have here used TurboID to map IQGAP3 proximity partners and identified the Wnt signaling members Axin1 and CK1α as IQGAP3-interacting proteins. Our functional studies demonstrated that overexpression of IQGAP3 increases β-catenin levels, while IQGAP3 depletion reduces β-catenin levels in gastric cancer cells. Mechanistically, IQGAP3 disrupts Axin1-CK1α interaction, thereby inhibiting β-catenin phosphorylation and ultimately leading to its accumulation. Importantly, we discovered that IQGAP3 itself is regulated by Wnt signaling, suggesting its involvement in a positive feedback loop in Wnt/β-catenin signaling through interactions with Axin1 and CK1α. These findings identify IQGAP3 as a novel mediator of β-catenin stabilization and underscore its potential as a target for cancer therapy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 40","pages":"3831-3849"},"PeriodicalIF":7.3,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03512-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Membrane flexibility induced by BST2 contributes to radioresistance in glioblastoma","authors":"Haksoo Lee, Dahye Kim, Byeongsoo Kim, Eunguk Shin, Hyunkoo Kang, Jae-Myung Lee, HyeSook Youn, BuHyun Youn","doi":"10.1038/s41388-025-03544-4","DOIUrl":"10.1038/s41388-025-03544-4","url":null,"abstract":"Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis due to its resistance to radiotherapy. Epidermal growth factor receptor variant III (EGFRvIII), a common mutation in GBM, promotes radioresistance through ligand-independent activation. We hypothesized that membrane flexibility influences EGFRvIII activation and enhances resistance. Bone marrow stromal antigen 2 (BST2, CD317, or TETHERIN) was identified as a key mediator linking membrane dynamics to EGFRvIII-driven survival signaling. Radiation-induced changes in membrane flexibility amplified BST2 activity, stabilizing lipid rafts and promoting EGFRvIII clustering. Pharmacological inhibition of BST2 with arbutin, an FDA-approved compound, disrupted this mechanism, increasing GBM radiosensitivity by enhancing mitochondrial reactive oxygen species (ROS) production and apoptosis. Additionally, BST2 downregulation impaired de novo lipogenesis and reduced lipid droplet accumulation, highlighting its role in metabolic reprogramming. In orthotopic xenograft models, BST2 inhibition suppressed tumor growth and prolonged survival. These findings establish BST2 as a key regulator of membrane-driven radioresistance in GBM. Targeting BST2-mediated membrane remodeling may provide a novel therapeutic strategy to enhance radiotherapy efficacy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 40","pages":"3816-3830"},"PeriodicalIF":7.3,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874333","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":"ARID1A: gene, protein, and function in endometrial cancer","authors":"Savannah E. LaBuda, Russell R. Broaddus, Andrew B. Gladden","doi":"10.1038/s41388-025-03539-1","DOIUrl":"10.1038/s41388-025-03539-1","url":null,"abstract":"ARID1A, a key structural subunit of the SWI/SNF chromatin remodeling complex, is the most frequently mutated SWI/SNF subunit in cancer with most mutations occurring in endometrial cancer. In a multitude of malignancies, loss of ARID1A protein correlates with poor patient prognosis, increased metastasis, and changes to key cancer pathways such as genomic instability. Despite this, little work has been done to deduce the molecular role of ARID1A in endometrial cancer progression and prognosis, and much of the present work is conflicting data. There is a growing body of work that shows a discordance between ARID1A mutation status and expression of ARID1A protein in endometrioid-type endometrial tumors. Several other malignancies have found that alternative mechanisms of ARID1A protein regulation can confer ARID1A protein loss. Therefore, relying solely on ARID1A sequencing may overlook a cohort of endometrial cancer patients with absence of ARID1A protein. With endometrial cancer being one of the sole malignancies increasing in both incidence and patient mortality since the mid-2000s, it is of upmost importance to assess the impacts and potential prognostic use of commonly mutated proteins such as ARID1A. This review will highlight the critical role of ARID1A in endometrial cancer pathogenesis, its potential therapeutic vulnerabilities, and emphasizes the need to move beyond ARID1A mutation as a sole diagnostic marker to elucidate its molecular and clinical implications in endometrial cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 36","pages":"3273-3283"},"PeriodicalIF":7.3,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874332","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":"Chromosomal abnormalities of mesenchymal stromal cells in hematological malignancies","authors":"Mateus de Oliveira Lisboa, Tamara Borgonovo, Letícia Fracaro, Aline Rangel Pozzo, Paulo Roberto Slud Brofman, Sabine Mai","doi":"10.1038/s41388-025-03528-4","DOIUrl":"10.1038/s41388-025-03528-4","url":null,"abstract":"Historically, hematological malignancies (HMs) and solid cancers were primarily attributed to cell-intrinsic mechanisms. However, overwhelming evidence highlights the crucial role of the tumor microenvironment in this process. Abnormalities in the bone marrow microenvironment (BMM) contribute to the development of HMs and affect patient outcomes. Bone Marrow Mesenchymal Stromal Cells (BM-MSCs) represent one of the key cell types within the BMM. Interestingly, a single specific gene mutation in BM-MSCs is sufficient to disrupt normal hematopoiesis and promote clonal malignant hematopoiesis in mice. Since a particular mutation may be sufficient, attention must also be given to chromosomal abnormalities (CAs), potentially affecting hundreds of genes. Notably, CAs have been identified in the majority of HMs BM-MSCs. CAs have been detected more frequently in BM-MSCs of HMs patients than in healthy donors. The primary explanation for CAs is chromosomal instability (CIN), a phenomenon characterized by increased rates of CAs. CIN can lead to abnormal gene expression, cellular senescence, and inflammation, altering MSCs. It may compromise their anti-tumorigenic functions and shift the BMM towards a supportive or protective state. Despite the importance of CAs and CIN, cytogenetic results in HM-MSCs appear controversial. This review discusses current studies, suggesting that some of the controversies may result from technical limitations. Furthermore, based on the high incidence of CAs and the lack of patterns (randomness), we suggest this is a case of CIN. Therefore, instead of looking for CAs patterns, we must focus on understanding the phenomenon of CIN in these cells. This includes verifying the frequencies of non-clonal CAs, looking for specific CIN mechanisms and distinguishing whether CIN is a driver or a consequence of HMs. To guide future research and address the existing knowledge gaps, we discuss potential approaches to the challenges in studying CAs in HM-MSCs.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 35","pages":"3155-3170"},"PeriodicalIF":7.3,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03528-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activated MAFB in ovarian cancer promotes cytoskeletal remodeling and immune microenvironment suppression by interfering with m6A modifications through WTAP competition","authors":"Qinke Li, Siying Zhang, Min Wang, Qiang Yi, Hang Xu, Jinlong Wang, Zhu Yang","doi":"10.1038/s41388-025-03522-w","DOIUrl":"10.1038/s41388-025-03522-w","url":null,"abstract":"The tumor microenvironment (TME) coordinates cancer progression through complex transcriptional networks, but the molecular mechanisms controlling immune evasion in ovarian cancer remain elusive. Here, by integrating immune dysfunction characteristics across multiple clinical cohorts and single-cell transcriptomics, we identified MAFB as a major regulator of ovarian cancer progression. MAFB expression exhibited stage-dependent elevation and was associated with immune checkpoint characteristics. Mechanistically, MAFB competitively binds to the core component WTAP of the m6A methyltransferase complex, thereby antagonizing the degradation of target gene mRNAs (WNT5A, CD55). This atypical regulatory axis leads to persistent expression of the target genes, further coordinating tumor cell invasiveness and immune landscape remodeling through cytoskeletal protein reorganization, M2 macrophage polarization, and regulatory T cell infiltration. Correlative analyses in patient cohorts and therapeutic effects in preclinical models support the clinical relevance of this pathway. Our findings uncover a novel mechanism by which MAFB promotes ovarian cancer progression through cytoskeletal remodeling and immune suppression, connecting transcriptional regulation with epitranscriptomic modifications, and identify the MAFB-WTAP-CD55 axis as a potential therapeutic target in ovarian cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 40","pages":"3799-3815"},"PeriodicalIF":7.3,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835975","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":"Immune evasion from macrophages by NEAT1-induced CD24 in liver cancer","authors":"Hiroyuki Tsuchiya, Takehiko Hanaki, Tomohiko Sakabe, Naruo Tokuyasu, Takakazu Nagahara, Yoshihisa Umekita, Hajime Isomoto, Yoshiyuki Fujiwara, Daisuke Nanba","doi":"10.1038/s41388-025-03537-3","DOIUrl":"10.1038/s41388-025-03537-3","url":null,"abstract":"The limited efficacy of immune checkpoint inhibitors in hepatocellular carcinoma (HCC) can arise from the involvement of immunosuppressive cells, such as macrophages. In the present study, we found that the long noncoding RNA NEAT1, particularly its short isoform (NEAT1v1) induced the expression of CD24, which is known as an immune checkpoint molecule for macrophages. Mechanistically, NEAT1v1 sponged miR-320a-3p to upregulate the transcription factor SP1, which in turn, activated CD24 transcription. A spheroid co-culture of primary or THP-1-derived macrophages with HCC cells revealed that NEAT1v1 suppressed M1 marker expression and phagocytic activity in macrophages. In a syngeneic subcutaneous model of HCC, Neat1v1 increased the tumor infiltration of M2-like macrophages and induced resistance to anti-Pd-1 antibody, while combination of the anti-Pd-1 and anti-Cd24 antibodies significantly suppressed the tumor growth. Finally, NEAT1, SP1, and CD24 expression increased in tumor tissues from patients with HCC, compared to adjacent normal tissues, whereas miR-320a-3p was significantly downregulated. Moreover, plasma NEAT1 cell-free RNA was significantly decreased after therapeutic intervention. Taken together, NEAT1v1 protects HCC cells from macrophages by sending a “Don’t Eat Me” signal via CD24, and is therefore, a potential target molecule for the treatment and diagnosis of HCC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 39","pages":"3652-3664"},"PeriodicalIF":7.3,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835977","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":"Coexistence of P53 and KRAS mutations enhances ERK1/2 signaling by inducing EGR1 expression through mutp53 and c-JUN interaction","authors":"Manxue Wang, Ailing Ji, Ruifang Gao, Sike Hu","doi":"10.1038/s41388-025-03536-4","DOIUrl":"10.1038/s41388-025-03536-4","url":null,"abstract":"The ERK1/2 signaling pathway, one of the most frequently dysregulated oncogenic pathways, can be initiated by diverse mutations, including those in RAS, BRAF, and amplifications of ERBB2 (HER2). Co-occurrence of ERK1/2 hyperactivation and TP53 mutations is common in multiple cancer types and correlates with significantly poorer clinical outcomes. However, the direct mechanisms underlying the cooperation between ERK1/2 signaling and mutant p53 remain largely unexplored. Our study demonstrates that oncogenic KRAS activates c-JUN, which facilitates physical interactions with mutant p53, leading to hyperactivation of several pro-metastatic transcriptional networks. Notably, mutant p53 and c-JUN collaboratively upregulate EGR1, a key driver of tumor invasion and metastasis. The combined effects of elevated EGR1 expression, along with signaling pathways activated by KRAS and mutant p53, significantly enhance pro-metastatic traits in cancer cells. These findings provide crucial insights into the co-enrichment of KRAS and p53 mutations and pave the way for novel therapeutic strategies targeting this interaction.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 40","pages":"3787-3798"},"PeriodicalIF":7.3,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835976","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":"Retraction Note to: KIFC1 regulated by miR-532-3p promotes epithelial-to-mesenchymal transition and metastasis of hepatocellular carcinoma via gankyrin/AKT signaling","authors":"Jihua Han, Fengyue Wang, Yaliang Lan, Jiabei Wang, Chunlei Nie, Yingjian Liang, Ruipeng Song, Tongsen Zheng, Shangha Pan, Tiemin Pei, Changming Xie, Guangchao Yang, Xirui Liu, Mingxi Zhu, Yan Wang, Yao Liu, Fanzheng Meng, Yifeng Cui, Bo Zhang, Yufeng Liu, Xianzhi Meng, Jiewu Zhang, Lianxin Liu","doi":"10.1038/s41388-025-03527-5","DOIUrl":"10.1038/s41388-025-03527-5","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 35","pages":"3272-3272"},"PeriodicalIF":7.3,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03527-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of RAPGEF3 as the therapeutic vulnerability of basal-subtype lung squamous cell carcinoma","authors":"Yijia Zhou, Hua Wang, Shijie Tang, Yayi He, Cai-guang Yang, Luonan Chen, Hongbin Ji","doi":"10.1038/s41388-025-03532-8","DOIUrl":"10.1038/s41388-025-03532-8","url":null,"abstract":"Lung squamous cell carcinoma (LUSC), particularly the basal-subtype, remains a leading cause of cancer-related mortality, with limited therapeutic options and poor survival rates. In this study, we identify RAPGEF3 as a critical driver of malignant progression in basal-subtype LUSC. Our findings show that RAPGEF3 is significantly upregulated in basal-subtype LUSC and plays a pivotal role in tumor progression by activating the RAP1A-AKT signaling axis, essential for cell proliferation and survival. We demonstrate that inhibiting RAPGEF3 with the selective inhibitor ESI-09 significantly suppresses tumor growth in patient-derived xenograft (PDX) models without notable toxicity. Furthermore, our results reveal that RAP1A, rather than its paralog RAP1B, mediates tumor survival and proliferation through AKT signaling, providing new insights into the functional differences between these isoforms. Given the lack of targeted therapies for basal-subtype LUSC, RAPGEF3 emerges as a novel and promising therapeutic target. These findings not only contribute to understanding the molecular mechanisms of basal-subtype LUSC but also suggest that RAPGEF3-targeted therapies may be applicable to other cancers with similar oncogenic signaling pathways.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 34","pages":"3142-3148"},"PeriodicalIF":7.3,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804491","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":"ALDH1A3 promotes aggressive basal-like pancreatic cancer through an AP-1/RUNX2 enhancer network","authors":"Xiaoping Zou, Shuang Nie, Jing Cao, Mengyue Shi, Kathleen Schuck, Zhao Shi, Lingling Zhang, Hongzhen Li, Yifeng Sun, Chao Fang, Jingxiong Hu, Yiqi Niu, Yuanyuan Yu, Zhiheng Zhang, Chao Li, Mingyue Hu, Lei Wang, Kuirong Jiang, Zipeng Lu, Jan Akkan, Susanne Raulefs, Christoph Kahlert, Susanne Roth, Ingrid Herr, Yuan Wan, Andre Mihaljevic, Xuetian Qian, Qi Zhang, Maggie Haitian Wang, Jörg Kleeff, Helmut Friess, Zuguang Gu, Christoph W. Michalski, Shanshan Shen, Bo Kong","doi":"10.1038/s41388-025-03530-w","DOIUrl":"10.1038/s41388-025-03530-w","url":null,"abstract":"The basal-like transcriptional subtype of pancreatic ductal adenocarcinoma (PDAC) is linked to therapy resistance and poor prognosis. The cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) is a critical enzyme in acetaldehyde metabolism, but the interconnection to the basal-like subtype is poorly understood. Here, we identified ALDH1A3 as a key gene, which correlates with reduced survival and increased tumor growth. Functional studies revealed interaction of ALDH1A3 with genes like FAM3C, MCC, PMEPA1, and IRS2, forming a network driving PDAC progression. Chromatin profiling showed that ALDH1A3 affects acetylation of histone 3, mediating AP-1 activity, particularly via FOS family members, activating oncogenic pathways such as MAPK and TNF signaling. RUNX2 emerged as a therapeutic target within this network, as its knockdown disrupted MAPK signaling and reduced tumor growth. These findings emphasize the role of ALDH1A3 in linking nuclear metabolic-epigenetic programming in basal-like PDAC, highlighting it as a promising therapeutic target for novel treatment strategies.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 40","pages":"3774-3786"},"PeriodicalIF":7.3,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03530-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}