Journal of Translational Medicine最新文献

{"title":"Inhibition of histone deacetylases 3 attenuates imiquimod-induced psoriatic dermatitis via targeting cGAS-STING signaling in keratinocytes.","authors":"Chong Zeng, Xiujuan Wen, Zibo Wei, Xinhuai Dong","doi":"10.1186/s12967-025-06544-w","DOIUrl":"10.1186/s12967-025-06544-w","url":null,"abstract":"<p><strong>Background: </strong>Psoriasis is a common chronic inflammatory skin disease characterized by epidermal keratinocyte hyperproliferation and persistent immune activation. Histone deacetylase 3 (HDAC3), a member of the class I HDAC family, plays critical roles in regulating immunity and inflammation. However, its precise expression profile and functional contribution to psoriasis pathogenesis remain poorly defined.</p><p><strong>Methods: </strong>We first performed bioinformatics analysis of HDAC3 expression using the Gene Expression Omnibus (GEO) database. Subsequently, we employed a combination of cellular and molecular techniques, including hematoxylin and eosin (H&E) staining, immunohistochemistry, flow cytometry, quantitative real-time PCR (qRT-PCR), western blotting, and transmission electron microscopy (TEM), to analyze the role of HDAC3 in IMQ-induced psoriasis-like inflammation in mice and in vitro psoriasis models.</p><p><strong>Results: </strong>HDAC3 expression was significantly upregulated in psoriasis lesions of patients and in both in vitro and in vivo models of psoriasis. Pharmacological inhibition of HDAC3 using the specific inhibitor RGFP966 alleviated IMQ-induced skin inflammation in mice and suppressed psoriasis-like phenotypes in vitro. Mechanistically, HDAC3 upregulation in an inflammatory microenvironment promoted oxidative stress, disrupted mitochondrial structural integrity, and triggered mitochondrial DNA leakage into the cytosol, thereby activating the cGAS-STING pathway in keratinocytes.</p><p><strong>Conclusion: </strong>Our findings establish HDAC3 as a pivotal mediator of psoriasis pathogenesis through the cGAS-STING pathway via mitochondrial dysfunction. The role of HDAC3 in exacerbating epidermal hyperproliferation and inflammation highlights its potential as a therapeutic target. Targeting HDAC3 in keratinocytes may offer a novel strategy for preventing and treating psoriasis by modulating epigenetic regulation, mitochondrial homeostasis, and innate immune responses.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"609"},"PeriodicalIF":6.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophages in prostate cancer: dual roles in tumor progression and immune evasion.","authors":"Ruihong Liu, Jianxin Lu, Jun Liu, Yilei Liao, Yinuo Guo, Peiqi Shi, Ziqiang Wang, Han Wang, Jingling Lai","doi":"10.1186/s12967-025-06519-x","DOIUrl":"10.1186/s12967-025-06519-x","url":null,"abstract":"<p><p>Prostate malignant tumors are notably common within the male urinary tract and present significant challenges in medical treatment. A crucial aspect of understanding the progression of these tumors involves examining the immune microenvironment, particularly the multifaceted role played by macrophages. These immune cells have dual functions: on the one hand, they can inhibit tumor growth, while on the other hand, they can also facilitate and accelerate the progression of prostate cancer. Investigations have shed light on the mechanisms through which macrophages contribute to cancer promotion. These mechanisms include their involvement in mediating inflammatory responses, the secretion of chemokines that attract other immune cells, and the production of macrophage extracellular traps (METs), all of which may create favorable environments for tumor development. In the context of advanced prostate cancer, immunotherapy has emerged as the primary treatment modality. However, the effectiveness of this approach often falls short, leading to disheartening prognoses for patients undergoing such therapies. The suboptimal efficacy and poor outcomes associated with immunotherapy may be correlated with the activity of macrophages within the tumor microenvironment (TME). Specifically, the infiltration of macrophages into tumor tissues, along with elevated levels of these cells in the peripheral blood, has been identified as an indicator of a poor prognosis for individuals with prostate cancer. This study provides a deeper understanding of the cancer-promoting effects of macrophages and the various mechanisms by which they operate, including the roles of chemokines and the production of macrophage extracellular traps in both the onset and progression of prostate cancer. Furthermore, we explored how these factors are related to local tumor infiltration and systemic macrophage counts, which are associated with unfavorable survival outcomes for patients with this disease.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"615"},"PeriodicalIF":6.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scutellarin prevents obesity-induced renal fibrosis via reduced activation of AP-1.","authors":"Haoan Yi, Yibing Jiang, Wei Li, Ling Shen, Wei Zhang, Shude Li, Yushan Xu, Fei Li","doi":"10.1186/s12967-025-06616-x","DOIUrl":"10.1186/s12967-025-06616-x","url":null,"abstract":"<p><strong>Background: </strong>Renal fibrosis is characterized by the formation of scar tissue in the kidney parenchyma. Obesity, with its rising global incidence, has become a significant cause of renal fibrosis. This study investigates the effect of Scutellarin (SCU) on obesity-induced renal fibrosis.</p><p><strong>Methods: </strong>Rats were fed a high-fat and high-sugar diet (HFSD) for 40 weeks. SCU was administered orally at doses of 25, 50, and 100 mg/kg/day during the last 8 weeks. Metabolic function was assessed by measuring serum triglycerides (TG), total cholesterol (TC), and glucose levels. Renal function was evaluated by analyzing serum uric acid (UA), creatinine (CRE), and blood urea nitrogen (BUN). RNA-seq was used to evaluate transcriptome changes in the kidney. Histopathological changes were examined using HE and Masson staining. Protein expressions and localization of FOS, JUN, FN, and TGF-β1 were analyzed by western blot, immunohistochemistry, and immunofluorescence.</p><p><strong>Results: </strong>HFSD-fed rats exhibited significant increases in body weight, serum TG, TC, and glucose levels, alongside elevated UA, CRE, and BUN levels, indicating metabolic and renal dysfunction. SCU treatment significantly improved these metabolic and renal parameters across all doses. Biochemical analyses and RNA-seq results confirmed the absence of dose-dependency in the effects of SCU. Histopathological analysis showed a reduction in glomerular hypertrophy and collagen deposition in the SCU-treated groups. RNA-seq data indicated a downregulation of Activator Protein 1 (AP-1), composed of FOS and JUN, at the transcriptional level. Western blot analysis confirmed that SCU treatment reduced both the expression and phosphorylation levels of FOS and JUN. Additionally, SCU downregulated the expression of fibrosis-related proteins TGF-β1 and FN, contributing to a reduction in renal fibrosis.</p><p><strong>Conclusion: </strong>SCU alleviates obesity-induced renal fibrosis through the downregulation of AP-1 activity and the expression level of fibrosis-related proteins TGF-β1 and FN.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"611"},"PeriodicalIF":6.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered macrophage membrane-coated dihydroartemisinin nanoparticles with enhanced CCR2 expression improved symptoms in MRL/LPR mice by metabolic reprogramming of proinflammatory macrophages.","authors":"Li Zhao, Yanlong Zhang, Rongrong Wang, Jiaqi Yang, Ruonan Wu, Zewen Wu, Jie Hu, Shuqiu Zhang, Liyun Zhang","doi":"10.1186/s12967-025-06574-4","DOIUrl":"10.1186/s12967-025-06574-4","url":null,"abstract":"<p><strong>Background: </strong>Systemic lupus erythematosus (SLE) is a debilitating autoimmune condition characterized by limited therapeutic options. Dihydroartemisinin (DHA), an antimalarial compound, exhibits promising immunomodulatory effects against SLE; however, its clinical application is limited by poor bioavailability.</p><p><strong>Methods: </strong>This study presented an innovative DHA delivery system based on macrophage membrane-coated nanoparticles (CCR2-MM@PEG-PCL/DHA), engineered to target SLE and its severe renal manifestation, lupus nephritis (LN). CCL2, a central mediator of leukocyte chemotaxis, contributes significantly to SLE pathogenesis. The targeting ability of nanoparticles to inflammatory sites is enhanced by genetically modifying the membrane of macrophages to over-express CCR2, and the nanoparticles can act as \"nanobait\" to capture CCL2 in the inflammatory microenvironment, thereby inhibiting macrophage-mediated inflammation. Efficacy was evaluated in vitro and in vivo using the MRL/lpr murine model.</p><p><strong>Results: </strong>The findings showed that this nanosystem effectively alleviated symptoms in the MRL/lpr mouse model of SLE. Furthermore, CCR2-MM@PEG-PCL/DHA modulated the renal immune microenvironment by reducing monocyte/macrophage infiltration and reprogramming the M1/M2 macrophage balance, thus mitigating kidney damage in SLE mice.</p><p><strong>Conclusions: </strong>The study establishes a mechanistically informed strategy for SLE intervention, substantiated by robust in vitro and in vivo data. These findings lay the foundation for translational research and potential clinical advancement in SLE therapy.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"608"},"PeriodicalIF":6.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EBV Reactivation-associated gene signature predicts poor prognosis in nasopharyngeal carcinoma.","authors":"Qingshuang Luo, Jingyi Long, Longtai Hu, Moyed Alsaadawe, Oluwasijibomi Damola Faleti, Xiaoming Lyu","doi":"10.1186/s12967-025-06549-5","DOIUrl":"10.1186/s12967-025-06549-5","url":null,"abstract":"<p><strong>Background: </strong>Epstein-Barr virus (EBV) reactivation is closely associated with poor prognosis in nasopharyngeal carcinoma (NPC). However, the molecular mechanisms underlying EBV reactivation in NPC progression remain unclear. This study aimed to identify key genes and pathways involved in EBV reactivation using an integrated multi-omics approach.</p><p><strong>Methods: </strong>An in vitro EBV reactivation model was established to investigate molecular changes associated with viral reactivation. Transcriptomic (RNA-seq) and proteomic (LC-MS/MS) analyses were performed to identify differentially expressed genes. Functional enrichment, protein-protein interaction network analysis, and survival analysis were conducted to elucidate the biological significance of key genes. RNA-seq data from NPC patients (GSE102349) were analyzed to assess the association between EBV reactivation (BZLF1 expression) and clinical outcomes.</p><p><strong>Results: </strong>A ten-gene signature (PLAUR, SBSN, LAMC2, CDC42EP1, F3, S100A, CYP24A1, KRT6B, PTGS2, and NQO1) was identified as significantly associated with EBV reactivation. These genes are involved in epithelial-mesenchymal transition (EMT), metabolic reprogramming, and hypoxia response. Pathway analysis highlighted their roles in complement and coagulation cascades, laminin interactions, keratin complex formation, and metabolic regulation, all of which contribute to EMT. Additionally, analysis of NPC patient data (GSE102349) revealed a correlation between BZLF1 expression and poor prognosis.</p><p><strong>Conclusions: </strong>This study identifies a novel prognostic gene signature associated with EBV reactivation in NPC through integrated multi-omics analyses, which provided insights into the molecular mechanisms of NPC progression. These findings suggest potential diagnostic and therapeutic targets for improving NPC.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"616"},"PeriodicalIF":6.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chimeric antigen receptors discriminate between tau and distinct amyloid-beta species.","authors":"Cynthia J Siebrand, Nicholas J Bergo, Suckwon Lee, Julie K Andersen, Chaska C Walton","doi":"10.1186/s12967-025-06572-6","DOIUrl":"10.1186/s12967-025-06572-6","url":null,"abstract":"<p><strong>Background: </strong>The lack of a definitive cure for Alzheimer's disease (AD) is fueling the search for innovative therapeutic strategies. Having revolutionized cancer immunotherapy, immune cell engineering with chimeric antigen receptors (CAR) is being explored to target AD. Whether CARs can recognize distinct amyloid-β (Aβ) species and tau neurofibrillary tangles (NFTs)-hallmark pathologies of AD-remains unclear.</p><p><strong>Methods: </strong>To investigate this, we engineered a series of CARs using single-chain fragment variable (scFv) derived from the variable light and heavy chains of antibodies tested in AD clinical trials. These included E2814 (E2814-CAR), targeting tau; Lecanemab (Lec-CAR) and Aducanumab (Adu-CAR), targeting Aβ; and Donanemab (Don-CAR) and Remternetug (Rem-CAR), targeting the truncated pyroglutamated Aβ species Aβp3-42. To evaluate CAR function, we utilized the murine DO11.10 CD4⁺ T-cell hybridoma line as a scalable and reproducible platform. CAR activation was assessed in response to tau preformed fibrils (PFFs), Aβ_1-42 oligomer-enriched aggregates, and Aβp3-42 aggregates, using flow cytometry for CD69 expression and ELISA for IL-2 secretion. To validate this platform, we tested Adu-CAR in primary mouse CD4⁺ T cells treated with Aβ_1-42 aggregates and assessed activation via flow cytometry for CD69 and CD25 expression.</p><p><strong>Results: </strong>DO11.10 cells expressing E2814-CAR-but not Lec-CAR-responded to tau PFFs. In contrast, cells expressing Adu-CAR, and to a lesser extent Lec-CAR-but not E2814-CAR-responded to Aβ_1-42 aggregates. For Aβp3-42 aggregates, Rem-CAR elicited the strongest response, followed by Adu-CAR, while E2814-CAR and Don-CAR showed no activation. The activation of Adu-CAR by Aβ_1-42 aggregates was recapitulated in primary CD4⁺ T cells, as measured by CD69 expression.</p><p><strong>Conclusions: </strong>Our findings demonstrate that CARs can detect and discriminate between tau PFFs, Aβ1-42, and Aβp3-42 aggregates. This highlights the potential of repurposing AD antibodies for CAR-based therapies to selectively target tau NFTs and distinct forms of Aβ senile plaques.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"605"},"PeriodicalIF":6.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interpenetrating network hydrogel-loaded embryonic stem cell-derived endocardial cells improves cardiac function after myocardial infarction.","authors":"Boshi Liu, Laiping Zhang, Xiao Guan, Jie Liu, Weinian Shou, Xin Chen, Xiaohui Li, Dayan Cao","doi":"10.1186/s12967-025-06603-2","DOIUrl":"10.1186/s12967-025-06603-2","url":null,"abstract":"<p><strong>Background: </strong>With an in-depth understanding of cardiac cell differentiation, cell therapy derived from stem cells has shown promising therapeutic effects in the treatment of myocardial infarction (MI). Although many types of cardiac or noncardiac cells have been found to play protective roles in MI, the specific role of endocardial cells (ECCs) in MI has not been reported.</p><p><strong>Methods: </strong>The current study was designed to determine whether human embryonic stem cell (hESC)-derived endocardial cells (hESC-ECCs) could be protective against MI. We first developed a cell delivery system by constructing a photosensitive interpenetrating network hydrogel consisting of gelatin methacryloyl (GelMA) and silk fibroin methacryloyl (SilMA). The sorted hESC-ECCs were loaded into the delivery system and then injected into the pericardium cavity of the MI rats.</p><p><strong>Results: </strong>These results show that the cell delivery system has good biocompatibility. Moreover, the delivered endocardial cells improved cardiac function and delayed capillary atrophy after MI. Further mechanistic analysis revealed that hESC-ECCs protect the mitochondria of cardiomyocytes from damage under oxidative stress and potentially promote the angiogenesis of cardiac endothelial cells.</p><p><strong>Conclusion: </strong>Our results demonstrated that hESC-ECCs have the potential to serve as a cell therapy strategy for MI treatment by maintaining cardiomyocyte survival and facilitating angiogenesis.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"603"},"PeriodicalIF":6.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YTHDF3 regulates IL32 mRNA stability to promote osteogenic differentiation of bone mesenchymal stem cells in ankylosing spondylitis.","authors":"Bole Zhou, Xinzhe Feng, Changhao Han, Yang Wu, Junjie Qiao, Wenwen Tong, Weidong Xu","doi":"10.1186/s12967-025-06607-y","DOIUrl":"10.1186/s12967-025-06607-y","url":null,"abstract":"<p><strong>Background: </strong>As a member of the family of the YTH domain and a an m6A reader, YTHDF3 is implicated in cancer and inflammatory diseases. However, its function in ankylosing spondylitis (AS)-a chronic inflammatory disease marked by aberrant bone formation-is still mysterious. The research set out to study how YTHDF3 may promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in AS and delineate the underlying mechanism.</p><p><strong>Methods: </strong>BMSCs were separated from AS and healthy controls patients. YTHDF3 expression was manipulated using lentiviral transduction. Alkaline phosphatase (ALP) activity and Alizarin Red staining were utilized to assess osteogenic differentiation. This work employed quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot (WB) analysis, and enzyme-linked immunosorbent assay to determine the expression of osteogenic markers, including RUNX2, SP7, BMP2, and OCN. Furthermore, RNA sequencing (RNA-seq), m6A sequencing (m6A-seq), and RNA immunoprecipitation were performed to identify downstream targets, particularly focusing interleukin 32 (IL32). Additionally, RNA stability assays and fluorescence in situ hybridization were used to evaluate the role of YTHDF3 in stabilizing IL32.</p><p><strong>Results: </strong>YTHDF3 expression was notably increased in AS-BMSCs in comparison with the control group. YTHDF3 overexpression promoted osteogenic differentiation, as shown by the rise in ALP activities, boosted calcium deposition, and upregulation of osteogenic markers. In contrast, the YTHDF3 knockdown inhibited these processes. IL32 was identified as a key downstream target using RNA-seq and m6A-seq, whose mRNA stability was directly regulated by YTHDF3 via m6A modifications. Notably, increased IL32 expression in AS contributed to osteogenesis.</p><p><strong>Conclusion: </strong>YTHDF3 prevents IL32 mRNA degradation and promotes osteogenic differentiation of AS-BMSCs in an m6A-dependent manner. The results shed light on previous questions regarding the molecular mechanisms behind ectopic bone formation in AS, identifying YTHDF3 as a potential therapeutic target for controlling pathological bone formation.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"604"},"PeriodicalIF":6.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironment.","authors":"Stephanie M Wilk, Kihak Lee, Caitlyn C Castillo, Mohamed Haloul, Alexa M Gajda, Virgilia Macias, Elizabeth L Wiley, Zhengjia Chen, Xinyi Liu, Xiaowei Wang, Maria Sverdlov, Kent F Hoskins, Ekrem Emrah Er","doi":"10.1186/s12967-025-06559-3","DOIUrl":"10.1186/s12967-025-06559-3","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic strategies. Myocardin-related transcription factors A and B (MRTFA/B also known as MKL1/2) are two related transcription factors that redundantly control cancer cell invasion and metastasis in mouse models of breast cancer, but their roles in human cancer are incompletely understood. Here, we investigated the expression and activation of these transcription factors to better assess their tumorigenic and metastatic impact on breast cancer and cells of the tumor microenvironment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We used a multiplexed immunofluorescence approach to label MRTFA, MRTFB, tumor cells by using pan Cytokeratin, endothelial cells by using CD31, and antigen presenting cells (APCs) by using HLA-DRA on two different breast cancer tissue microarrays (TMA): The breast cancer progression TMA provided by the Cooperative Human Tissue Network (CHTN_BrCaProg3) and the University of Illinois Breast Cancer Working Group (TMA BCWG UIC-001-TMA) that included primary tumor and lymph node metastases from patients residing in the West Side and South Side of Chicago. We also used bioinformatics analyses of the TCGA and METABRIC databases and the Broad Institute's single-cell RNA sequencing portal to investigate MRTFA/B expression patterns in the cells of the tumor microenvironment (TME).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We found that in human tumors, MRTFA/B are concurrently activated in cancer cells, but they show distinct patterns of expression across different histological subtypes and in the cells of the TME. Importantly, MRTFA expression was elevated in metastatic tumors of African American patients, who disproportionately die from breast cancer. Interestingly, in contrast to publicly available mRNA expression data, MRTFA was similarly expressed across estrogen receptor (ER) positive and negative breast tumors, while MRTFB expression was highest in ER+ breast tumors. Furthermore, MRTFA was specifically expressed in the perivascular antigen-presenting cells (APCs), which has been previously associated with immune suppression and breast cancer progression. We also found that MRTFA expression correlated with the expression of the immune checkpoint protein V-set immunoregulatory receptor (VSIR) in the TCGA data and found that MRTFA activity promotes VSIR expression in THP-1 monocytes and cultured HEK293 cells.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our results provide unique insights into how MRTFA and MRTFB promote metastasis in human cancer, the differences of their expression patterns, and their immune suppressive function within the breast cancer TME. Our results will guide future studies on targeting MRTFA/B transcriptional activity and the resulting immune suppression in breast","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"599"},"PeriodicalIF":6.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA profiling and immunohistochemistry analyses of circRNAs in imatinib-resistant gastrointestinal stromal tumors.","authors":"Hanxing Tong, Ning Jia, Wenyang Li, Jingjing Xu, Qiuyue Li, Xiaomeng He, Huaqin Sun, Christopher Corpe, Jin Wang","doi":"10.1186/s12967-025-06598-w","DOIUrl":"10.1186/s12967-025-06598-w","url":null,"abstract":"<p><strong>Background: </strong>Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal sarcomas of the upper digestive tract. Imatinib is the first-line therapy for patients with metastatic or unresectable GISTs. However, the majority of GIST patients eventually develop imatinib resistance.</p><p><strong>Methods: </strong>To identify the factors that are responsible for imatinib resistance, we investigated the differentially expressed mRNAs and circRNAs in imatinib-naïve and imatinib-resistant GISTs via ceRNA microarrays. The expression levels of circ-BRIP1, circ-EPHB4 and their host genes were validated via quantitative real-time PCR analyses and formalin-fixed and paraffin-embedded (FFPE) tissue microarrays (TMAs).</p><p><strong>Results: </strong>We found that 107 mRNAs and 521 circRNAs were differentially expressed between imatinib-resistant and imatinib-naïve GIST tissue samples. Among them, circ-BRIP1, circ-EPHB4 and their host genes were upregulated in imatinib-resistant GISTs and associated with imatinib resistance, tumor relapse and progression, and metastasis in GIST patients. The expression level of EPHB4 was significantly greater in high-grade GISTs than in low-grade GISTs and was correlated with imatinib resistance.</p><p><strong>Conclusions: </strong>Our results demonstrated that the circRNA in situ hybridization-immunohistochemistry could not only be applied to FFPE-TMAs for high-throughput analysis of circRNA expression in tumors but also suggested a possible role for circ-BRIP1, circ-EPHB4, and their host genes in the progression of GISTs.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"601"},"PeriodicalIF":6.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}