Pub Date : 2025-12-08DOI: 10.1038/s41388-025-03650-3
Rita Pinto, Ingrid Vikan Sjurgard, Heidi Pharo, Tom Mala, Hege Marie Vedeld, Guro Elisabeth Lind
Genome-wide molecular profiling has emerged as a promising approach for advancing the clinical management of esophageal adenocarcinoma (EAC), with the potential to improve prognostic accuracy and enable more personalized treatment strategies. In this review, we summarize current evidence from genomic and epigenomic EAC stratification studies, highlighting the proposed molecular subtypes and evaluating their clinical relevance. We discuss how these subclassifications may inform disease outcomes, refine patient selection for specific therapies and uncover new treatment opportunities aligned with tumor molecular profiles. Additionally, we explore molecular subtypes associated with Barrett’s esophagus, a precursor lesion of EAC, and consider how these insights can help elucidate the mechanisms underlying EAC development. Such understanding may inform improved strategies for early tumor detection, risk stratification and prevention, ultimately aiming to reduce the burden of EAC. We also address the current challenges limiting the clinical application of these molecular classifiers, including restricted sample availability, insufficient validation and the difficulty of translating genome-wide findings into practical and clinical useful biomarkers. Integrating molecular subtyping into clinical workflows is a key step toward precision medicine in EAC, with the goal of enhancing treatment response rates and patient outcomes. Future advances will require collaborative efforts and robust clinical validation in large prospective studies to ensure that molecular stratification strategies can be effectively translated into improved management of EAC.
{"title":"Molecular stratification of esophageal adenocarcinoma: implications for prognosis and treatment strategy","authors":"Rita Pinto, Ingrid Vikan Sjurgard, Heidi Pharo, Tom Mala, Hege Marie Vedeld, Guro Elisabeth Lind","doi":"10.1038/s41388-025-03650-3","DOIUrl":"10.1038/s41388-025-03650-3","url":null,"abstract":"Genome-wide molecular profiling has emerged as a promising approach for advancing the clinical management of esophageal adenocarcinoma (EAC), with the potential to improve prognostic accuracy and enable more personalized treatment strategies. In this review, we summarize current evidence from genomic and epigenomic EAC stratification studies, highlighting the proposed molecular subtypes and evaluating their clinical relevance. We discuss how these subclassifications may inform disease outcomes, refine patient selection for specific therapies and uncover new treatment opportunities aligned with tumor molecular profiles. Additionally, we explore molecular subtypes associated with Barrett’s esophagus, a precursor lesion of EAC, and consider how these insights can help elucidate the mechanisms underlying EAC development. Such understanding may inform improved strategies for early tumor detection, risk stratification and prevention, ultimately aiming to reduce the burden of EAC. We also address the current challenges limiting the clinical application of these molecular classifiers, including restricted sample availability, insufficient validation and the difficulty of translating genome-wide findings into practical and clinical useful biomarkers. Integrating molecular subtyping into clinical workflows is a key step toward precision medicine in EAC, with the goal of enhancing treatment response rates and patient outcomes. Future advances will require collaborative efforts and robust clinical validation in large prospective studies to ensure that molecular stratification strategies can be effectively translated into improved management of EAC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 3","pages":"353-367"},"PeriodicalIF":7.3,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03650-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708620","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 : 2025-12-07DOI: 10.1038/s41388-025-03655-y
Yichun Ma, Ying Xiang, Mei Yang, Yanmei Zhu, Yani Pan, Nannan Zhang, Xueni Fu, Ping Jiang, Yinya Pan, Hai Wu, Qiong Yan, Wenjun Li, Hongji Tao, Shangtao Mao, Yufei Tao, Jiale Li, Linzhe Su, Guangtao Gao, Fangmei An, Zhangding Wang, Guifang Xu
RNA-binding proteins (RBPs) critically regulate post-transcriptional gene expression, yet their roles in chemotherapy resistance remain underexplored. Here, through a targeted siRNA screen of 40 RBM family members, we identified RNA-binding motif protein 8 A (RBM8A) as central orchestrator of oxaliplatin-induced DNA damage in gastric cancer (GC). Functional studies demonstrated that RBM8A promotes tumor proliferation and chemoresistance by recruiting the RNA helicase eIF4A3 to stabilize epidermal growth factor receptor (EGFR) mRNA, shielding it from exonucleolytic degradation. This stabilization sustains EGFR protein levels, enabling nuclear EGFR-DNA-PKcs complex formation to drive non-homologous end joining (NHEJ)-mediated DNA repair and suppress oxaliplatin-induced apoptosis. Therapeutic targeting of this axis with the EGFR inhibitor gefitinib restored oxaliplatin sensitivity in vitro and synergistically suppressed RBM8A-driven xenograft growth in vivo. Additionally, single-cell RNA-seq revealed RBM8A enrichment in malignant gastric epithelial cells, while tissue microarrays confirmed that dual RBM8A/EGFR overexpression predicts the poorest survival outcomes. Collectively, our findings define the RBM8A-eIF4A3-EGFR axis as a druggable determinant of chemoresistance and establish RBM8A as both a prognostic biomarker and therapeutic target in GC.
{"title":"RBM8A confers oxaliplatin resistance in gastric cancer by maintaining EGFR mRNA stability","authors":"Yichun Ma, Ying Xiang, Mei Yang, Yanmei Zhu, Yani Pan, Nannan Zhang, Xueni Fu, Ping Jiang, Yinya Pan, Hai Wu, Qiong Yan, Wenjun Li, Hongji Tao, Shangtao Mao, Yufei Tao, Jiale Li, Linzhe Su, Guangtao Gao, Fangmei An, Zhangding Wang, Guifang Xu","doi":"10.1038/s41388-025-03655-y","DOIUrl":"10.1038/s41388-025-03655-y","url":null,"abstract":"RNA-binding proteins (RBPs) critically regulate post-transcriptional gene expression, yet their roles in chemotherapy resistance remain underexplored. Here, through a targeted siRNA screen of 40 RBM family members, we identified RNA-binding motif protein 8 A (RBM8A) as central orchestrator of oxaliplatin-induced DNA damage in gastric cancer (GC). Functional studies demonstrated that RBM8A promotes tumor proliferation and chemoresistance by recruiting the RNA helicase eIF4A3 to stabilize epidermal growth factor receptor (EGFR) mRNA, shielding it from exonucleolytic degradation. This stabilization sustains EGFR protein levels, enabling nuclear EGFR-DNA-PKcs complex formation to drive non-homologous end joining (NHEJ)-mediated DNA repair and suppress oxaliplatin-induced apoptosis. Therapeutic targeting of this axis with the EGFR inhibitor gefitinib restored oxaliplatin sensitivity in vitro and synergistically suppressed RBM8A-driven xenograft growth in vivo. Additionally, single-cell RNA-seq revealed RBM8A enrichment in malignant gastric epithelial cells, while tissue microarrays confirmed that dual RBM8A/EGFR overexpression predicts the poorest survival outcomes. Collectively, our findings define the RBM8A-eIF4A3-EGFR axis as a druggable determinant of chemoresistance and establish RBM8A as both a prognostic biomarker and therapeutic target in GC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 2","pages":"339-351"},"PeriodicalIF":7.3,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701351","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 : 2025-12-05DOI: 10.1038/s41388-025-03656-x
Qinke Li, Siying Zhang, Min Wang, Qiang Yi, Hang Xu, Jinlong Wang, Zhu Yang
{"title":"Correction: 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/s41388-025-03656-x","DOIUrl":"10.1038/s41388-025-03656-x","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 1","pages":"121-121"},"PeriodicalIF":7.3,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03656-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687735","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}
The endoplasmic reticulum (ER) membrane protein complex (EMC) is an ER multiprotein complex that affects a wide range of pathophysiological processes. Recently, the function of EMC6, a subunit of EMC, has been attracting attention for its role in cancers. However, research on EMC6 in the context of hepatocellular carcinoma (HCC) remains unknown. Here, we first observed the decreased EMC6 expression in human HCC tissues, and diminished expression level of EMC6 was associated with poor prognosis of HCC patients. In parallel, the knockdown of EMC6 promoted tumor progression both in HCC cell lines and in tumor-cell bearing nude mice. To delineate the in vivo roles of EMC6, we generated a hepatocyte-specific knockout of Emc6 (Emc6f/f;Alb-Cre, named Emc6 LKO) using a floxed Emc6 line. Emc6 LKO mice exhibited progressive liver dysfunction, fibrosis and spontaneous carcinogenesis phenotypes. Significant lipid metabolic disorder in the Emc6 LKO liver was revealed by combined metabolomic and proteomic analysis. Moreover, drastic elevation of 17β-Hydroxysteroid dehydrogenase type 13 (HSD17B13), a lipid droplet-associated enzyme, was identified to be involved in the process of EMC6-induced lipid metabolic disorder and HCC progression. Inhibition of HSD17B13 by a Pharmacological inhibitor BI-3231 effectively mitigated EMC6-driven HCC progression in vitro and in vivo. Taken together, these results unveiled a novel regulatory mechanism of EMC in HCC progression through lipid metabolism and may provide a new biomarker and therapeutic target for HCC.
{"title":"Unveiling EMC6 as a novel pathogenic determinant in hepatocellular carcinoma: orchestration of lipid metabolism through regulation of lipid droplet-associated enzyme HSD17B13","authors":"Yun Zhang, Chanyu Xiong, Zhilin Jiang, Xiao Wang, Zihao Wang, Junyao Chen, Qiong Li, Yangyang Luo, Xudan Yang, Chen Chu, Shikai Zhu, Xianjun Zhu, Yu Zhou","doi":"10.1038/s41388-025-03649-w","DOIUrl":"10.1038/s41388-025-03649-w","url":null,"abstract":"The endoplasmic reticulum (ER) membrane protein complex (EMC) is an ER multiprotein complex that affects a wide range of pathophysiological processes. Recently, the function of EMC6, a subunit of EMC, has been attracting attention for its role in cancers. However, research on EMC6 in the context of hepatocellular carcinoma (HCC) remains unknown. Here, we first observed the decreased EMC6 expression in human HCC tissues, and diminished expression level of EMC6 was associated with poor prognosis of HCC patients. In parallel, the knockdown of EMC6 promoted tumor progression both in HCC cell lines and in tumor-cell bearing nude mice. To delineate the in vivo roles of EMC6, we generated a hepatocyte-specific knockout of Emc6 (Emc6f/f;Alb-Cre, named Emc6 LKO) using a floxed Emc6 line. Emc6 LKO mice exhibited progressive liver dysfunction, fibrosis and spontaneous carcinogenesis phenotypes. Significant lipid metabolic disorder in the Emc6 LKO liver was revealed by combined metabolomic and proteomic analysis. Moreover, drastic elevation of 17β-Hydroxysteroid dehydrogenase type 13 (HSD17B13), a lipid droplet-associated enzyme, was identified to be involved in the process of EMC6-induced lipid metabolic disorder and HCC progression. Inhibition of HSD17B13 by a Pharmacological inhibitor BI-3231 effectively mitigated EMC6-driven HCC progression in vitro and in vivo. Taken together, these results unveiled a novel regulatory mechanism of EMC in HCC progression through lipid metabolism and may provide a new biomarker and therapeutic target for HCC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 2","pages":"322-338"},"PeriodicalIF":7.3,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669123","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}
DNA methylation plays a crucial role in the progression and metastasis of colorectal cancer (CRC), yet the mechanisms underlying its effect at specific loci remain poorly understood. We previously identified cg24067911 hypomethylation as a potential biomarker associated with poor CRC prognosis. To investigate the role of cg24067911 methylation in CRC metastasis and elucidate its underlying molecular mechanisms, we utilized the CRISPR-dCas9-DNMT3a system to specifically modify the methylation status of cg24067911. Then, we performed high-throughput transposase-accessible chromatin sequencing, RNA sequencing, and chromatin immunoprecipitation analysis. We demonstrated that cg24067911 was located within an enhancer region of the ATXN1 gene, where it was bound by BCL6. Hypomethylation of cg24067911 improved the binding of BCL6 to this enhancer, leading to upregulated transcription of ATXN1. Furthermore, ATXN1 was found to act as a transcription factor that upregulates CDH2, promoting epithelial-mesenchymal transition and facilitating CRC metastasis. These findings not only reveal that cg24067911 methylation modulates CRC metastasis through a novel epigenetic mechanism involving ATXN1 and CDH2, but also highlight cg24067911 as a potential prognostic marker for CRC and suggest that targeted epigenetic therapies could be an effective strategy for treating CRC metastasis in the future.
{"title":"Targeted methylation of cg24067911 suppresses colorectal cancer metastasis through BCL6-ATXN1-CDH1 axis","authors":"Lu-Ping Yang, Jia-Qian Huang, Chiu-Wing Yeung, Qi-Hua Zhang, Xiao-Li Wei, Qi-Nian Wu, Zi-Xin Qin, Ya-Shang Zheng, Yu-Hong Xu, Meng Yang, Kai-Ying Zhang, Zhi-Jun Zuo, Zhen-Yong Quan, Lang Zhao, Dong-Yang He, Jia Liu, Rui-Hua Xu, Hui-Yan Luo","doi":"10.1038/s41388-025-03638-z","DOIUrl":"10.1038/s41388-025-03638-z","url":null,"abstract":"DNA methylation plays a crucial role in the progression and metastasis of colorectal cancer (CRC), yet the mechanisms underlying its effect at specific loci remain poorly understood. We previously identified cg24067911 hypomethylation as a potential biomarker associated with poor CRC prognosis. To investigate the role of cg24067911 methylation in CRC metastasis and elucidate its underlying molecular mechanisms, we utilized the CRISPR-dCas9-DNMT3a system to specifically modify the methylation status of cg24067911. Then, we performed high-throughput transposase-accessible chromatin sequencing, RNA sequencing, and chromatin immunoprecipitation analysis. We demonstrated that cg24067911 was located within an enhancer region of the ATXN1 gene, where it was bound by BCL6. Hypomethylation of cg24067911 improved the binding of BCL6 to this enhancer, leading to upregulated transcription of ATXN1. Furthermore, ATXN1 was found to act as a transcription factor that upregulates CDH2, promoting epithelial-mesenchymal transition and facilitating CRC metastasis. These findings not only reveal that cg24067911 methylation modulates CRC metastasis through a novel epigenetic mechanism involving ATXN1 and CDH2, but also highlight cg24067911 as a potential prognostic marker for CRC and suggest that targeted epigenetic therapies could be an effective strategy for treating CRC metastasis in the future.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 2","pages":"295-306"},"PeriodicalIF":7.3,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03638-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655020","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 : 2025-12-01DOI: 10.1038/s41388-025-03611-w
Chenghui Xu, Jie Zhang, Han Zhang, Lan Chen, Jinchao Zhao, Guizhu Yang, Ranran Xiao, Jiayan Zhu, Chengting Fan, Yanli Yao, Shuyang Sun
Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy characterized by extensive extracellular matrix (ECM) remodeling and microtubule dynamics, which drive tumor progression and therapeutic resistance. Here, we identify HOMER3 as a novel and pivotal regulator that integrates ECM stiffness and microtubule dynamics to promote OSCC malignancy. HOMER3 expression follows a distinct gradient, increasing from low levels in normal tissues to elevated levels in oral leukoplakia and highest levels in OSCC, with high expression significantly associated with advanced stages and poor survival. Mechanistically, HOMER3 acts as a scaffold protein forming two distinct functional complexes: HOMER3-CAMKK1-TRPV6, which mediates calcium influx and activates AMPK/AKT/mTOR and B-Raf/MEK/ERK pathways to promote proliferation, invasion, and ECM remodeling; and HOMER3-CAMKK1-TUBB3, which regulates microtubule dynamics and drives resistance to the chemotherapeutic agent docetaxel. Functional studies reveal that HOMER3 overexpression enhances ECM stiffness, type I collagen deposition, and Aβ accumulation in the tumor stroma, leading to tumor growth and aggressiveness, while HOMER3 knockdown reduces ECM stiffness, disrupts collagen composition, and increases sensitivity to docetaxel. These findings establish HOMER3 as a pivotal regulator of OSCC malignancy and chemoresistance, providing novel insights into its role in orchestrating the tumor microenvironment and identifying it as a promising therapeutic target for OSCC.
{"title":"HOMER3 drives oral squamous cell carcinoma progression through TRPV6 calcium influx and TUBB3 microtubule stabilization","authors":"Chenghui Xu, Jie Zhang, Han Zhang, Lan Chen, Jinchao Zhao, Guizhu Yang, Ranran Xiao, Jiayan Zhu, Chengting Fan, Yanli Yao, Shuyang Sun","doi":"10.1038/s41388-025-03611-w","DOIUrl":"10.1038/s41388-025-03611-w","url":null,"abstract":"Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy characterized by extensive extracellular matrix (ECM) remodeling and microtubule dynamics, which drive tumor progression and therapeutic resistance. Here, we identify HOMER3 as a novel and pivotal regulator that integrates ECM stiffness and microtubule dynamics to promote OSCC malignancy. HOMER3 expression follows a distinct gradient, increasing from low levels in normal tissues to elevated levels in oral leukoplakia and highest levels in OSCC, with high expression significantly associated with advanced stages and poor survival. Mechanistically, HOMER3 acts as a scaffold protein forming two distinct functional complexes: HOMER3-CAMKK1-TRPV6, which mediates calcium influx and activates AMPK/AKT/mTOR and B-Raf/MEK/ERK pathways to promote proliferation, invasion, and ECM remodeling; and HOMER3-CAMKK1-TUBB3, which regulates microtubule dynamics and drives resistance to the chemotherapeutic agent docetaxel. Functional studies reveal that HOMER3 overexpression enhances ECM stiffness, type I collagen deposition, and Aβ accumulation in the tumor stroma, leading to tumor growth and aggressiveness, while HOMER3 knockdown reduces ECM stiffness, disrupts collagen composition, and increases sensitivity to docetaxel. These findings establish HOMER3 as a pivotal regulator of OSCC malignancy and chemoresistance, providing novel insights into its role in orchestrating the tumor microenvironment and identifying it as a promising therapeutic target for OSCC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 2","pages":"278-294"},"PeriodicalIF":7.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654988","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}
Triple-negative breast cancer (TNBC) is the most malignant breast cancer subtype. The 5-year overall survival rate of TNBC patients is 77%, but once cancer metastasis occurs, this rate drops to 12%. To date, the discovery of biomarkers associated with TNBC metastasis remains a major challenge. In this study, we identified a novel translated product, XLH-36 micropeptide, encoded by lncRNA (long non-coding RNA) C5orf66-AS1, which acts as an “oncogenic driver” in TNBC. Through conservation analyses across 101 species, we found that XLH-36 is highly conserved in humans and primates. Analysis of RNA-seq data from 1295 breast cancer patients, including 165 TNBC patients from different cohorts, revealed significantly elevated XLH-36 expression levels in breast cancer and TNBC. Specifically, TNBC patients with low C5orf66-AS1 (encoding XLH-36) expression demonstrated a 20% higher overall survival rate compared to those with high C5orf66-AS1 expression over a 50-month follow-up. XLH-36 knockout inhibited the growth and metastasis of TNBC xenografts in mice. Furthermore, we found that XLH-36 directly binds Gemin4, causing it to remain in the cytoplasm and preventing it from carrying out its role in promoting S100A4 mRNA splicing in the nucleus. This leads to a compensatory increase in ICAM1 levels, ultimately resulting in the promotion of epithelial-to-mesenchymal transition (EMT) in TNBC cells and an increase in tumor metastasis. In summary, our findings highlight the crucial role of XLH-36 in TNBC metastasis, which could be exploited in the development of therapeutic and diagnostic strategies for TNBC patients.
{"title":"The novel endogenous micropeptide XLH-36 binds Gemin4 to promote triple-negative breast cancer metastasis","authors":"Mengwei Li, Wenwei Xie, Kexin Hu, Tiantian Li, Xin Li, Li Shun, Xiaowei Xu, Junhui Chen, Hanmei Xu","doi":"10.1038/s41388-025-03621-8","DOIUrl":"10.1038/s41388-025-03621-8","url":null,"abstract":"Triple-negative breast cancer (TNBC) is the most malignant breast cancer subtype. The 5-year overall survival rate of TNBC patients is 77%, but once cancer metastasis occurs, this rate drops to 12%. To date, the discovery of biomarkers associated with TNBC metastasis remains a major challenge. In this study, we identified a novel translated product, XLH-36 micropeptide, encoded by lncRNA (long non-coding RNA) C5orf66-AS1, which acts as an “oncogenic driver” in TNBC. Through conservation analyses across 101 species, we found that XLH-36 is highly conserved in humans and primates. Analysis of RNA-seq data from 1295 breast cancer patients, including 165 TNBC patients from different cohorts, revealed significantly elevated XLH-36 expression levels in breast cancer and TNBC. Specifically, TNBC patients with low C5orf66-AS1 (encoding XLH-36) expression demonstrated a 20% higher overall survival rate compared to those with high C5orf66-AS1 expression over a 50-month follow-up. XLH-36 knockout inhibited the growth and metastasis of TNBC xenografts in mice. Furthermore, we found that XLH-36 directly binds Gemin4, causing it to remain in the cytoplasm and preventing it from carrying out its role in promoting S100A4 mRNA splicing in the nucleus. This leads to a compensatory increase in ICAM1 levels, ultimately resulting in the promotion of epithelial-to-mesenchymal transition (EMT) in TNBC cells and an increase in tumor metastasis. In summary, our findings highlight the crucial role of XLH-36 in TNBC metastasis, which could be exploited in the development of therapeutic and diagnostic strategies for TNBC patients.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 2","pages":"264-277"},"PeriodicalIF":7.3,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03621-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145637015","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 : 2025-11-28DOI: 10.1038/s41388-025-03584-w
Shuang Liu, Yunlong He, Xin Ning, Wei Xu, Xiaowei Hu, Ling Qin, Yupeng Yang, Xihai Chen, Rong Ma
In the treatment of ovarian cancer, PARP inhibitors such as olaparib have shown promise, yet resistance in advanced cases remains a significant challenge. Our study identified SLC7A5 as a key gene associated with olaparib resistance through differential gene expression and prognostic analysis. High SLC7A5 expression was found to correlate with poor prognosis. In vivo and in vitro experiments revealed that SLC7A5 enhances olaparib resistance by stabilizing ACLY and promoting de novo lipid synthesis via the ERBB2 axis, independent of leucine. Mechanistically, SLC7A5 upregulates ERBB2 transcription through ELK1, and ERBB2 competes with CUL3 to prevent ACLY degradation. These findings suggest that targeting SLC7A5 may reverse olaparib resistance, offering new strategies for combination therapies and improving clinical outcomes in ovarian cancer treatment.
{"title":"SLC7A5-ERBB2 axis drives olaparib resistance via de novo lipid synthesis in ovarian cancer","authors":"Shuang Liu, Yunlong He, Xin Ning, Wei Xu, Xiaowei Hu, Ling Qin, Yupeng Yang, Xihai Chen, Rong Ma","doi":"10.1038/s41388-025-03584-w","DOIUrl":"10.1038/s41388-025-03584-w","url":null,"abstract":"In the treatment of ovarian cancer, PARP inhibitors such as olaparib have shown promise, yet resistance in advanced cases remains a significant challenge. Our study identified SLC7A5 as a key gene associated with olaparib resistance through differential gene expression and prognostic analysis. High SLC7A5 expression was found to correlate with poor prognosis. In vivo and in vitro experiments revealed that SLC7A5 enhances olaparib resistance by stabilizing ACLY and promoting de novo lipid synthesis via the ERBB2 axis, independent of leucine. Mechanistically, SLC7A5 upregulates ERBB2 transcription through ELK1, and ERBB2 competes with CUL3 to prevent ACLY degradation. These findings suggest that targeting SLC7A5 may reverse olaparib resistance, offering new strategies for combination therapies and improving clinical outcomes in ovarian cancer treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 2","pages":"140-263"},"PeriodicalIF":7.3,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03584-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145637031","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 : 2025-11-27DOI: 10.1038/s41388-025-03607-6
Tao Liu, Xiaofeng Zuo, Shijie Sun, Kailong Du, Chuntao Tao, Xing Xia, Linli Yu, Chunxue Zhang, Zhengmei Yang, Yitao Wang, Junhong Ye, Youquan Bu
Gene pairing is a highly conserved and special mode of eukaryotic gene organization, and critically implicated in development and diseases including cancer. We previously found that PRR11 and SKA2 constitute a classic head-to-head gene pair. Here, we further demonstrate that PRR11, SKA2, and its intronic miR301a and miR454 constitute a more exquisite bidirectional transcription unit that are overexpressed in various types of cancers. Functional studies using lung cancer as a model system reveal that co-overexpression of PRR11, SKA2, miR301a and miR454 together remarkably accelerates cell growth, cell cycle progression and cell motility in lung cancer cells, and promotes tumor growth in mouse models in vivo, whereas CRISPRi-mediated repression of the entire transcription unit inhibits these malignant phenotypes. Mechanistically, the four component genes do not display any additive or synergistic effect, but rather compensate for each other for robustly sustained activation of PI3K-AKT pathway, with PRR11 interacting with GRB2, and SKA2 with EGFR. Notably, miR301a and miR454 exert their oncogenic functions at least partially via repressing PTEN translation. Moreover, the transcription unit presents as a prominent prognostic meta-marker for lung cancer. Collectively, these findings demonstrate the essential and coordinated roles of PRR11-SKA2-miR301a/454 bidirectional transcription unit in lung cancer progression, highlighting its potential diagnostic and therapeutic values in cancers.
{"title":"Overexpressed PRR11-SKA2-miR301a/454 bidirectional transcription unit essentially and coordinately promotes PI3K-AKT pathway activation and lung cancer progression","authors":"Tao Liu, Xiaofeng Zuo, Shijie Sun, Kailong Du, Chuntao Tao, Xing Xia, Linli Yu, Chunxue Zhang, Zhengmei Yang, Yitao Wang, Junhong Ye, Youquan Bu","doi":"10.1038/s41388-025-03607-6","DOIUrl":"10.1038/s41388-025-03607-6","url":null,"abstract":"Gene pairing is a highly conserved and special mode of eukaryotic gene organization, and critically implicated in development and diseases including cancer. We previously found that PRR11 and SKA2 constitute a classic head-to-head gene pair. Here, we further demonstrate that PRR11, SKA2, and its intronic miR301a and miR454 constitute a more exquisite bidirectional transcription unit that are overexpressed in various types of cancers. Functional studies using lung cancer as a model system reveal that co-overexpression of PRR11, SKA2, miR301a and miR454 together remarkably accelerates cell growth, cell cycle progression and cell motility in lung cancer cells, and promotes tumor growth in mouse models in vivo, whereas CRISPRi-mediated repression of the entire transcription unit inhibits these malignant phenotypes. Mechanistically, the four component genes do not display any additive or synergistic effect, but rather compensate for each other for robustly sustained activation of PI3K-AKT pathway, with PRR11 interacting with GRB2, and SKA2 with EGFR. Notably, miR301a and miR454 exert their oncogenic functions at least partially via repressing PTEN translation. Moreover, the transcription unit presents as a prominent prognostic meta-marker for lung cancer. Collectively, these findings demonstrate the essential and coordinated roles of PRR11-SKA2-miR301a/454 bidirectional transcription unit in lung cancer progression, highlighting its potential diagnostic and therapeutic values in cancers.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 1","pages":"68-86"},"PeriodicalIF":7.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145637033","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}
Tumour-derived fucosylated exosomes (FUC-Exo) play significant roles in cancer progression. However, the functions and mechanisms of fucosylated exosome-derived miRNAs in oesophageal squamous cell carcinoma (ESCC) remain largely unknown. Using lentil lectin (LCA)-coated magnetic beads for FUC-Exo isolation, small RNA sequencing and RT-qPCR identified miR-6842-3p as a novel ESCC biomarker. In vitro and in vivo assays explored its oncogenic role and pro-angiogenic function. Dual-luciferase assays, ChIP-qPCR, western blot and rescue assays were performed to elucidate angiogenic mechanisms. miR-6842-3p is upregulated in ESCC tissues and serum FUC-Exo, significantly associated with advanced clinical stages, worse prognosis and serves as an early diagnostic biomarker for ESCC. miR-6842-3p acts as an oncogene, promoting tumour growth, metastasis and angiogenesis in ESCC. Tumour-derived fucosylated exosomal miR-6842-3p, when internalised by HUVECs, downregulates PTEN, triggering the phosphorylation of AKT and mTOR. This is followed by the inhibition of IRF1 expression, thereby downregulating CXCL10 expression and driving angiogenesis. These findings elucidate that miR-6842-3p functions as a key driver of ESCC growth, metastasis and angiogenesis. Fucosylated exosomal miR-6842-3p promotes angiogenesis by mediating the PTEN/AKT/mTOR/IRF1/CXCL10 axis, highlighting its potential as a novel biomarker and therapeutic target for ESCC.
{"title":"Cancer-derived fucosylated exosomal miR-6842-3p as a novel marker promotes ESCC angiogenesis and metastasis via the PTEN/AKT/mTOR/IRF1/CXCL10 axis","authors":"Jianlin Chen, Jing Chen, Xiang Lv, Xiongfeng Chen, Liu Ming, Xinghua Huang, Fuli Wen, Haijun Tang, Qi Gao, Chengxiu Liu, Jiamiao Weng, Zhixin Huang, Yue Zheng, Fan Lin, Wenshu Chen, Xiuling Shang, Chundong Yu, Yi Huang","doi":"10.1038/s41388-025-03643-2","DOIUrl":"10.1038/s41388-025-03643-2","url":null,"abstract":"Tumour-derived fucosylated exosomes (FUC-Exo) play significant roles in cancer progression. However, the functions and mechanisms of fucosylated exosome-derived miRNAs in oesophageal squamous cell carcinoma (ESCC) remain largely unknown. Using lentil lectin (LCA)-coated magnetic beads for FUC-Exo isolation, small RNA sequencing and RT-qPCR identified miR-6842-3p as a novel ESCC biomarker. In vitro and in vivo assays explored its oncogenic role and pro-angiogenic function. Dual-luciferase assays, ChIP-qPCR, western blot and rescue assays were performed to elucidate angiogenic mechanisms. miR-6842-3p is upregulated in ESCC tissues and serum FUC-Exo, significantly associated with advanced clinical stages, worse prognosis and serves as an early diagnostic biomarker for ESCC. miR-6842-3p acts as an oncogene, promoting tumour growth, metastasis and angiogenesis in ESCC. Tumour-derived fucosylated exosomal miR-6842-3p, when internalised by HUVECs, downregulates PTEN, triggering the phosphorylation of AKT and mTOR. This is followed by the inhibition of IRF1 expression, thereby downregulating CXCL10 expression and driving angiogenesis. These findings elucidate that miR-6842-3p functions as a key driver of ESCC growth, metastasis and angiogenesis. Fucosylated exosomal miR-6842-3p promotes angiogenesis by mediating the PTEN/AKT/mTOR/IRF1/CXCL10 axis, highlighting its potential as a novel biomarker and therapeutic target for ESCC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 1","pages":"104-120"},"PeriodicalIF":7.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03643-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145637070","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}
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