Oncogene最新文献_第3页

CBX3 promotes multidrug resistance by suppressing ferroptosis in colorectal carcinoma via the CUL3/NRF2/GPX2 axis. CBX3通过CUL3/NRF2/GPX2轴抑制结直肠癌中的铁变态反应，从而促进多药耐受性

IF 6.9 1区医学

Oncogene Pub Date : 2025-03-16 DOI: 10.1038/s41388-025-03337-9

Xiaoming Bai, Tinghong Duan, Jiaofang Shao, Yutong Zhang, Guangyuan Xing, Jie Wang, Xue Liu, Min Wang, Yuanqiao He, Hai Wang, Zhi-Yuan Zhang, Min Ni, Jin-Yong Zhou, Jinshun Pan

{"title":"CBX3 promotes multidrug resistance by suppressing ferroptosis in colorectal carcinoma via the CUL3/NRF2/GPX2 axis.","authors":"Xiaoming Bai, Tinghong Duan, Jiaofang Shao, Yutong Zhang, Guangyuan Xing, Jie Wang, Xue Liu, Min Wang, Yuanqiao He, Hai Wang, Zhi-Yuan Zhang, Min Ni, Jin-Yong Zhou, Jinshun Pan","doi":"10.1038/s41388-025-03337-9","DOIUrl":"10.1038/s41388-025-03337-9","url":null,"abstract":"Chemoresistance poses a significant challenge in colorectal cancer (CRC) treatment. However, the mechanisms underlying chemoresistance remain unclear. CBX3 promoted proliferation and metastasis in CRC. However, the role and mechanism of CBX3 in chemoresistance remain unknown. Therefore, we aimed to investigate the effects and mechanisms of CBX3 on multidrug resistance in CRC. Our studies showed that higher levels of CBX3 expression were associated with poor survival, especially in groups with progression following chemotherapy. CBX3 overexpression increased Irinotecan and Oxaliplatin resistance, whereas CBX3 knockdown suppressed multidrug resistance in CRC cells. Additionally, CBX3 inhibited ferroptosis associated with multidrug resistance, and the ferroptosis activators prevented CBX3 overexpression-mediated cell survival. RNA sequencing revealed that the NRF2-signaling pathway was involved in this process. CBX3-upregulated NRF2 protein expression by directly binding to the promoter of Cullin3 (CUL3) to suppress CUL3 transcription and CUL3-mediated NRF2 degradation. Moreover, Glutathione Peroxidase 2 (GPX2) was downstream of the CBX3-NRF2 pathway in CRC chemoresistance. ML385, an NRF2 inhibitor, suppressed GPX2 expression, and increased ferroptosis in PDX models. Our study identified CBX3/NRF2/GPX2 axis may be a novel signaling pathway that mediates multidrug resistance in CRC. This study proposes developing novel strategies for cancer treatment to overcome drug resistance in the future.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634374","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}

引用次数: 0

CBX2 as a therapeutic target in colorectal cancer: insights into the altered chromatin accessibility via RUNX1-CBX2-MAP4K1 axis

IF 6.9 1区医学

Oncogene Pub Date : 2025-03-13 DOI: 10.1038/s41388-025-03331-1

Bangting Wang, Shijie Zhang, Yumeng Guo, Wenqing Gao, Hao Wu, Jiankun Wang, Yan Wang, Chunming Tang, Li Liu

{"title":"CBX2 as a therapeutic target in colorectal cancer: insights into the altered chromatin accessibility via RUNX1-CBX2-MAP4K1 axis","authors":"Bangting Wang, Shijie Zhang, Yumeng Guo, Wenqing Gao, Hao Wu, Jiankun Wang, Yan Wang, Chunming Tang, Li Liu","doi":"10.1038/s41388-025-03331-1","DOIUrl":"10.1038/s41388-025-03331-1","url":null,"abstract":"Chromobox homolog 2 (CBX2), a component of the polycomb repressive complex 1, is overexpressed in various cancers, but its specific role in colorectal cancer (CRC) is not fully understood. This study aimed to characterize the functional and regulatory roles of CBX2 in CRC. Tissue microarray analysis revealed the elevated CBX2 levels in tumor compared to adjacent normal tissues, which is significantly correlated with poor prognosis. Gain and loss of function studies demonstrated that CBX2 significantly promoted CRC progression and chemoresistance in cell lines, patient-derived CRC organoids and xenografts. In the AOM/DSS mouse model, treatment with the innovatively-developed cy5-PBAE/siCBX2 nanoparticle significantly reduced tumor aggressiveness. Mechanistic studies unveiled that the transcription factor RUNX1 is the positive regulator of CBX2. RNA-seq, ATAC-seq and CUT & RUN results indicated CBX2 knockdown induced epigenetic changes, especially alterations in chromatin accessibility. Moreover, we further identified MAP4K1 as a target gene of RUNX1-CBX2, with significant clinical and prognostic relevance in CRC. Collectively, these findings suggest the pivotal role of RUNX1-CBX2-MAP4K1 axis in CRC progression and underscore CBX2 as a promising biomarker and therapeutic target.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 13","pages":"909-926"},"PeriodicalIF":6.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625583","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}

引用次数: 0

Human CSPG4-targeting CAR-macrophages inhibit melanoma growth.

IF 6.9 1区医学

Oncogene Pub Date : 2025-03-13 DOI: 10.1038/s41388-025-03332-0

Daniel Greiner, Qian Xue, Trinity Qa Waddell, Elena Kurudza, Piyush Chaudhary, Rachel L Belote, Gianpietro Dotti, Robert L Judson-Torres, Melissa Q Reeves, Samuel H Cheshier, Minna Roh-Johnson

{"title":"Human CSPG4-targeting CAR-macrophages inhibit melanoma growth.","authors":"Daniel Greiner, Qian Xue, Trinity Qa Waddell, Elena Kurudza, Piyush Chaudhary, Rachel L Belote, Gianpietro Dotti, Robert L Judson-Torres, Melissa Q Reeves, Samuel H Cheshier, Minna Roh-Johnson","doi":"10.1038/s41388-025-03332-0","DOIUrl":"10.1038/s41388-025-03332-0","url":null,"abstract":"Approximately half of melanoma patients relapse or fail to respond to current standards of care, highlighting the need for new treatment options. Engineering T-cells with chimeric antigen receptors (CARs) has revolutionized the treatment of hematological malignancies but has been clinically less effective in solid tumors. We therefore sought to engineer alternative immune cell types to inhibit melanoma progression. Engineering macrophages with CARs has emerged as a promising approach to overcome some of the challenges faced by CAR-T cells; however, whether these engineered macrophages can effectively inhibit melanoma growth is unknown. To determine whether CAR-macrophages (CAR-Ms) specifically target and kill melanoma cells, we engineered CAR-Ms targeting chondroitin sulfate proteoglycan 4 (CSPG4), an antigen expressed in melanoma. CSPG4-targeting CAR-Ms exhibited specific phagocytosis of CSPG4-expressing melanoma cells. We developed 3D approaches to show that CSPG4-targeting CAR-Ms efficiently infiltrated melanoma spheroids. Furthermore, combining CSPG4-targeting CAR-Ms with strategies inhibiting CD47/SIRPα \"don't eat me\" signaling synergistically enhanced CAR-M-mediated phagocytosis and robustly inhibited melanoma spheroid growth in 3D. Importantly, CSPG4-targeting CAR-Ms inhibited melanoma tumor growth in mouse models. These results suggest engineering macrophages against melanoma antigens is a promising solid tumor immunotherapy approach for treating melanoma.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624701","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}

引用次数: 0

Targeting KPNB1 suppresses AML cells by inhibiting HMGB2 nuclear import.

IF 6.9 1区医学

Oncogene Pub Date : 2025-03-13 DOI: 10.1038/s41388-025-03340-0

Yuxin Xie, Runlong Zhao, Yingjiao Zheng, Yan Li, Feng Wu, Yufei Lei, Lei Li, Hanqing Zeng, Zhe Chen, Yu Hou

{"title":"Targeting KPNB1 suppresses AML cells by inhibiting HMGB2 nuclear import.","authors":"Yuxin Xie, Runlong Zhao, Yingjiao Zheng, Yan Li, Feng Wu, Yufei Lei, Lei Li, Hanqing Zeng, Zhe Chen, Yu Hou","doi":"10.1038/s41388-025-03340-0","DOIUrl":"https://doi.org/10.1038/s41388-025-03340-0","url":null,"abstract":"Acute myeloid leukemia (AML) represents the most prevalent malignancy within the hematologic system, characterized by refractory relapses and a scarcity of effective treatment options. Karyopherin subunit beta-1 (KPNB1) is a member of karyopherin β family, mediating the nuclear import of its cargoes. In this study, we found that elevated expression levels of KPNB1 are associated with unfavorable outcomes in patients with AML. The knockdown of KPNB1 resulted in growth inhibition and apoptosis in AML cells. Additionally, pharmacological inhibition of KPNB1 using the specific inhibitor importazole (IPZ) significantly reduced tumor burden and prolonged survival in MLL-AF9-induced AML mice. Notably, the inhibition of KPNB1 by IPZ significantly enhanced the sensitivity of both AML cell lines and patient-derived cells to venetoclax in vitro and in xenograft mice models. At the molecular level, we identified an unrecognized cargo of KPNB1, high mobility group 2 (HMGB2), which plays a crucial role in DNA damage repair. Inhibition of KPNB1 resulted in impaired nuclear import of HMGB2, eventually leading to compromised DNA damage repair in AML cells. Overall, our findings elucidate the essential roles of KPNB1 in AML cells through the HMGB2-DNA damage repair axis and highlight a promising therapeutic target for AML intervention.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625082","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}

引用次数: 0

N6-methyadenosine-modified YWHAE mRNA promotes proliferation and inhibits ferroptosis in hepatoblastoma by mediating SLC7A11 expression.

IF 6.9 1区医学

Oncogene Pub Date : 2025-03-12 DOI: 10.1038/s41388-025-03334-y

Jiquan Zhou, Jing Wang, Liyuan Yang, Tingyi Fu, Hui Li, Yuhua Shan, Hongxiang Gao, Chenjie Xie, Lei Zhang, Min Zhang, Ji Ma, Li Liu, Houshun Fang, Dapeng Jiang, Min Xu, Qiuhui Pan, Song Gu

{"title":"N6-methyadenosine-modified YWHAE mRNA promotes proliferation and inhibits ferroptosis in hepatoblastoma by mediating SLC7A11 expression.","authors":"Jiquan Zhou, Jing Wang, Liyuan Yang, Tingyi Fu, Hui Li, Yuhua Shan, Hongxiang Gao, Chenjie Xie, Lei Zhang, Min Zhang, Ji Ma, Li Liu, Houshun Fang, Dapeng Jiang, Min Xu, Qiuhui Pan, Song Gu","doi":"10.1038/s41388-025-03334-y","DOIUrl":"https://doi.org/10.1038/s41388-025-03334-y","url":null,"abstract":"Hepatoblastoma (HB) is a rare but predominant liver cancer in children, with few treatment choices in advanced stages. YWHAE is closely related to several human diseases and acts as a molecular scaffold for malignant transformation. However, whether YWHAE promotes HB development remains unknown. Conducting RNA and m6A sequencing on HB tissues, we found that YWHAE was upregulated and modified by N6-methyadenosine. Functionally, YWHAE promoted proliferation and inhibited cell death in HB by in vitro and in vivo studies. Mechanistically, METTL3-dependent m6A modification activated YWHAE mRNA expression, and the m6A reader IGF2BP2 recognized and bound to the m6A site on YWHAE mRNA, thereby enhancing the mRNA stability of YWHAE. Interestingly, RNA sequencing revealed that YWHAE knockdown was involved in regulating ferroptosis of HB cells by mediating SLC7A11 expression. Moreover, knockdown of YWHAE significantly increased the levels of lipid ROS and peroxides in HB cells, promoting the susceptibility of HB cells to ferroptosis. In summary, these findings illuminated the role of YWHAE in HB progression and uncovered its relevance to ferroptosis as a new therapeutic target for HB.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616705","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}

引用次数: 0

Virus-mediated immunosuppression in head and neck cancer

IF 6.9 1区医学

Oncogene Pub Date : 2025-03-12 DOI: 10.1038/s41388-025-03295-2

Sayuri Miyauchi, Souvick Roy, Nathalie Boutros, Andrew B. Sharabi

引用次数: 0

RBMS3-loss impedes TRIM21-induced ubiquitination of ANGPT2 in an RNA-independent manner and drives sorafenib resistance in hepatocellular carcinoma.

IF 6.9 1区医学

Oncogene Pub Date : 2025-03-11 DOI: 10.1038/s41388-025-03335-x

Jinrong Zhu, Lei Wang, Xiaoya Nie, Shengming Ou, Jianfei Shen, Shuxia Zhang, Geyan Wu

{"title":"RBMS3-loss impedes TRIM21-induced ubiquitination of ANGPT2 in an RNA-independent manner and drives sorafenib resistance in hepatocellular carcinoma.","authors":"Jinrong Zhu, Lei Wang, Xiaoya Nie, Shengming Ou, Jianfei Shen, Shuxia Zhang, Geyan Wu","doi":"10.1038/s41388-025-03335-x","DOIUrl":"https://doi.org/10.1038/s41388-025-03335-x","url":null,"abstract":"Sorafenib, a first-line targeted drug for advanced hepatocellular carcinoma (HCC), has limited clinical application due to intrinsic/acquired resistance. In this study, we have identified the RNA-binding protein RBMS3 as a pivotal regulator involved in sorafenib resistance among patients with HCC. Loss- and gain-of-function experiments further demonstrate that downregulation of RBMS3 promotes angiogenesis and confers resistance to sorafenib by augmenting the capacity of HCC cells to express and secrete ANGPT2, while upregulation of RBMS3 reverse these phenotypes.Through immunoprecipitation mass spectrometry experiments and co-immunoprecipitation (co-IP), we further verified that RBMS3 can facilitate the K48-linked ubiquitination and subsequent protein degradation of ANGPT2 by recruiting the ubiquitin E3 ligase TRIM21 in an RNA-independent manner.Additionally, RBMS3 is found to be deleted in HCC tissues and exhibits a significant positive correlation with angiogenesis and resistance to sorafenib treatment. Importantly, the combination of ANGPT2 antibody in RBMS3-deficient HCC cells restores sensitivity to sorafenib both in vitro and in vivo. These findings uncovered a novel molecular basis for post-translational upregulation of ANGPT2, suggesting that RBMS3-loss plays an oncogenic role in HCC by promoting angiogenesis and conferring resistance to sorafenib treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605881","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}

引用次数: 0

ROS-ATM-CHK2 axis stabilizes HIF-1α and promotes tumor angiogenesis in hypoxic microenvironment. ROS-ATM-CHK2 轴可稳定 HIF-1α 并促进缺氧微环境中的肿瘤血管生成。

IF 6.9 1区医学

Oncogene Pub Date : 2025-03-08 DOI: 10.1038/s41388-025-03336-w

Ming Bai, Pengzhi Xu, Rong Cheng, Na Li, Sunrun Cao, Qiqiang Guo, Xiaoxun Wang, Chunlu Li, Ning Bai, Bo Jiang, Xuan Wu, Xiaoyu Song, Chen Sun, Mingfang Zhao, Liu Cao

引用次数: 0

The complex roles of IL-36 and IL-38 in cancer: friends or foes?

IF 6.9 1区医学

Oncogene Pub Date : 2025-03-08 DOI: 10.1038/s41388-025-03293-4

Méabh Finucane, Elizabeth Brint, Aileen Houston

{"title":"The complex roles of IL-36 and IL-38 in cancer: friends or foes?","authors":"Méabh Finucane, Elizabeth Brint, Aileen Houston","doi":"10.1038/s41388-025-03293-4","DOIUrl":"10.1038/s41388-025-03293-4","url":null,"abstract":"The interleukin-36 (IL-36) family comprises of three pro-inflammatory receptor agonists (IL-36α, IL-36β and IL-36γ), two anti-inflammatory receptor antagonists (IL-36RA and IL-38) along with the IL-36 receptor (IL-36R). Part of the IL-1 cytokine superfamily, the IL-36 family was discovered in the early 2000s due to the homology of its member sequences to the IL-1 cytokines. As pro- and anti-inflammatory cytokines, respectively, IL-36α, IL-36β, IL-36γ and IL-38 aid in maintaining homoeostasis by reciprocally regulating the body’s response to damage and disease through IL-36R-associated signalling. With the significant roles of IL-36α, IL-36β and IL-36γ in regulating the immune response realised, interest has grown in investigating their roles in cancer. While initial studies indicated solely tumour-suppressing roles, more recent work has identified tumour-promoting roles in cancer, suggesting a more complex dual functionality of the IL-36 cytokines. The activity of IL-38 in cancer is similarly complex, with the receptor antagonist displaying distinct tumour-suppressive roles, particularly in colorectal cancer (CRC), in addition to broad tumour-promoting roles in various other malignancies. This review provides a comprehensive overview of the IL-36 and IL-38 cytokines, their activation and IL-36R signalling, the physiological functions of these cytokines, and their activity in cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 13","pages":"851-861"},"PeriodicalIF":6.9,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-025-03293-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586384","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}

引用次数: 0

Cellular polarity pilots breast cancer progression and immunosuppression

IF 6.9 1区医学

Oncogene Pub Date : 2025-03-08 DOI: 10.1038/s41388-025-03324-0

Jie Huang, Shufeng Luo, Juan Shen, Maya Lee, Rachel Chen, Shenglin Ma, Lun-Quan Sun, Jian Jian Li

{"title":"Cellular polarity pilots breast cancer progression and immunosuppression","authors":"Jie Huang, Shufeng Luo, Juan Shen, Maya Lee, Rachel Chen, Shenglin Ma, Lun-Quan Sun, Jian Jian Li","doi":"10.1038/s41388-025-03324-0","DOIUrl":"10.1038/s41388-025-03324-0","url":null,"abstract":"Disrupted cellular polarity (DCP) is a hallmark of solid cancer, the malignant disease of epithelial tissues, which occupies ~90% of all human cancers. DCP has been identified to affect not only the cancer cell’s aggressive behavior but also the migration and infiltration of immune cells, although the precise mechanism of DCP-affected tumor-immune cell interaction remains unclear. This review discusses immunosuppressive tumor microenvironments (TME) caused by DCP-driven tumor cell proliferation with DCP-impaired immune cell functions. We will revisit the fundamental roles of cell polarity (CP) proteins in sustaining mammary luminal homeostasis, epithelial transformation, and breast cancer progression. Then, the current data on CP involvement in immune cell activation, maturation, migration, and tumor infiltration are evaluated. The CP status on the immune effector cells and their targeted tumor cells are highlighted in tumor immune regulation, including the antigen presentation and the formation of immune synapses (IS). CP-regulated antigen presentation and delivery and the formation of IS between the immune cells, especially between the immune effectors and tumor cells, will be addressed. Alterations of CP on the tumor cells, infiltrated immune effector cells, or both are discussed with these aspects. We conclude that CP-mediated tumor aggressiveness coupled with DCP-impaired immune cell disability may decide the degree of immunosuppressive status and responsiveness to immune checkpoint blockade (ICB). Further elucidating the dynamics of CP- or DCP-mediated immune regulation in TME will provide more critical insights into tumor-immune cell dynamics, which is required to invent more effective approaches for cancer immunotherapy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 12","pages":"783-793"},"PeriodicalIF":6.9,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-025-03324-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586403","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}

引用次数: 0