Pub Date : 2025-12-17DOI: 10.1038/s41388-025-03666-9
David R. Butcher, Christopher N. Parris, Scott J. Crichton, Fiona C. Dempsey, Hussein N. Al-Ali
The renin-angiotensin system is a key regulator of blood pressure homeostasis, with its primary effector, the angiotensin II type 1 receptor (AT1R), mediating vasoconstriction and processes fundamental to cancer progression, including proliferation, angiogenesis, and metastasis. Elevated AT1R expression is consistently linked to poor prognosis and therapeutic resistance across various malignancies. Preclinical studies provide compelling evidence that AT1R activation drives key cancer related processes, while its inhibition by angiotensin receptor blockers (ARBs) suppresses tumour growth, induces apoptosis, reduces angiogenesis, and inhibits metastasis across a wide range of cancer models. Critically, ARBs effectively modulate the tumour microenvironment (TME), alleviating fibrosis, promoting anti-tumour immune cell phenotypes, and enhancing the efficacy of targeted therapies, chemotherapies, and immunotherapies. Despite this strong preclinical evidence and supporting retrospective population studies, clinical translation of ARBs in oncology remains inconsistent, with trials often limited by design, patient heterogeneity, and supra-therapeutic ARB dosages required for acute anti-cancer effects. This review seeks to summarise the current understanding of AT1R’s role in cancer, highlight preclinical and clinical investigations of targeting RAS, and suggest further strategies to unlock its therapeutic potential. Realising the full therapeutic promise of AT1R targeting in oncology requires a multifaceted approach, including the development of innovative delivery systems, such as TME-activated ARBs, and the exploration of advanced therapeutic modalities, such as antibody based AT1R inhibitors. Rigorously designed clinical trials that include biomarker-driven patient stratification to identify responsive cohorts are crucial to define the context-dependent role of AT1R and conclusively establish its clinical utility as a combinatorial strategy to enhance patient outcomes.
{"title":"Unlocking the potential of targeting the angiotensin II type 1 receptor in cancer","authors":"David R. Butcher, Christopher N. Parris, Scott J. Crichton, Fiona C. Dempsey, Hussein N. Al-Ali","doi":"10.1038/s41388-025-03666-9","DOIUrl":"10.1038/s41388-025-03666-9","url":null,"abstract":"The renin-angiotensin system is a key regulator of blood pressure homeostasis, with its primary effector, the angiotensin II type 1 receptor (AT1R), mediating vasoconstriction and processes fundamental to cancer progression, including proliferation, angiogenesis, and metastasis. Elevated AT1R expression is consistently linked to poor prognosis and therapeutic resistance across various malignancies. Preclinical studies provide compelling evidence that AT1R activation drives key cancer related processes, while its inhibition by angiotensin receptor blockers (ARBs) suppresses tumour growth, induces apoptosis, reduces angiogenesis, and inhibits metastasis across a wide range of cancer models. Critically, ARBs effectively modulate the tumour microenvironment (TME), alleviating fibrosis, promoting anti-tumour immune cell phenotypes, and enhancing the efficacy of targeted therapies, chemotherapies, and immunotherapies. Despite this strong preclinical evidence and supporting retrospective population studies, clinical translation of ARBs in oncology remains inconsistent, with trials often limited by design, patient heterogeneity, and supra-therapeutic ARB dosages required for acute anti-cancer effects. This review seeks to summarise the current understanding of AT1R’s role in cancer, highlight preclinical and clinical investigations of targeting RAS, and suggest further strategies to unlock its therapeutic potential. Realising the full therapeutic promise of AT1R targeting in oncology requires a multifaceted approach, including the development of innovative delivery systems, such as TME-activated ARBs, and the exploration of advanced therapeutic modalities, such as antibody based AT1R inhibitors. Rigorously designed clinical trials that include biomarker-driven patient stratification to identify responsive cohorts are crucial to define the context-dependent role of AT1R and conclusively establish its clinical utility as a combinatorial strategy to enhance patient outcomes.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 4","pages":"479-490"},"PeriodicalIF":7.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03666-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775257","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}
Pub Date : 2025-12-17DOI: 10.1038/s41388-025-03659-8
Hülya Dogan, Martin Liptay, Joana S. Barbosa, Ewa Gogola, Alexandra A. Duarte, Jonas A. Schmid, Ismar Klebic, Merve Mutlu, Myriam Siffert, Paola Francica, Israel Salguero, Marieke van de Ven, Renske de Korte-Grimmerink, Stephen P. Jackson, Jos Jonkers, Massimo Lopes, Diego Dibitetto, Sven Rottenberg
MDC1 is a key protein in DNA damage signaling. When DNA double-strand breaks (DSBs) occur, MDC1 localizes to the sites of DNA damage to promote the recruitment of other factors, including the 53BP1-mediated DSB repair pathway. By studying mechanisms of poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in BRCA2; p53-deficient mouse mammary tumors, we identified a thus far unknown role of MDC1 in replication fork biology. Our results show that MDC1 localizes at active replication forks during normal DNA replication and regulates replication fork progression. It suppresses spontaneous fork reversal and regulates fork nucleolytic processing thereby promoting sensitivity to PARPi and cisplatin. In this way, MDC1 loss improves DNA damage tolerance and causes chemoresistance in BRCA1/2-deficient cells. We demonstrate that limiting MRE11 activity abolishes the reduced fork speed while MRE11 inhibition/depletion overcomes PARPi resistance in these cells. Overall, our data provides new insights into the role of MDC1 in replication fork progression that mediates PARPi- and cisplatin-induced DNA damage, in addition to its role in DSB repair.
{"title":"MDC1 counteracts replication fork reversal and mediates chemosensitivity in BRCA1/2-deficient tumors","authors":"Hülya Dogan, Martin Liptay, Joana S. Barbosa, Ewa Gogola, Alexandra A. Duarte, Jonas A. Schmid, Ismar Klebic, Merve Mutlu, Myriam Siffert, Paola Francica, Israel Salguero, Marieke van de Ven, Renske de Korte-Grimmerink, Stephen P. Jackson, Jos Jonkers, Massimo Lopes, Diego Dibitetto, Sven Rottenberg","doi":"10.1038/s41388-025-03659-8","DOIUrl":"10.1038/s41388-025-03659-8","url":null,"abstract":"MDC1 is a key protein in DNA damage signaling. When DNA double-strand breaks (DSBs) occur, MDC1 localizes to the sites of DNA damage to promote the recruitment of other factors, including the 53BP1-mediated DSB repair pathway. By studying mechanisms of poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in BRCA2; p53-deficient mouse mammary tumors, we identified a thus far unknown role of MDC1 in replication fork biology. Our results show that MDC1 localizes at active replication forks during normal DNA replication and regulates replication fork progression. It suppresses spontaneous fork reversal and regulates fork nucleolytic processing thereby promoting sensitivity to PARPi and cisplatin. In this way, MDC1 loss improves DNA damage tolerance and causes chemoresistance in BRCA1/2-deficient cells. We demonstrate that limiting MRE11 activity abolishes the reduced fork speed while MRE11 inhibition/depletion overcomes PARPi resistance in these cells. Overall, our data provides new insights into the role of MDC1 in replication fork progression that mediates PARPi- and cisplatin-induced DNA damage, in addition to its role in DSB repair.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 4","pages":"491-504"},"PeriodicalIF":7.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03659-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775245","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}
Pub Date : 2025-12-17DOI: 10.1038/s41388-025-03665-w
Minghan Huang, Wenqing Xie, Meihua Wu, Zhimei Ou, Caibin Li, Shuhui Ji, Wanjun Liu, Min Zhi, Daici Chen
Metastasis to distant organs represents the most fatal prognostic factor for colorectal cancer (CRC). The distant metastasis of tumor cells results from the collaborative effort of multiple subcellular structures, with dynamic cytoskeletal remodeling underlying this entire process. Here, we found that knockdown of KRT81 expression (shKRT81) inhibited the proliferation, invasion, and migration, while ectopic overexpression of KRT81 enhanced the CRC cells migration. Furthermore, we identified a potential downstream effector of KRT81, ezrin, a member of the ezrin/radixin/moesin (ERM) protein family that regulates cell morphology and motility. Phenotypically, the shKRT81 attenuated ezrin protein expression and reduced the number and length of filopodia in CRC cells, which were restored when KRT81 was re-overexpressed. Mechanistically, KRT81 formed a complex with ezrin, and recruitment of ezrin to the membrane and phosphorylation at the Thr567 residue were significantly abolished in shKRT81 cells. Interestingly, we found that Myosin 1B (MYO1B) might provide the driving force for the recruitment of ezrin. Notably, combinatorial inhibition (shKRT81 + ezrin-specific inhibitor) exerted significantly greater suppression of CRC cell migration and invasion than either intervention alone. Consistently, KRT81 expression was increased in CRC, and relatively high expression of KRT81 was associated with a poor prognosis. In summary, we identified a novel regulatory axis that involves KRT81, MYO1B, and ezrin, which regulates filopodia formation and migration behavior in CRC. Therefore, KRT81 may serve as a therapeutic target for CRC.
{"title":"KRT81 promotes metastasis of colorectal cancer by acting as a protein scaffold for ezrin","authors":"Minghan Huang, Wenqing Xie, Meihua Wu, Zhimei Ou, Caibin Li, Shuhui Ji, Wanjun Liu, Min Zhi, Daici Chen","doi":"10.1038/s41388-025-03665-w","DOIUrl":"10.1038/s41388-025-03665-w","url":null,"abstract":"Metastasis to distant organs represents the most fatal prognostic factor for colorectal cancer (CRC). The distant metastasis of tumor cells results from the collaborative effort of multiple subcellular structures, with dynamic cytoskeletal remodeling underlying this entire process. Here, we found that knockdown of KRT81 expression (shKRT81) inhibited the proliferation, invasion, and migration, while ectopic overexpression of KRT81 enhanced the CRC cells migration. Furthermore, we identified a potential downstream effector of KRT81, ezrin, a member of the ezrin/radixin/moesin (ERM) protein family that regulates cell morphology and motility. Phenotypically, the shKRT81 attenuated ezrin protein expression and reduced the number and length of filopodia in CRC cells, which were restored when KRT81 was re-overexpressed. Mechanistically, KRT81 formed a complex with ezrin, and recruitment of ezrin to the membrane and phosphorylation at the Thr567 residue were significantly abolished in shKRT81 cells. Interestingly, we found that Myosin 1B (MYO1B) might provide the driving force for the recruitment of ezrin. Notably, combinatorial inhibition (shKRT81 + ezrin-specific inhibitor) exerted significantly greater suppression of CRC cell migration and invasion than either intervention alone. Consistently, KRT81 expression was increased in CRC, and relatively high expression of KRT81 was associated with a poor prognosis. In summary, we identified a novel regulatory axis that involves KRT81, MYO1B, and ezrin, which regulates filopodia formation and migration behavior in CRC. Therefore, KRT81 may serve as a therapeutic target for CRC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 3","pages":"459-475"},"PeriodicalIF":7.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775188","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}
While third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, have significantly improved patient survival in non-small cell lung cancer (NSCLC), acquired resistance remains a major clinical challenge, and its underlying mechanisms are incompletely understood. In this study, we demonstrate that YTHDC2 expression is significantly downregulated in osimertinib-resistant patient-derived xenograft (PDX) tissues and lung cancer cell lines compared to their osimertinib-sensitive counterparts. Further investigation revealed that YTHDC2 overcomes osimertinib resistance in lung cancer cells by promoting cuproptosis. Mechanistically, YTHDC2 binds to m6A-modified sites (specifically at nucleotides A1223 and A2824) within the mRNA of the copper transporter SLC31A1 in an m6A-dependent manner. This interaction enhances SLC31A1 mRNA stability and protein expression, thereby increasing intracellular copper transport and inducing cuproptosis in tumor cells. Additionally, we found that the copper ionophore disulfiram (DSF) overcame osimertinib resistance by augmenting YTHDC2 expression. Collectively, our findings elucidate a novel YTHDC2-SLC31A1-cuproptosis axis as a key mechanism underlying EGFR-TKI resistance and propose new therapeutic strategies for its reversal.
{"title":"YTHDC2 inhibits the resistance of lung cancer to EGFR-TKI through cuproptosis","authors":"Jizhuang Luo, Xin Xu, Yaohui Chen, Yiwen Huang, Yiman Huang, Yajuan Zhang, Lifang Ma, Tianxiang Chen","doi":"10.1038/s41388-025-03660-1","DOIUrl":"10.1038/s41388-025-03660-1","url":null,"abstract":"While third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, have significantly improved patient survival in non-small cell lung cancer (NSCLC), acquired resistance remains a major clinical challenge, and its underlying mechanisms are incompletely understood. In this study, we demonstrate that YTHDC2 expression is significantly downregulated in osimertinib-resistant patient-derived xenograft (PDX) tissues and lung cancer cell lines compared to their osimertinib-sensitive counterparts. Further investigation revealed that YTHDC2 overcomes osimertinib resistance in lung cancer cells by promoting cuproptosis. Mechanistically, YTHDC2 binds to m6A-modified sites (specifically at nucleotides A1223 and A2824) within the mRNA of the copper transporter SLC31A1 in an m6A-dependent manner. This interaction enhances SLC31A1 mRNA stability and protein expression, thereby increasing intracellular copper transport and inducing cuproptosis in tumor cells. Additionally, we found that the copper ionophore disulfiram (DSF) overcame osimertinib resistance by augmenting YTHDC2 expression. Collectively, our findings elucidate a novel YTHDC2-SLC31A1-cuproptosis axis as a key mechanism underlying EGFR-TKI resistance and propose new therapeutic strategies for its reversal.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 3","pages":"431-445"},"PeriodicalIF":7.3,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768536","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}
Pub Date : 2025-12-15DOI: 10.1038/s41388-025-03657-w
Zhiqiang Fang, Doudou Liu, Yuanyuan Su, Fengxin Hao, Ruodong Qin, Guodong Li, Jun Chen
The Polycomb group (PcG) protein chromobox 8 (CBX8) is the subunit of Polycomb repressive complex 1 (PRC1) and recognizes the trimethylation of histone H3 on Lysine 27 (H3K27me3), and coordinates with PRC2 complex to function as an epigenetic gene silencer. CBX8 plays a key role in cell proliferation, stem cell biology, cell senescence, and cancer development. However, the post-translational modifications of CBX8 remain poorly understood. Here, we report that protein kinase D1 (PKD1) interacts and phosphorylates CBX8 at Thr234 and Ser256 /311 residues. PKD1-mediated CBX8 phosphorylation at Thr234 reduced its expression level by promoting its ubiquitination-mediated degradation, whereas Ser256/311 phosphorylation decreased CBX8 binding to other PRC1 components BMI1 and RING1A. Overall, CBX8 phosphorylation by PKD1 impaired PRC1 complex integrity and activity, mitigated H2AK119ub1 level, caused the upregulation of multiple target genes repressed by CBX8, and decreased CBX8, H2AK119ub1, and H3K27me3 enrichment at INK4A/ARF locus, thereby derepressing p16INK4A and facilitating cellular senescence. Collectively, these results suggest that PKD1-mediated CBX8 phosphorylation at T234 and S256/311 is a key mechanism governing CBX8 function, including cell senescence.
{"title":"Phosphorylation of CBX8 by PKD1 suppresses PRC1 activity and promotes cell senescence","authors":"Zhiqiang Fang, Doudou Liu, Yuanyuan Su, Fengxin Hao, Ruodong Qin, Guodong Li, Jun Chen","doi":"10.1038/s41388-025-03657-w","DOIUrl":"10.1038/s41388-025-03657-w","url":null,"abstract":"The Polycomb group (PcG) protein chromobox 8 (CBX8) is the subunit of Polycomb repressive complex 1 (PRC1) and recognizes the trimethylation of histone H3 on Lysine 27 (H3K27me3), and coordinates with PRC2 complex to function as an epigenetic gene silencer. CBX8 plays a key role in cell proliferation, stem cell biology, cell senescence, and cancer development. However, the post-translational modifications of CBX8 remain poorly understood. Here, we report that protein kinase D1 (PKD1) interacts and phosphorylates CBX8 at Thr234 and Ser256 /311 residues. PKD1-mediated CBX8 phosphorylation at Thr234 reduced its expression level by promoting its ubiquitination-mediated degradation, whereas Ser256/311 phosphorylation decreased CBX8 binding to other PRC1 components BMI1 and RING1A. Overall, CBX8 phosphorylation by PKD1 impaired PRC1 complex integrity and activity, mitigated H2AK119ub1 level, caused the upregulation of multiple target genes repressed by CBX8, and decreased CBX8, H2AK119ub1, and H3K27me3 enrichment at INK4A/ARF locus, thereby derepressing p16INK4A and facilitating cellular senescence. Collectively, these results suggest that PKD1-mediated CBX8 phosphorylation at T234 and S256/311 is a key mechanism governing CBX8 function, including cell senescence.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 3","pages":"398-413"},"PeriodicalIF":7.3,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763466","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}
Gemcitabine resistance remains a major obstacle in the treatment of pancreatic adenocarcinoma (PDAC). Through gain- and loss-of-function experiments, we identified USP10 as a positive regulator of tumor growth and gemcitabine resistance. Mechanistically, we demonstrate that USP10 stabilizes IGF2BP3 by removing its K48- and K63-linked ubiquitin chains, thereby inhibiting proteasomal degradation. The stabilized IGF2BP3 binds to and enhances the stability of STEAP3 mRNA in an m⁶A-dependent manner. Upregulation of STEAP3 suppresses ferroptosis by increasing glutathione levels and reducing lipid peroxidation, ultimately promoting tumor proliferation and gemcitabine resistance. Our study identifies the USP10-IGF2BP3-STEAP3 axis as a critical mechanism underlying chemoresistance in pancreatic cancer, suggesting that targeting USP10 may offer a promising therapeutic strategy for overcoming gemcitabine resistance.
{"title":"USP10 promotes cell proliferation and gemcitabine resistance in pancreatic cancer by the regulation of IGF2BP3-STEAP3","authors":"Yong-Ling Liang, Cheng-Rui Zhong, Jia-Yan Wu, Ze-Jin Lin, Zhu Lin, Tai-Jun Yi, Zhi-Ping Chen, Hui-Lin Jin, Jian-Dong Yu, Ze-Yu Lin, Yun-Le Wan, Guo-Lin Li","doi":"10.1038/s41388-025-03654-z","DOIUrl":"10.1038/s41388-025-03654-z","url":null,"abstract":"Gemcitabine resistance remains a major obstacle in the treatment of pancreatic adenocarcinoma (PDAC). Through gain- and loss-of-function experiments, we identified USP10 as a positive regulator of tumor growth and gemcitabine resistance. Mechanistically, we demonstrate that USP10 stabilizes IGF2BP3 by removing its K48- and K63-linked ubiquitin chains, thereby inhibiting proteasomal degradation. The stabilized IGF2BP3 binds to and enhances the stability of STEAP3 mRNA in an m⁶A-dependent manner. Upregulation of STEAP3 suppresses ferroptosis by increasing glutathione levels and reducing lipid peroxidation, ultimately promoting tumor proliferation and gemcitabine resistance. Our study identifies the USP10-IGF2BP3-STEAP3 axis as a critical mechanism underlying chemoresistance in pancreatic cancer, suggesting that targeting USP10 may offer a promising therapeutic strategy for overcoming gemcitabine resistance.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 3","pages":"383-397"},"PeriodicalIF":7.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743311","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}
Pancreatic ductal adenocarcinoma (PDAC) has two subtypes: the “classical/progenitor” type and “basal-like/squamous” type, the latter of which has poor clinical outcomes with no effective treatment strategies. We aimed to elucidate the role of epithelial membrane protein 1 (EMP1) in PDAC and its potential as a therapeutic target, particularly in aggressive disease such as “basal-like/squamous” type of PDAC. We examined the association of EMP1 expression using patient-derived organoids (PDOs) of human PDAC, K-RASLSL-G12D, Trp 53LSL-R172H, and Pdx1-Cre recombinase mice, human PDAC cell lines, and publicly available clinical datasets. The functional roles of EMP1 were evaluated in vitro and in vivo through its knockout and stable overexpression. EMP1 knockout reduced proliferation, metastasis, and drug resistance, whereas overexpression enhanced malignant features. Transcriptomic analysis revealed that EMP1 promotes epithelial-mesenchymal transition (EMT), extracellular matrix remodeling, and the K-RAS signaling pathway. EMP1 expression is inversely implicated in the oxidative phosphorylation pathway, which is characteristic of the “classical/progenitor” type. Furthermore, integrated analysis revealed an association between EMP1 expression and ERK phosphorylation. EMP1 plays a crucial role in the pathogenesis of PDAC, as it contributes to the proliferative and metastatic characteristics of PDAC. This study suggests that EMP1 may be a potential therapeutic target gene for aggressive disease.
{"title":"Role of a transmembrane protein, epithelial membrane protein 1, in the pathogenesis of pancreatic ductal adenocarcinoma","authors":"Akihisa Ohno, Nao Fujimori, Kazuhide Matsumoto, Shojiro Haji, Osamu Sugahara, Ayumu Takeno, Takeo Yamamoto, Akihiko Suenaga, Shotaro Kakehashi, Takahiro Ueda, Masatoshi Murakami, Katsuhito Teramatsu, Keijiro Ueda, Takamasa Oono, Yoshinao Oda, Keiichi I. Nakayama, Yoshihiro Ogawa","doi":"10.1038/s41388-025-03633-4","DOIUrl":"10.1038/s41388-025-03633-4","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) has two subtypes: the “classical/progenitor” type and “basal-like/squamous” type, the latter of which has poor clinical outcomes with no effective treatment strategies. We aimed to elucidate the role of epithelial membrane protein 1 (EMP1) in PDAC and its potential as a therapeutic target, particularly in aggressive disease such as “basal-like/squamous” type of PDAC. We examined the association of EMP1 expression using patient-derived organoids (PDOs) of human PDAC, K-RASLSL-G12D, Trp 53LSL-R172H, and Pdx1-Cre recombinase mice, human PDAC cell lines, and publicly available clinical datasets. The functional roles of EMP1 were evaluated in vitro and in vivo through its knockout and stable overexpression. EMP1 knockout reduced proliferation, metastasis, and drug resistance, whereas overexpression enhanced malignant features. Transcriptomic analysis revealed that EMP1 promotes epithelial-mesenchymal transition (EMT), extracellular matrix remodeling, and the K-RAS signaling pathway. EMP1 expression is inversely implicated in the oxidative phosphorylation pathway, which is characteristic of the “classical/progenitor” type. Furthermore, integrated analysis revealed an association between EMP1 expression and ERK phosphorylation. EMP1 plays a crucial role in the pathogenesis of PDAC, as it contributes to the proliferative and metastatic characteristics of PDAC. This study suggests that EMP1 may be a potential therapeutic target gene for aggressive disease.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 2","pages":"307-321"},"PeriodicalIF":7.3,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145725167","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}
Pub Date : 2025-12-08DOI: 10.1038/s41388-025-03652-1
Pingjuan Xiang, Le Tang, Yi Zhang, Juana Jessica Mendoza, Qijia Yan, Lei Shi, Bo Xiang, Zhaoyang Zeng, Pan Chen, Dan Wang, Wei Xiong
Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck with a high prevalence in Southeast Asia. Although radiotherapy remains the primary treatment modality, resistance to radiation in a subset of patients with advanced-stage disease significantly limits therapeutic outcomes, and the underlying molecular mechanisms remain poorly understood. In this study, we identified the circular RNA circSETD3 as a critical regulator of radioresistance in NPC. Functional assays in both in vitro and in vivo models demonstrated that circSETD3 enhances radioresistance by suppressing autophagy and apoptosis. Mechanistically, circSETD3 binds to the 3′ untranslated region (3′UTR) of PDIA6 mRNA, stabilizing the transcript and increasing PDIA6 protein expression and its localization to the endoplasmic reticulum (ER). Elevated PDIA6 promotes the refolding of radiation-induced misfolded proteins, maintains ER proteostasis, and suppresses the unfolded protein response (UPR). This alleviation of ER stress reduces radiation-induced autophagy and apoptosis, ultimately enhancing NPC cell survival under radiotherapeutic stress. Together, these findings reveal a pivotal role for circSETD3 in promoting NPC radioresistance via PDIA6-mediated modulation of endoplasmic reticulum stress, and they provide a novel mechanistic framework and promising therapeutic target for improving radiotherapy efficacy in NPC.
{"title":"circSETD3 confers radiotherapy resistance in nasopharyngeal carcinoma by attenuating ER stress-induced autophagy and apoptosis via PDIA6 upregulation","authors":"Pingjuan Xiang, Le Tang, Yi Zhang, Juana Jessica Mendoza, Qijia Yan, Lei Shi, Bo Xiang, Zhaoyang Zeng, Pan Chen, Dan Wang, Wei Xiong","doi":"10.1038/s41388-025-03652-1","DOIUrl":"10.1038/s41388-025-03652-1","url":null,"abstract":"Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck with a high prevalence in Southeast Asia. Although radiotherapy remains the primary treatment modality, resistance to radiation in a subset of patients with advanced-stage disease significantly limits therapeutic outcomes, and the underlying molecular mechanisms remain poorly understood. In this study, we identified the circular RNA circSETD3 as a critical regulator of radioresistance in NPC. Functional assays in both in vitro and in vivo models demonstrated that circSETD3 enhances radioresistance by suppressing autophagy and apoptosis. Mechanistically, circSETD3 binds to the 3′ untranslated region (3′UTR) of PDIA6 mRNA, stabilizing the transcript and increasing PDIA6 protein expression and its localization to the endoplasmic reticulum (ER). Elevated PDIA6 promotes the refolding of radiation-induced misfolded proteins, maintains ER proteostasis, and suppresses the unfolded protein response (UPR). This alleviation of ER stress reduces radiation-induced autophagy and apoptosis, ultimately enhancing NPC cell survival under radiotherapeutic stress. Together, these findings reveal a pivotal role for circSETD3 in promoting NPC radioresistance via PDIA6-mediated modulation of endoplasmic reticulum stress, and they provide a novel mechanistic framework and promising therapeutic target for improving radiotherapy efficacy in NPC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 3","pages":"368-382"},"PeriodicalIF":7.3,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708527","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}
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