Cell Death & Disease最新文献_第4页

Genetically edited human placental organoids cast new light on the role of ACE2.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-02-07 DOI: 10.1038/s41419-025-07400-x

Anya L Arthurs, Bianca Dietrich, Martin Knöfler, Caleb J Lushington, Paul Q Thomas, Fatwa Adikusuma, Jessica M Williamson, Susan Babikha, Tyla Damhuis, Tanja Jankovic-Karasoulos, Melanie D Smith, Kirsty G Pringle, Claire T Roberts

{"title":"Genetically edited human placental organoids cast new light on the role of ACE2.","authors":"Anya L Arthurs, Bianca Dietrich, Martin Knöfler, Caleb J Lushington, Paul Q Thomas, Fatwa Adikusuma, Jessica M Williamson, Susan Babikha, Tyla Damhuis, Tanja Jankovic-Karasoulos, Melanie D Smith, Kirsty G Pringle, Claire T Roberts","doi":"10.1038/s41419-025-07400-x","DOIUrl":"10.1038/s41419-025-07400-x","url":null,"abstract":"ACE2 expression is altered in pregnancy disorders and ACE2 gene variants are associated with several major pregnancy complications including small-for-gestational-age, fetal growth restriction and preeclampsia. This study utilised gene-editing to generate both ACE2 knockout and ACE2 rs2074192 placental organoids, facilitating mechanistic studies into the role of ACE2 in placental development, and the effect of fetal carriage of ACE2 rs2074192 CC, CT and TT genotypes. Parameters of cell and organoid growth were measured, together with qPCR, Western Blotting, and ELISA assessments, in all groups from both organoid models. Here, we report that ACE2 knockout results in delayed placental cell growth and increased cell death. ACE2 knockout organoids had lower ACE protein expression, reduced organoid diameters and asymmetrical growth. Placental organoids with the ACE2 rs2074192 TT genotype had significantly higher expression of ACE2 mRNA and ACE2 protein with elevated ACE2:ACE expression ratio and no change in ACE protein. Despite increased expression of ACE2 protein, ACE2 enzyme activity was significantly decreased in ACE2 rs2074192 TT placental organoids. TT organoids also had reduced diameters and asymmetrical growth. Our research provides a new molecular understanding of the role of ACE2 in placental development, with potential implications for pregnancy in the carriage of the ACE2 rs2074192 gene variant.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"78"},"PeriodicalIF":8.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-02-07 DOI: 10.1038/s41419-025-07387-5

Chuyu He, Xuejuan Wang, Yi-Shiou Chiou, Basappa Basappa, Tao Zhu, Vijay Pandey, Peter E Lobie

{"title":"Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma.","authors":"Chuyu He, Xuejuan Wang, Yi-Shiou Chiou, Basappa Basappa, Tao Zhu, Vijay Pandey, Peter E Lobie","doi":"10.1038/s41419-025-07387-5","DOIUrl":"10.1038/s41419-025-07387-5","url":null,"abstract":"The interaction between HER2 and ERα signaling pathways contributes to resistance to anti-estrogen and HER2-targeted therapies, presenting substantial treatment challenges in ER-positive (ER+) HER2-positive (HER2+) mammary carcinoma (MC). Trefoil Factor-3 (TFF3) has been reported to mediate resistance to both anti-estrogen and anti-HER2 targeted therapies in ER+ and ER+HER2+ MC, respectively. Herein, the function and mechanism of TFF3 in ER+HER2+ MC were delineated; and novel combinatorial therapeutic strategies were identified. Elevated expression of TFF3 promoted the oncogenicity of ER+HER2+ MC cells, including enhanced cell proliferation, survival, anchorage-independent growth, 3D growth, cancer stem cell-like (CSC-like) phenotype, migration, invasion, and xenograft growth. Targeting TFF3 with an interfering RNA plasmid or a small-molecule inhibitor (AMPC) inhibited these oncogenic characteristics, highlighting the therapeutic potential of targeting TFF3 in ER+HER2+ MC. Furthermore, a high-throughput combinatorial anti-cancer compound library screening revealed that AMPC preferentially synergized with receptor tyrosine kinase c-MET inhibitors (c-METis) to reduce cell survival and the CSC-like phenotype. The combination of AMPC and c-METis also synergistically suppressed the in vivo growth of ER+HER2+ MC cell-derived xenografts and abrogated lung metastasis. Mechanistically, TFF3 was observed to activate c-MET signaling through a positive-feedback loop to enhance the CSC-like phenotype of ER+HER2+ MC. Therefore, proof of concept is provided herein that antagonizing of TFF3 is a promising therapeutic strategy in combination with c-MET inhibition for the treatment of ER+HER2+ MC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"76"},"PeriodicalIF":8.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Overcoming immunotherapy resistance in gastric cancer: insights into mechanisms and emerging strategies.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-02-07 DOI: 10.1038/s41419-025-07385-7

Dingtian Luo, Jing Zhou, Shuiliang Ruan, Binzhong Zhang, Huali Zhu, Yangming Que, Shijie Ying, Xiaowen Li, Yuanmin Hu, Zhengwei Song

{"title":"Overcoming immunotherapy resistance in gastric cancer: insights into mechanisms and emerging strategies.","authors":"Dingtian Luo, Jing Zhou, Shuiliang Ruan, Binzhong Zhang, Huali Zhu, Yangming Que, Shijie Ying, Xiaowen Li, Yuanmin Hu, Zhengwei Song","doi":"10.1038/s41419-025-07385-7","DOIUrl":"10.1038/s41419-025-07385-7","url":null,"abstract":"Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as a promising therapeutic approach. However, a significant proportion of patients exhibit primary or acquired resistance, limiting the overall efficacy of immunotherapy. This review provides a comprehensive analysis of the mechanisms underlying immunotherapy resistance in GC, including the role of the tumor immune microenvironment, dynamic PD-L1 expression, compensatory activation of other immune checkpoints, and tumor genomic instability. Furthermore, the review explores GC-specific factors such as molecular subtypes, unique immune evasion mechanisms, and the impact of Helicobacter pylori infection. We also discuss emerging strategies to overcome resistance, including combination therapies, novel immunotherapeutic approaches, and personalized treatment strategies based on tumor genomics and the immune microenvironment. By highlighting these key areas, this review aims to inform future research directions and clinical practice, ultimately improving outcomes for GC patients undergoing immunotherapy.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"75"},"PeriodicalIF":8.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-02-06 DOI: 10.1038/s41419-025-07412-7

Yue Dai, Hongchen Li, Shiyin Fan, Kai Wang, Ziyi Cui, Xinyu Zhao, Xue Sun, Mingen Lin, Jiaxi Li, Yi Gao, Ziyin Tian, Hui Yang, Bingbing Zha, Lei Lv, Yanping Xu

{"title":"Dimethyl fumarate promotes the degradation of HNF1B and suppresses the progression of clear cell renal cell carcinoma.","authors":"Yue Dai, Hongchen Li, Shiyin Fan, Kai Wang, Ziyi Cui, Xinyu Zhao, Xue Sun, Mingen Lin, Jiaxi Li, Yi Gao, Ziyin Tian, Hui Yang, Bingbing Zha, Lei Lv, Yanping Xu","doi":"10.1038/s41419-025-07412-7","DOIUrl":"10.1038/s41419-025-07412-7","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC) is the most lethal subtype of renal cancer, and its treatment options remain limited. Therefore, there is an urgent need to discover therapeutic agents for ccRCC treatment. Here, we demonstrate that dimethyl fumarate (DMF), an approved medication for multiple sclerosis [1] and psoriasis, can inhibit the proliferation of ccRCC cells. Mechanistically, hepatocyte nuclear factor 1β (HNF1B), a transcription factor highly expressed in ccRCC, is succinated by DMF at cysteine residues, leading to its proteasomal degradation. Furthermore, HNF1B interacts with and stabilizes Yes-associated protein (YAP), thus DMF-mediated HNF1B degradation decreases YAP protein level and the expression of its target genes, resulting in the suppression of ccRCC cell proliferation. Importantly, oral administration of DMF sensitizes ccRCC to sunitinib treatment and enhances its efficacy in mice. In summary, we provide evidences supporting DMF as a potential drug for clinical treatment of ccRCC by targeting HNF1B and reveal a previously unrecognized role of HNF1B in regulating YAP in ccRCC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"71"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endoplasmic reticulum stress-related super enhancer promotes epithelial-mesenchymal transformation in hepatocellular carcinoma through CREB5 mediated activation of TNC.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-02-06 DOI: 10.1038/s41419-025-07356-y

Anqi Wang, Sitong Yan, Jiatao Liu, Xiang Chen, Mengyao Hu, Xiao Du, Weijia Jiang, Zhipeng Pan, Lulu Fan, Guoping Sun

{"title":"Endoplasmic reticulum stress-related super enhancer promotes epithelial-mesenchymal transformation in hepatocellular carcinoma through CREB5 mediated activation of TNC.","authors":"Anqi Wang, Sitong Yan, Jiatao Liu, Xiang Chen, Mengyao Hu, Xiao Du, Weijia Jiang, Zhipeng Pan, Lulu Fan, Guoping Sun","doi":"10.1038/s41419-025-07356-y","DOIUrl":"10.1038/s41419-025-07356-y","url":null,"abstract":"Super-enhancers (SEs) are associated with key genes that control cellular state and cell identity. Endoplasmic reticulum stress (ERS) regulates epithelial-mesenchymal transformation (EMT). However, whether SEs are involved in ERS-related activation of EMT in hepatocellular carcinoma (HCC) is unknown. In this study, we identified 17 ERS-related SEs by comparing ERS-HCC cells with untreated control cells using ChIP-seq and RNA-seq. CRISPR-Cas9 and RT-qPCR identified CAMP responsive element binding protein 5 (CREB5) as a key target of ERS-related SE. Analyses of TCGA datasets and tissue arrays showed that CREB5 mRNA and protein expression levels were higher in liver cancer tissues than in paired normal tissues. In addition, overexpression of CREB5 was associated with poor prognosis and an aggressive phenotype in patients with HCC. We also found that activation of ERS enhanced the expression of CREB5, and upregulation of CREB5 significantly increased cell proliferation, migration, and invasion, and promoted EMT, but inhibited apoptosis. More importantly, ERS activation increased the expression of several EMT markers by modulating the expression of CREB5. Mechanistically, CREB5 upregulates the transcription of tenascin-C (TNC) by directly binding to its promoter region, thereby promoting EMT in liver cancer cells. In summary, our findings suggest that ERS activation promotes EMT in liver cancer cells via SE-mediated upregulation of the CREB5/TNC pathway. This result provides a new direction for uncovering how ERS regulates EMT and a foundation for preventing the progression of EMT in HCC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"73"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Blimp-1 orchestrates macrophage polarization and metabolic homeostasis via purine biosynthesis in sepsis.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-02-06 DOI: 10.1038/s41419-025-07405-6

Wenjuan Peng, Qiushi Qin, Rui Li, Yujia Liu, Lan Li, Yue Zhang, Liuluan Zhu

{"title":"Blimp-1 orchestrates macrophage polarization and metabolic homeostasis via purine biosynthesis in sepsis.","authors":"Wenjuan Peng, Qiushi Qin, Rui Li, Yujia Liu, Lan Li, Yue Zhang, Liuluan Zhu","doi":"10.1038/s41419-025-07405-6","DOIUrl":"10.1038/s41419-025-07405-6","url":null,"abstract":"Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection, leading to systemic inflammation and organ dysfunction. Macrophage polarization plays a critical role in pathogenesis of sepsis, and the influence of B lymphocyte-induced maturation protein-1 (Blimp-1) on this polarization is an underexplored yet pivotal aspect. This study aimed to elucidate the role of Blimp-1 in macrophage polarization and metabolism during sepsis. Using a murine cecal ligation and puncture model, we observed elevated Blimp-1 expression in M2 macrophages. Knockdown of Blimp-1 by macrophage-targeted adeno-associated virus in this model resulted in decreased survival rates, exacerbated tissue damage, and impaired M2 polarization, underscoring its protective role in sepsis. In vitro studies with bone marrow-derived macrophage (BMDM), RAW264.7, and THP-1 cells further demonstrated Blimp-1 promotes M2 polarization and modulates key metabolic pathways. Metabolomics and dual-luciferase assays revealed Blimp-1 significantly influences purine biosynthesis and the downstream Ornithine cycle, which are essential for M2 macrophage polarization. In vitro studies with BMDM further suggested that the purine biosynthesis and Ornithine cycle metabolic regulation is involved in Blimp-1's effects on M2 macrophage polarization, and mediates Blimp-1's impact on septic mice. Our findings unveil a novel mechanism by which Blimp-1 modulates macrophage polarization through metabolic regulation, presenting potential therapeutic targets for sepsis. This study highlights the significance of Blimp-1 in orchestrating macrophage responses and metabolic adaptations in sepsis, offering valuable insights into its role as a critical regulator of immune and metabolic homeostasis.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"72"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Myeloma cell-derived CXCL7 facilitates proliferation of tumor cells and occurrence of osteolytic lesions through JAK/STAT3 pathway.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-02-06 DOI: 10.1038/s41419-025-07413-6

Yue Wang, Tianwei Lan, Qiongyan Zhang, Chi Zhou, Peng Liu

{"title":"Myeloma cell-derived CXCL7 facilitates proliferation of tumor cells and occurrence of osteolytic lesions through JAK/STAT3 pathway.","authors":"Yue Wang, Tianwei Lan, Qiongyan Zhang, Chi Zhou, Peng Liu","doi":"10.1038/s41419-025-07413-6","DOIUrl":"10.1038/s41419-025-07413-6","url":null,"abstract":"Osteolytic lesions and pathological fractures are hallmark manifestations of multiple myeloma (MM), profoundly influencing the quality of life and self-care ability of MM patients. By analyzing transcriptome data and single-cell RNA-seq data from our center and the GEO database, a subset of MM cells with high expression levels of chemokine CXCL7 was identified. This subset of MM cells possesses a high capacity for proliferation and activation of osteoclast signaling pathway. CXCL7 might be a crucial regulator of osteolytic damage in MM. Subsequently, the association between the expression level of CXCL7 and pathological fractures in patients was investigated, and the impact of CXCL7 on MM proliferation was confirmed both in vivo and in vitro. A mouse xenograft tumor model was established through intravenous injection of myeloma cell lines based on the homing ability of plasma cells. Moreover, the mechanism by which CXCL7 promotes the activation of osteoclast signaling pathways in MM was explored. Our findings reveal that elevated CXCL7 levels significantly enhance MM cell proliferation, increasing the risk of pathological fractures in MM patients. Additionally, our mouse xenograft tumor model demonstrated that CXCL7 can induce femoral fractures and reduce bone mineral density. Concurrently, it was discovered that CXCL7 could activate the JAK/STAT3 pathway via CXCR2 and upregulate the expression levels of MMP13 and C-myc, facilitating MM cell proliferation and activation of the osteoclast signaling pathway. Our study offers novel insights into the pathogenic mechanism of osteolytic lesions and implies that targeting CXCL7 may present a new therapeutic avenue for MM.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"74"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of mitochondrial carrier homolog 2 as an important therapeutic target of castration-resistant prostate cancer.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-02-05 DOI: 10.1038/s41419-025-07406-5

Yankui Liu, Anjie Chen, Yufan Wu, Jiang Ni, Rong Wang, Yong Mao, Ning Sun, Yuanyuan Mi

{"title":"Identification of mitochondrial carrier homolog 2 as an important therapeutic target of castration-resistant prostate cancer.","authors":"Yankui Liu, Anjie Chen, Yufan Wu, Jiang Ni, Rong Wang, Yong Mao, Ning Sun, Yuanyuan Mi","doi":"10.1038/s41419-025-07406-5","DOIUrl":"10.1038/s41419-025-07406-5","url":null,"abstract":"We here investigate the expression of the mitochondrial carrier homolog 2 (MTCH2) and its potential function in castration-resistant prostate cancer (CRPC). Bioinformatic analyses reveal that MTCH2 overexpression is associated with critical clinical parameters of prostate cancer. Single-cell sequencing data indicate elevated MTCH2 expression in the prostate cancer epithelium. MTCH2 is also upregulated in locally treated CRPC tissue and various primary human CRPC cells. Using genetic silencing via shRNA and knockout (KO) through the CRISPR-sgRNA approach, we showed that the depletion of MTCH2 impaired mitochondrial function, resulting in a reduced oxygen consumption rate, diminished complex I activity, and decreased ATP levels, mitochondrial depolarization, and increased reactive oxygen species production in primary CRPC cells. The silencing or KO of MTCH2 significantly inhibited cell viability, proliferation, and migration, together with a marked increase in apoptosis in the primary CRPC cells. In contrast, ectopic expression of MTCH2 provided CRPC cells with pro-tumorigenic properties, enhancing ATP production and promoting cell proliferation and migration. MTCH2 silencing also markedly inhibited the growth of subcutaneous xenografts of the primary CRPC cells in nude mice. The MTCH2-silenced xenografts exhibited increased apoptosis, elevated lipid peroxidation, and decreased ATP levels. These results provide new insights into the role of MTCH2 in supporting mitochondrial function and CRPC progression.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"70"},"PeriodicalIF":8.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma. GP73 介导的 PKM2 和 GP73 分泌可促进肝细胞癌的血管生成和 M2 样巨噬细胞极化。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-02-05 DOI: 10.1038/s41419-025-07391-9

Shujie Wang, Tongjia Zhang, Yue Zhou, Zitao Jiao, Kejia Lu, Xinyi Liu, Wei Jiang, Zhe Yang, Hui Li, Xiaowei Zhang

{"title":"GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma.","authors":"Shujie Wang, Tongjia Zhang, Yue Zhou, Zitao Jiao, Kejia Lu, Xinyi Liu, Wei Jiang, Zhe Yang, Hui Li, Xiaowei Zhang","doi":"10.1038/s41419-025-07391-9","DOIUrl":"10.1038/s41419-025-07391-9","url":null,"abstract":"Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Abnormally high expression of Golgi protein 73 (GP73) and pyruvate kinase M2 (PKM2) is intimately associated with HCC progression. However, as secreted proteins, the role of their extracellular secretions in HCC progression remains unclear. Here, we demonstrated that the expression of extracellular GP73 was positively correlated with extracellular PKM2. GP73 interacted with PKM2 to promote SUMO1 modification of PKM2, which in turn enhanced the interaction of GP73 and PKM2. This process continuously promoted the transfer of PKM2 from the cytoplasm to the membrane in HCC cells, and finally secretion. Extracellular PKM2 and GP73 synergistically promoted angiogenesis and polarization of M2-type macrophages, thereby leading to malignant progression and sorafenib resistance in HCC. Sorafenib combined with shikonin, a specific inhibitor of PKM2, has a strong anti-tumor effect. This study reveals the role of GP73 in enhancing PKM2 and GP73 secretion in promoting HCC progression, providing a theoretical basis and drug targets for HCC therapy.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"69"},"PeriodicalIF":8.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CDCA7 enhances STAT3 transcriptional activity to regulate aerobic glycolysis and promote pancreatic cancer progression and gemcitabine resistance. CDCA7 可增强 STAT3 的转录活性，从而调节有氧糖酵解并促进胰腺癌的进展和吉西他滨的耐药性。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-02-04 DOI: 10.1038/s41419-025-07399-1

Dijie Zheng, Yazhu Deng, Lu Deng, Zhiwei He, Xinghao Sun, Yanyu Gong, Binbin Shi, Deqin Lu, Chao Yu

{"title":"CDCA7 enhances STAT3 transcriptional activity to regulate aerobic glycolysis and promote pancreatic cancer progression and gemcitabine resistance.","authors":"Dijie Zheng, Yazhu Deng, Lu Deng, Zhiwei He, Xinghao Sun, Yanyu Gong, Binbin Shi, Deqin Lu, Chao Yu","doi":"10.1038/s41419-025-07399-1","DOIUrl":"10.1038/s41419-025-07399-1","url":null,"abstract":"Cell division cycle associated 7 (CDCA7) plays a role in various malignancies, especially pancreatic cancer (PC). However, its expression pattern and functional significance in PC require further research. Therefore, this study aimed to investigate CDCA7 expression levels and biological functions in PC using in vitro and in vivo experiments. Western blotting, immunohistochemistry, and real-time polymerase chain reaction were performed to detect CDCA7 expression in PC cells and tissues. Additionally, the biological functions of CDCA7 were assessed using cell proliferation, wound healing, and Transwell assays. CDCA7 overexpression promoted PC cell proliferation, migration, and invasion, and increased resistance to the chemotherapy drug gemcitabine, possibly through enhanced aerobic glycolysis. Additionally, immunoprecipitation assay showed that CDCA7 interacted with STAT3 protein and affected the transcriptional regulation of hexokinase 2. Conclusively, targeting CDCA7 might be a promising therapeutic strategy to increase gemcitabine sensitivity by inhibiting glycolysis in PC cells.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"68"},"PeriodicalIF":8.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0