Journal of Molecular Medicine-Jmm最新文献

{"title":"WNT2B high‑expressed fibroblasts induce the fibrosis of IBD by promoting NK cells secreting IL-33.","authors":"Yanling Cheng, Shuzhe Xiao, Lin Lan, Danqiong Liu, Rui Tang, Jianbiao Gu, Li Ma, Zhihua He, Xirong Chen, Lanlan Geng, Peiyu Chen, Huiwen Li, Lu Ren, Yun Zhu, Yang Cheng, Sitang Gong","doi":"10.1007/s00109-024-02477-x","DOIUrl":"10.1007/s00109-024-02477-x","url":null,"abstract":"<p><p>Fibrosis is an important pathological change in inflammatory bowel disease (IBD), but the mechanism has yet to be elucidated. WNT2B high‑expressed fibroblasts are enriched in IBD intestinal tissues, although the precise function of this group of fibroblasts remains unclear. This study investigated whether WNT2B high‑expressed fibroblasts aggravated intestinal tissue damage and fibrosis. Our study provides evidence that WNT2B high‑expressed fibroblasts and NK cells were enriched in colitis tissue of patients with IBD. WNT2B high‑expressed fibroblasts secreted wnt2b, which bound to FZD4 on NK cells and activated the NF-κB and STAT3 pathways to enhance IL-33 expression. TCF4, a downstream component of the WNT/β-catenin pathway, bound to p65 and promoted binding to IL-33 promoter. Furthermore, Salinomycin, an inhibitor of the WNT/β-catenin pathway, inhibited IL-33 secretion in colitis, thereby reducing intestinal inflammation.Knocking down WNT2B reduces NK cell infiltration and IL-33 secretion in colitis, and reduce intestinal inflammation and fibrosis. In conclusion, WNT2B high‑expressed fibroblasts activate NK cells by secreting wnt2b, which activates the WNT/β-catenin and NF-κB pathways to promote IL-33 expression and secretion, potentially culminating in the induction of colonic fibrosis in IBD. KEY MESSAGES: WNT2B high-expressed fibroblasts and NK cells are enriched in colitis tissue, promoting NK cells secreting IL-33. Wnt2b activates NF-κB and STAT3 pathways promotes IL-33 expression by activating p65 and not STAT3. syndrome TCF4 binds to p65 and upregulates the NF- κB pathway. Salinomycin reduces NK cell infiltration and IL-33 secretion in colitis. Knocking down WNT2B mitigates inflammation and fibrosis in chronic colitis.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoplasmic reticulum stress induces hepatic steatosis through interaction between PPARα and FoxO6 in vivo and in vitro.","authors":"Dae Hyun Kim","doi":"10.1007/s00109-024-02480-2","DOIUrl":"10.1007/s00109-024-02480-2","url":null,"abstract":"<p><p>Endoplasmic reticulum (ER) stress is a major cause of hepatic steatosis through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signaling to glucose and lipid metabolism. Therefore, dysregulated FoxO6 is involved in hepatic lipogenesis. This study elucidated the role of FoxO6 in ER stress-induced hepatic steatosis in vivo and in vitro. Hepatic ER stress responses and β-oxidation were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. For the in vitro study, liver cells overexpressing constitutively active FoxO6 and FoxO6-siRNA were treated with high glucose, and lipid metabolism alterations were measured. ER stress-induced FoxO6 activation suppressed hepatic β-oxidation in vivo. The expression and transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) were significantly decreased in the constitutively active FoxO6 allele. Otherwise, inhibiting β-oxidation genes were reduced in the FoxO6-siRNA and FoxO6-KO mice. Our data showed that the FoxO6-induced hepatic lipid accumulation was negatively regulated by insulin signaling. High glucose treatment as a hyperglycemia condition caused the expression of ER stress-inducible genes, which was deteriorated by FoxO6 activation in liver cells. However, high glucose-mediated ER stress suppressed β-oxidation gene expression through interactions between PPARα and FoxO6 corresponding to findings in the in vivo study-lipid catabolism is also regulated by FoxO6. Furthermore, insulin resistance suppressed b-oxidation through the interaction between FoxO6 and PPARα promotes hepatic steatosis, which, due to hyperglycemia-induced ER stress, impairs insulin signaling. KEY MESSAGES: Our original aims were to delineate the interrelation between the regulation of PPARα and the transcription factor FoxO6 pathway in relation to lipid metabolism at molecular levels. Evidence on high glucose promoted FoxO6 activation induced lipid accumulation in liver cells. The effect of PPARα activation of the insulin signaling. FoxO6 plays a pivotal role in hepatic lipid accumulation through inactivation of PPARα in FoxO6-overexpression mice.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11416408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Adrenergic blockade attenuates adverse adipose tissue responses after burn.","authors":"Shayahati Bieerkehazhi, Abdikarim Abdullahi, Fadi Khalaf, Dalia Barayan, Lauar de Brito Monteiro, Osai Samadi, Graham Rix, Marc G Jeschke","doi":"10.1007/s00109-024-02478-w","DOIUrl":"10.1007/s00109-024-02478-w","url":null,"abstract":"<p><p>Severe burn injuries are defined by a prolonged hypermetabolic response characterized by increases in resting energy expenditure, systemic catabolism, and multi-organ dysfunction. The sustained elevation of catecholamines following a burn injury is thought to significantly contribute to this hypermetabolic response, leading to changes in adipose tissue such as increased lipolysis and the browning of subcutaneous white adipose tissue (WAT). Failure to mitigate these adverse changes within the adipose tissue has been shown to exacerbate the post-burn hypermetabolic response and lead to negative outcomes. Propranolol, a non-selective β-blocker, has been clinically administered to improve outcomes of pediatric and adult burn patients, but there is inadequate knowledge of its effects on the distinct adipose tissue depots. In this study, we investigated the adipose depot-specific alterations that occur in response to burn injury. Moreover, we explored the therapeutic effects of β-adrenoceptor blockade via the drug propranolol in attenuating these burn-induced pathophysiological changes within the different fat depots. Using a murine model of thermal injury, we show that burn injury induces endoplasmic reticulum (ER) stress in the epididymal (eWAT) but not in the inguinal (iWAT) WAT depot. Conversely, burn injury induces the activation of key lipolytic pathways in both eWAT and iWAT depots. Treatment of burn mice with propranolol effectively mitigated adverse burn-induced alterations in the adipose by alleviating ER stress in the eWAT and reducing lipolysis in both depots. Furthermore, propranolol treatment in post-burn mice attenuated UCP1-mediated subcutaneous WAT browning following injury. Overall, our findings suggest that propranolol serves as an effective therapeutic intervention to mitigate the adverse changes induced by burn injury, including ER stress, lipotoxicity, and WAT browning, in both adipose tissue depots. KEY MESSAGES: Burn injury adversely affects adipose tissue metabolism via distinct changes in both visceral and subcutaneous adipose depots. Propranolol, a non-selective β-adrenergic blocker, attenuates many of the adverse adipose tissue changes mediated by burn injury.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights into the mechanisms and therapeutic strategies of chondrocyte autophagy in osteoarthritis.","authors":"Lujia Tang, Jiatong Ding, Kangping Yang, Zhen Zong, Rui Wu, Hui Li","doi":"10.1007/s00109-024-02473-1","DOIUrl":"10.1007/s00109-024-02473-1","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a chronic joint disease with an unclear cause characterized by secondary osteophytes and degenerative changes in the articular cartilage. More than 250 million people are expected to be affected by it by 2050, putting a tremendous socioeconomic strain on the entire world. OA cannot currently be treated with any effective medications that change the illness. Over time, chondrocytes undergo gradual metabolic, structural, and functional changes as a result of aging or abuse. The degenerative progression of osteoarthritis is significantly influenced by the imbalance of chondrocyte homeostasis. By continuously recycling and rebuilding macromolecules or organelles, autophagy functions as a crucial regulatory system to maintain homeostasis during an individual's growth and development. This review uses chondrocytes as its starting point and establishes a strong connection between autophagy and osteoarthritis in order to thoroughly examine the mechanisms behind chondrocyte autophagy in osteoarthritis. Biomarkers of chondrocyte autophagy will be identified, and prospective targeted medications and novel treatment approaches for slowing or preventing the course of OA will be developed based on chondrocyte senescence, autophagy, and apoptosis in OA. KEY MESSAGES: Currently, OA has not been treated with any drugs that can effectively cure it. We hope that by exploring specific targets in the course of osteoarthritis, we can promote the progress of treatment strategies. The degenerative progression of osteoarthritis is significantly influenced by the imbalance of chondrocyte balance. Through the continuous recovery and reconstruction of macromolecules or organelles, autophagy is an important regulatory system for maintaining homeostasis during individual growth and development. In this paper, the close relationship between autophagy and osteoarthritis was established with chondrocytes as the starting point, in order to further explore the mechanism of chondrocyte autophagy in osteoarthritis. The development process of osteoarthritis was studied from the perspective of chondrocytes, and the change of autophagy level had a significant impact on osteoarthritis. Chondrocyte autophagy is mainly determined by intracellular mitochondrial autophagy, so we are committed to finding relevant molecules. Through PI3K/AKT- and MAPK-related pathways, the biomarkers of chondrocyte autophagy were identified, and chondrocyte senescence, autophagy, and apoptosis based on osteoarthritis provided a constructive idea for the development of prospective targeted drugs and new therapies to slow down or prevent the progression of osteoarthritis.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current treatment of Psoriasis triggered by Cytokine Storm and future immunomodulation strategies.","authors":"Geórgia de Carvalho Braga, Gabriel Rossi Francisco, Margarete Dulce Bagatini","doi":"10.1007/s00109-024-02481-1","DOIUrl":"10.1007/s00109-024-02481-1","url":null,"abstract":"<p><p>Psoriasis is a chronic condition caused by an inflammation mediated mainly by cytokines and T cells. In COVID-19, the same type of imbalance is common, generating the Cytokine Storm and promoting a worsening in the skin conditions of patients with autoimmune disorders, such as Psoriasis. In this context, one of the main mediators of immune responses presented by SARS-CoV-2 infected patients is the Purinergic System. This immunological resource is capable of stimulating the hyperinflammatory state presented by infected individuals, mainly by the activity of the P2X7 receptor, culminating in the Cytokine Storm and consequently in the Psoriasis crisis. Currently, different drugs are used for patients with Psoriasis, such as immunosuppressants and small molecules; however, the safety of these drugs in infected patients has not been analyzed yet. In this context, studies are being developed to evaluate the possible administration of these traditional drugs to COVID-19 patients with Psoriasis crisis. Along with that, researchers must evaluate the potential of administrating P2X7 antagonists to these patients as well, improving both the systemic and the dermatological prognostics of patients, by reducing the Cytokine Storm and its general effects, but also avoiding the provocation of Psoriasis crisis.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.","authors":"Giuseppina Bruno, Michele Pietrafesa, Fabiana Crispo, Annamaria Piscazzi, Francesca Maddalena, Guido Giordano, Vincenza Conteduca, Marianna Garofoli, Almudena Porras, Franca Esposito, Matteo Landriscina","doi":"10.1007/s00109-024-02479-9","DOIUrl":"10.1007/s00109-024-02479-9","url":null,"abstract":"<p><p>Metabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60-70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells. KEY MESSAGES: TRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours. TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells. TRAP1 silencing favours mitochondrial biogenesis in CRC cells.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11416412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral pyrophosphate protects Abcc6^-/- mice against vascular calcification induced by chronic kidney disease.","authors":"Elise Bouderlique, Jennifer Kervadec, Ellie Tang, Jeremy Zaworski, Amélie Coudert, Isabelle Rubera, Christophe Duranton, Edmat Khan, Jean-Philippe Haymann, Georges Leftheriotis, Michel Daudon, Emmanuel Letavernier","doi":"10.1007/s00109-024-02468-y","DOIUrl":"10.1007/s00109-024-02468-y","url":null,"abstract":"<p><p>One of the hallmarks of chronic kidney disease (CKD) is the development of vascular calcification. Inorganic pyrophosphate is a potent inhibitor of calcification, and previous studies have reported low plasma pyrophosphate levels in hemodialysis patients. A long-term mouse model of CKD-accelerated vascular calcification was developed to study pyrophosphate metabolism and to test whether oral pyrophosphate supplementation attenuates the propensity for arterial calcification. CKD was induced by repeated injections of aristolochic acid in wild-type and Abcc6^-/- mice, which tend to develop vascular calcifications. CKD accelerated the development of vascular calcifications in Abcc6^-/- mice, in the aorta and small renal arteries, and decreased circulating pyrophosphate levels. Oral pyrophosphate supplementation for 6 months attenuated CKD-induced vascular calcification in this model. These results show that oral pyrophosphate may be of interest in preventing vascular calcification in patients with CKD. KEY MESSAGES: Chronic kidney disease accelerates the development of vascular calcification in pyrophosphate-deficient mice. Oral pyrophosphate supplementation for 6 months attenuates chronic kidney disease-induced vascular calcification in a mouse model. Oral pyrophosphate may be of interest in preventing vascular calcification in patients with chronic kidney disease.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141972226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New CRISPR/Cas9-based Fgfr2^C361Y/+ mouse model of Crouzon syndrome exhibits skull and behavioral abnormalities.","authors":"Ying Ying Yue, Chen-Zhi Lai, Xiao-Shuang Guo, Chang-Sheng Yang, Yu Wang, Guo-Dong Song, Xiao-Lei Jin","doi":"10.1007/s00109-024-02476-y","DOIUrl":"10.1007/s00109-024-02476-y","url":null,"abstract":"<p><p>Crouzon syndrome (CS), a syndromic craniosynostosis, is a craniofacial developmental deformity caused by mutations in fibroblast growth factor receptor 2 (FGFR2). Previous CS mouse models constructed using traditional gene editing techniques faced issues such as low targeting efficiency, extended lineage cycles, and inconsistent and unstable phenotypes. In this study, a CRISPR/Cas9-mediated strategy was employed to induce a functional augmentation of the Fgfr2 point mutation in mice. Various techniques, including bone staining, micro-CT, histological methods, and behavioral experiments, were employed to systematically examine and corroborate phenotypic disparities between mutant mice (Fgfr2^C361Y/+) and their wild-type littermates. Confirmed via PCR-Sanger sequencing, we successfully induced the p.Cys361Tyr missense mutation in the Fgfr2 IIIc isoform of the extracellular domain (corresponding to the p.Cys342Tyr mutation in humans) based on Fgfr2-215 transcript (ENSMUST00000122054.8). Fgfr2^C361Y/+ mice exhibited characteristics consistent with the phenotypic features associated with CS, including skull-vault craniosynostosis, skull deformity, shallow orbits accompanied by exophthalmos, midface hypoplasia with malocclusion, and shortened skull base, notably without any apparent limb defects. Furthermore, mutant mice displayed behavioral abnormalities encompassing deficits in learning and memory, social interaction, and motor dysfunction, without anxiety-related disorders. Histopathological examination of the hippocampal region revealed structural abnormalities, suggesting possible brain development impairment secondary to craniosynostosis. In conclusion, we constructed a novel gene-edited Fgfr2^C361Y/+ mice strain based on CRISPR/Cas9, which displayed skull and behavioral abnormalities, serving as a new model for studying genetic molecular mechanisms and exploring treatments for CS. KEY MESSAGES: CRISPR/Cas9 crafted a Crouzon model by enhancing Fgfr2-C361Y in mice. Fgfr2^C361Y/+ mice replicate CS phenotypes-craniosynostosis and midface anomalies. Mutant mice show diverse behavioral abnormalities, impacting learning and memory. Fgfr2^C361Y/+ mice offer a novel model for cranial suture studies and therapeutic exploration.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extragustatory bitter taste receptors in head and neck health and disease.","authors":"Jacob C Harris, Robert J Lee, Ryan M Carey","doi":"10.1007/s00109-024-02490-0","DOIUrl":"https://doi.org/10.1007/s00109-024-02490-0","url":null,"abstract":"<p><p>Taste receptors, first described for their gustatory functions within the oral cavity and oropharynx, are now known to be expressed in many organ systems. Even intraoral taste receptors regulate non-sensory pathways, and recent literature has connected bitter taste receptors to various states of health and disease. These extragustatory pathways involve previously unexplored, clinically relevant roles for taste signaling in areas including susceptibility to infection, antibiotic efficacy, and cancer outcomes. Among other physicians, otolaryngologists who manage head and neck diseases should be aware of this growing body of evidence and its relevance to their fields. In this review, we describe the role of extragustatory taste receptors in head and neck health and disease, highlighting recent advances, clinical implications, and directions for future investigation. Additionally, this review will discuss known TAS2R polymorphisms and the associated implications for clinical prognosis.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The oncogenic role of EIF4A3/CDC20 axis in the endometrial cancer.","authors":"Yan Lin, Lili Kong, Yiting Zhao, Fengguang Zhai, Ziqing Zhan, Yuxuan Li, Zheng Jingfei, Yan Chunhong, Xiaofeng Jin","doi":"10.1007/s00109-024-02486-w","DOIUrl":"https://doi.org/10.1007/s00109-024-02486-w","url":null,"abstract":"<p><p>Eukaryotic initiation factor 4A-3 (EIF4A3) is a key component of the exon junction complex (EJC) and is extensively involved in RNA splicing, inducing mRNA decay, and regulating the cell cycle and apoptosis. However, the potential role of EIF4A3 in EC has not been comprehensively investigated and remains unknown. Here, we report that the expression level of EIF4A3 is dramatically elevated in endometrial cancer (EC) samples compared with normal EC samples via bioinformatics analysis and immunohistochemistry analysis, and that high expression of EIF4A3 promotes the proliferation, migration, and invasion of EC cells. Mechanistically, we found that high EIF4A3 expression stabilized cell division cyclin 20 (CDC20) mRNA, and high EIF4A3 expression induced pro-carcinogenic effects in EC cells that were efficiently antagonized upon knockdown of CDC20, as well as Apcin, an inhibitor of CDC20. These findings reveal a novel mechanism by which high expression of EIF4A3 induces CDC20 upregulation, thus leading to EC tumorigenesis and metastasis, indicating a potential treatment strategy for EC patients with high EIF4A3 expression using Apcin. KEY MESSAGES: The expression level of EIF4A3 was dramatically elevated in endometrial cancer (EC) samples compared with normal endometrial cancer samples. High EIF4A3 expression stabilized CDC20 mRNA, and high EIF4A3 expression induced pro-carcinogenic effect in EC cells which was efficiently antagonized upon knockdown of CDC20. Apcin, an inhibitor of CDC20, could effectively counteract high expression of EIF4A3 inducing EC tumourigenesis and metastasis, indicating the potential treatment strategy for EC patients with EIF4A3 high expression by using Apcin.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}