Biology Direct最新文献

{"title":"Prmt1-mediated methylation regulates Ncoa4 stability to transactivate Adamts genes and promote bone extracellular matrix degradation in chronic hematogenous osteomyelitis.","authors":"Xun Chen, Ning Duan, Wentao Zhang, Tao Song, Fei Cong","doi":"10.1186/s13062-025-00652-9","DOIUrl":"https://doi.org/10.1186/s13062-025-00652-9","url":null,"abstract":"<p><strong>Background: </strong>Protein arginine methyltransferases (Prmts) are essential regulators of various biological processes and have been implicated in the pathogenesis of numerous diseases. However, their role in osteomyelitis remains poorly understood.</p><p><strong>Methods: </strong>A mouse model of chronic hematogenous osteomyelitis (CHOM) was established by intravenous inoculation with Staphylococcus aureus (S. aureus). Gene and protein expression levels were quantified using RT-qPCR and immunoblot analysis, respectively. Protein interactions were determined via immunoprecipitation and co-immunoprecipitation assays. In vitro and in vivo assays were employed to evaluate protein methylation and ubiquitination. Bone destruction was assessed through histological staining.</p><p><strong>Results: </strong>Among 9 Prmt members, Prmt1 was the only one significantly upregulated in osteomyelitis-affected mice. Our findings revealed that the inflammatory microenvironment specifically upregulated Prmt1 expression in osteoblasts and osteocytes, which facilitated its interaction with the transcriptional activator Ncoa4 (nuclear receptor coactivator 4) and mediated Ncoa4 arginine methylation, thereby enhancing Ncoa4 protein stability. Methylated Ncoa4 formed a transcriptional complex with the histone acetyltransferase Cbp (CREB-binding protein) and transcription factor Ap1 (Activator protein 1), driving the expression of four Adamts genes (Adamts3/8/12/14) that promoted extracellular matrix (ECM) degradation in osteoblasts and osteocytes. In contrast, depletion or pharmacological inhibition of Prmt1 prevented Ncoa4 methylation upon stimulation with pro-inflammatory cytokines, leading to Ncoa4 ubiquitination by Rnf8 (Ring finger protein 8) E3 ligase and subsequent proteasomal degradation, eventually leading to downregulation of Adamts expression. Importantly, treatment with Prmt1 inhibitors TCE-5003 and MS023 significantly mitigated bone ECM degradation and prevented osteomyelitis progression in S. aureus-infected mice.</p><p><strong>Conclusion: </strong>These findings identify Prmt1 as a pivotal regulator of bone ECM degradation in osteomyelitis through stabilization of Ncoa4 and highlight Prmt1 as a promising therapeutic target for osteomyelitis treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"60"},"PeriodicalIF":5.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidation of short linear motif-based interactions of the MIT and rhodanese domains of the ubiquitin-specific protease 8.","authors":"Aimiliani Konstantinou, Julia K Varga, Alicia Córdova-Pérez, Leandro Simonetti, Lidia Gomez-Lucas, Ora Schueler-Furman, Norman E Davey, Yogesh Kulathu, Ylva Ivarsson","doi":"10.1186/s13062-025-00638-7","DOIUrl":"https://doi.org/10.1186/s13062-025-00638-7","url":null,"abstract":"<p><p>Ubiquitin-specific protease 8 (USP8) is a deubiquitinating enzyme with essential functions in protein trafficking and stability. It is a multidomain protein, with an N-terminal MIT (microtubule interacting and trafficking) domain, followed by a non-catalytic rhodanese (Rhod) domain, a long intrinsically disordered region, and a C-terminal catalytic domain. The N-terminal MIT domain of USP8 is known to mediate protein-protein interactions through binding to short linear motifs. The non-catalytic Rhod domain is also involved in protein-protein interactions, however detailed insights into these interactions remain limited. In this study we explore the short linear motif-based interactions of the MIT and Rhod domains of USP8 using a combination of proteomic peptide-phage display, peptide arrays and deep mutational scanning. We show that the MIT domain can bind ligands with a general [DE][LIF]x{2,3}R[FYIL]xxL[LV] consensus motif. We uncover that the rhodanese domain of USP8 is a peptide-binding domain, and define two distinct binding motifs (Rx[LI]xGxxxPxxL and G[LV][DE][IM]WExKxxxLxE) for this domain by deep mutational scanning of two different peptide ligands. Using the motif information, we predict binding sites within known USP8 interactors and substrates and validate interactions through peptide array analysis. Our findings demonstrate that both the USP8 MIT and rhodanese domains are peptide-binding domains that can be bound by degenerate and distinct binding motifs. The detailed information on the peptide binding preference of the two N-terminal domains of USP8 provide novel insights into the molecular recognition events that underlie the function of this essential deubiquitinating enzyme.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"59"},"PeriodicalIF":5.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of M2 macrophage-related genes associated with diffuse large B-cell lymphoma via bioinformatics and machine learning approaches.","authors":"Jiayi Zhang, Zhixiang Jia, Jiahui Zhang, Xiaohui Mu, Limei Ai","doi":"10.1186/s13062-025-00649-4","DOIUrl":"https://doi.org/10.1186/s13062-025-00649-4","url":null,"abstract":"<p><p>M2 macrophages play a crucial role in the initiation and progression of various tumors, including diffuse large B-cell lymphoma (DLBCL). However, the characterization of M2 macrophage-related genes in DLBCL remains incomplete. In this study, we downloaded DLBCL-related datasets from the Gene Expression Omnibus (GEO) database and identified 77 differentially expressed genes (DEGs) between the control group and the treat group. We assessed the immune cell infiltration using CIBERSORT analysis and identified modules associated with M2 macrophages through weighted gene co-expression network analysis (WGCNA). Using the Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine Recursive Feature Elimination (SVM-RFE), and Random Forest (RF) algorithms, we screened for seven potential diagnostic biomarkers with strong diagnostic capabilities: SMAD3, IL7R, IL18, FAS, CD5, CCR7, and CSF1R. Subsequently, the constructed logistic regression model and nomogram demonstrated robust predictive performance. We further investigated the expression levels, prognostic values, and biological functions of these biomarkers. The results showed that SMAD3, IL7R, IL18, FAS and CD5 were associated with the survival of DLBCL patients and could be used as markers to predict the prognosis of DLBCL. Our study introduces a novel diagnostic strategy and provides new insights into the potential mechanisms underlying DLBCL. However, further validation of the practical value of these genes in DLBCL diagnosis is warranted before clinical application.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"58"},"PeriodicalIF":5.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of IGF2BP2 in macrophage-mediated NLRP3 inflammasome activation in the pathogenesis of dry AMD.","authors":"Yuqing Zhao, Yu Zhang, Junfang Li, Yifei Zhang, Yi Qu","doi":"10.1186/s13062-025-00648-5","DOIUrl":"https://doi.org/10.1186/s13062-025-00648-5","url":null,"abstract":"<p><strong>Background: </strong>Dry age-related macular degeneration (AMD) is a common chronic degenerative eye disease for which there is currently no effective treatment. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is a recently identified m6A reader that binds RNA and maintains its stability, thereby participating in various biological processes. However, its role in dry AMD remains unclear.</p><p><strong>Methods: </strong>In this study, we investigated the role of IGF2BP2 in macrophage NLRP3 inflammasomes using a sodium iodate-induced dry AMD model.</p><p><strong>Results: </strong>Our results demonstrated that IGF2BP2 is highly expressed in the retinal-choroidal tissue induced by sodium iodate, with its effects primarily occurring in macrophages. The loss of IGF2BP2 ameliorating dry AMD. Mechanistically, methylated NLRP3 transcripts were subsequently directly recognized by the specific m 6 A \"reader\", IGF2BP2, to prevent NLRP3 mRNA degradation. Furthermore, in in vivo experiments, to maintain the eye's \"immune privilege\", we employed mesoporous silica-based cell therapy to target and regulate macrophage IGF2BP2, providing a foundation for the evaluation and translation of therapies targeting this gene.</p><p><strong>Conclusion: </strong>our study reveals that the molecular mechanism of dry AMD pathogenesis involves IGF2BP2-mediated NLRP3 inflammasome activation in macrophages, highlighting IGF2BP2 as a promising biomarker and therapeutic target for dry AMD treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"57"},"PeriodicalIF":5.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating machine learning models with multi-omics analysis to decipher the prognostic significance of mitotic catastrophe heterogeneity in bladder cancer.","authors":"Haojie Dai, Zijie Yu, You Zhao, Ke Jiang, Zhenyu Hang, Xin Huang, Hongxiang Ma, Li Wang, Zihao Li, Ming Wu, Jun Fan, Weiping Luo, Chao Qin, Weiwen Zhou, Jun Nie","doi":"10.1186/s13062-025-00650-x","DOIUrl":"https://doi.org/10.1186/s13062-025-00650-x","url":null,"abstract":"<p><strong>Background: </strong>Mitotic catastrophe is well-known as a major pathway of endogenous tumor death, but the prognostic significance of its heterogeneity regarding bladder cancer (BLCA) remains unclear.</p><p><strong>Methods: </strong>Our study focused on digging deeper into the TCGA and GEO databases. Through differential expression analysis as well as Weighted Gene Co-expression Network Analysis (WGCNA), we identified dysregulated mitotic catastrophe-associated genes, followed by univariate cox regression as well as ten machine learning algorithms to construct robust prognostic models. Based on prognostic stratification, we revealed intergroup differences by enrichment analysis, immune infiltration assessment, and genomic variant analysis. Subsequently by multivariate cox regression as well as survshap(t) model we screened core prognostic gene and identified it by Mendelian randomization. Integration of qRT-PCR, immunohistochemistry, and single-cell analysis explored the core gene expression landscape. In addition, we explored the ceRNA axis containing upstream non-coding RNAs after detailed analysis of pathway activation, immunoregulation, and methylation functions of the core genes. Finally, we performed drug screening and molecular docking experiments based on the core gene in the DSigDB database.</p><p><strong>Results: </strong>Our efforts culminated in the establishment of an accurate prognostic model containing 16 genes based on Coxboost as well as the Random Survival Forest (RSF) algorithm. Detailed analysis from multiple perspectives revealed a strong link between model scores and many key indicators: pathway activation, immune infiltration landscape, genomic variant landscape, and personalized treatment. Subsequently ANLN was identified as the core of the model, and prognostic analysis revealed that it portends a poor prognosis, further corroborated by Mendelian randomization analysis. Interestingly, ANLN expression was significantly upregulated in cancer cells and specifically clustered in epithelial cells and provided multiple pathways to mediate cell division. In addition, ANLN regulated immune infiltration patterns and was also inseparable from overall methylation levels. Further analysis revealed potential regulation of the MIR4435-2HG, hsa-miR-15a-5p, ANLN axis and highlighted a range of potential therapeutic agents including Phytoestrogens.</p><p><strong>Conclusion: </strong>The model we developed was a powerful predictive tool for BLCA prognosis and revealed the impact of mitotic catastrophe heterogeneity on BLCA in multiple dimensions, which then guided clinical decision-making. Furthermore, we highlighted the potential of ANLN as a BLCA target.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"56"},"PeriodicalIF":5.7,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gliadin-dependent UPR induction directly triggers the expression of TG2 and pro-inflammatory cytokines, dysregulates intestinal permeability, and reduces CFTR expression in intestinal epithelial cells of celiac disease patients.","authors":"Romina Monzani, Mara Gagliardi, Valentina Saverio, Nausicaa Clemente, Alice Monzani, Ivana Rabbone, Francesca Nigrelli, Samuele Pellizzaro, Emanuele Ferrario, Silvia Saettone, Nico Pagano, Luigina De Leo, Dmitry Lim, Daniele Sblattero, Marco Corazzari","doi":"10.1186/s13062-025-00644-9","DOIUrl":"https://doi.org/10.1186/s13062-025-00644-9","url":null,"abstract":"<p><strong>Background: </strong>Celiac disease (CD) is an autoimmune disorder that primarily affects the gut of genetically predisposed individuals and is triggered by gliadin peptides (PT) produced by the digestion of gluten. Although inappropriate activation of the immune system is thought to be the main trigger of CD, the interaction between PT and intestinal epithelial cells (IECs) remains a key step. Recently, the possible involvement of ER stress in the pathogenesis of CD has been pointed out, although its role is still largely unclear. Therefore, discovering the molecular mechanism(s) activated in IECs exposed to PT represents a unique opportunity to better understand the disease and define new potential therapeutic targets.</p><p><strong>Methods: </strong>In this study we used three different experimental set-ups: intestinal biopsies from CD patients and non-CD control subjects, an in vitro model, based on human CaCo-2 cells, and an ex vivo model, based on our recently described mouse gut-ex-vivo system (GEVS), with the latter two systems were studied after stimulation with gliadin peptides (PT). To understand the signaling pathways involved we monitor the expression of a number of proteins by qPCR, Western blotting, IF, ELISA or a combination of tests. Specifically, we have analyzed the level of CD, ER stress, tissue permeability, and inflammation markers.</p><p><strong>Results: </strong>Indeed, our study demonstrated a prompt induction of the transcription factors ATF4, ATF6 and XBP1 in IECs upon PT exposure. Thus, the upregulation of TG2 and downregulation of CFTR were prevented by ER stress inhibition/buffering by a pharmacological chaperone, also leading to restored physiological expression of OCL, CLD-2 and CLD-15, while preventing the expression of IFNγ, IL-15 and IL-17 A.</p><p><strong>Conclusion: </strong>Overall, our analysis has highlighted the key role of ER stress in the pathogenesis of CD and identified the chemical chaperones as a new potential valuable therapeutic treatment for CD patients.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"55"},"PeriodicalIF":5.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12007252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"L-741626 inhibits hepatocellular carcinoma progression by targeting Ref-1 to suppress MAPK/ERK signalling pathway activity.","authors":"Shuiling Jin, Qi Zhao, Xiao Sun, Jinsong Su, Peiwen Wang, Peixian Li, Jing Guo, Yibing Zhang, Hong Zong, Xiaoli Gan","doi":"10.1186/s13062-025-00624-z","DOIUrl":"https://doi.org/10.1186/s13062-025-00624-z","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a common and challenging malignancy of the digestive tract. Unfortunately, patients with advanced HCC frequently experience limited long-term benefits from current treatments, highlighting the critical need for innovative therapeutic agents. The discovery and development of new small-molecule compounds that target tumours have become crucial aspects of cancer research. In this study, we report on L-741626, a compound that has significant inhibitory effects on HCC. Both in vivo and in vitro experiments confirmed that L-741626 inhibited the growth of HCC by suppressing the MAPK/ERK signalling pathway. Molecular docking simulations and drug affinity responsive target stability assays further identified redox Factor 1 (Ref-1) as a target of L-741626. Ref-1 is overexpressed in HCC and is correlated with poor prognosis and high stage. Further studies demonstrated that Ref-1 interacts with CRAF, a crucial component of the MAPK/ERK signalling pathway. Knockdown of Ref-1 in HCC cells led to inhibition of the MAPK/ERK pathway. Sorafenib is a well-established targeted therapy for the treatment of HCC, with its primary antitumor mechanism being the inhibition of the MAPK/ERK signalling pathway. However, the presence of tumor stem cells is a key factor contributing to resistance to sorafenib. Our study demonstrates that L-741626 can suppress tumor stemness in HCC. The combination of L-741626 and sorafenib significantly enhances the sensitivity of HCC, resulting in increased tumoricidal effects. Our findings reveal a novel pharmacological effect of L-741626, which inhibits MAPK/ERK signalling activity in HCC by targeting Ref-1. Furthermore, L-741626 exhibits a synergistic effect when combined with sorafenib, suggesting a new potential approach for HCC treatment.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"54"},"PeriodicalIF":5.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AQP5 trafficking is regulated by its C-terminal tail and interaction with prolactin-inducible protein.","authors":"Claudia D'Agostino, Egor Zindy, Louise Conrard, Amel Takkal, Françoise Gregoire, Nargis Bolaky, Susanna Törnroth-Horsefield, Jason Perret, Christine Delporte","doi":"10.1186/s13062-025-00647-6","DOIUrl":"https://doi.org/10.1186/s13062-025-00647-6","url":null,"abstract":"<p><strong>Background: </strong>Aquaporin-5 (AQP5) is a crucial membrane protein involved in water transport across cellular membranes, particularly within exocrine glands such as salivary glands. Dysregulation of AQP5, including its mislocalization, has been associated with various diseases, emphasizing the need to understand the molecular mechanisms governing its trafficking. This study investigates the multifaceted regulatory mechanisms of AQP5 trafficking, with specific emphasis on the role of the carboxyl-terminal (C-terminal) tail and the functional involvement of prolactin-inducible protein (PIP) as an interacting protein partner.</p><p><strong>Methods: </strong>An innovative 2D-custom model employing SNAP-tag human AQP5 constructs together with a novel automated algorithm-based methodology was used following immunofluorescence and confocal microscopy to assess hAQP5 localization to the plasma membrane of stably transfected normal salivary gland-SV40 transformed-acinar cells (NS-SV-AC). The expression of the constructs was verified by Western blot analysis.</p><p><strong>Results: </strong>The expression of SNAP-hAQP5 constructs expressed in stably transfected NS-SV-AC cells allowed to explore the involvement of hAQP5 C-terminal tail and the hAQP5-hPIP interaction in hAQP5 trafficking upon stimulation. The use of C-terminal truncation constructs revealed distinct responses to intracellular 3',5'-cyclic adenosine monophosphate (cAMP) and calcium increase, shedding light on the importance of specific regions within the highly flexible distal part of the C-terminal tail for AQP5 trafficking. Furthermore, our investigation of the interplay between hAQP5 and hPIP revealed that PIP promotes AQP5 translocation to the plasma membrane, blunting the effects of calcium- and cAMP-dependent pathways on AQP5 sub-cellular localization.</p><p><strong>Conclusion: </strong>In summary, this study advances our understanding of AQP5 trafficking dynamics and provides critical insights into the regulatory roles of the C-terminal tail and its interaction with PIP. The innovative methodology to assess AQP5 translocation to the plasma membrane sets the stage for future investigations to identify the role of individual amino acids and phosphorylation sites within the distal AQP5 C-terminus in the trafficking mechanism and protein-protein interaction, and to explore the dynamic of the process by high resolution live cell imaging. Further research in this area is warranted to uncover critical insights into the regulation of AQP5, offering opportunities for the development of innovative therapeutic strategies.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"53"},"PeriodicalIF":5.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colon cancer exosome-associated HSP90B1 initiates pre-metastatic niche formation in the liver by polarizing M1 macrophage into M2 phenotype.","authors":"ShuJie Li, Xue Fu, Deng Ning, QiuMeng Liu, JunFang Zhao, Qi Cheng, XiaoPing Chen, Li Jiang","doi":"10.1186/s13062-025-00623-0","DOIUrl":"https://doi.org/10.1186/s13062-025-00623-0","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) frequently metastasizes to the liver, worsening patient outcomes. The formation of a pre-metastatic niche (PMN) is essential for this process, but how the primary colon tumor orchestrates the PMN formation remains unclear.</p><p><strong>Methods: </strong>This study investigated the role of CRC-derived exosomes using CT-26 murine colon carcinoma cells. The effects of these exosomes on immune cells, specifically M1 macrophage polarization and CD8 + T cell viability, were assessed. HSP90B1 expression in CT-26-derived exosomes was analyzed to understand its contribution to PMN formation. HSP90B1 silencing experiments were conducted to evaluate its impact on immunosuppressive PMN creation and liver metastasis. Patient blood samples were also examined to correlate exosomal HSP90B1 levels with CRC progression.</p><p><strong>Results: </strong>Exosomes from CT-26 cells were found to polarize M1 macrophages into an M2 phenotype and decrease CD8 + T cell viability, promoting liver metastasis. High expression of HSP90B1 in CT-26 cell-derived exosomes was identified as a key factor in inducing M2 macrophage polarization and creating an immunosuppressive PMN. Silencing HSP90B1 significantly inhibited the exosome-mediated formation of the immunosuppressive PMN and reduced liver metastasis. Furthermore, elevated levels of HSP90B1 in patient-derived exosomes were associated with advanced CRC and poorer prognosis.</p><p><strong>Conclusions: </strong>CRC-derived exosomes promote liver metastasis by forming an immunosuppressive PMN through HSP90B1. Targeting HSP90B1 in CRC exosomes may offer a new therapeutic strategy to prevent liver metastasis and improve patient outcomes.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"52"},"PeriodicalIF":5.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipidome atlas of p53 mutant variants in pancreatic cancer.","authors":"Kian Cotton, Charley Comer, Sabrina Caporali, Alessio Butera, Stephanie Gurres, Francesco Capradossi, Angelo D'Alessandro, Ivano Amelio, Maria Victoria Niklison-Chirou","doi":"10.1186/s13062-025-00635-w","DOIUrl":"https://doi.org/10.1186/s13062-025-00635-w","url":null,"abstract":"<p><p>Mutations in the tumour suppressor protein p53 are present in 70% of human pancreatic ductal adenocarcinomas (PDAC), subsequently to highly common activation mutation of the oncogene KRAS. These p53 mutations generate stable expression of mutant proteins, such as p53^R175H and p53^R273H, which do not retain p53 wild type function. In this study, we investigated the impact of two specific p53 mutant variants on lipid metabolism of pancreatic cancer. Lipids critically participate to tumorigenesis with to their roles in membrane biosynthesis, energy storage and production of signalling molecules. Using cell lines derived from mouse models of PDAC generated by knock-in p53 alleles carrying point mutations at codons R172H and R270H (equivalent to R175H and R273H in humans), we found that silencing p53^R172H and p53^R270H in pancreatic cancer cells significantly alters lipid metabolism, with patterns of common and variant specific changes. Specifically, loss of p53^R172H in these cells reduces lipid storage. Additionally, silencing either p53^R172H or p53^R270H individually leads to marked increases in lysophospholipid levels. These findings offer new insights into the lipidome reprogramming induced by the loss of mutant p53 and underscore changes in lipid storage as a potential key molecular mechanism in PDAC pathogenesis.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":"20 1","pages":"51"},"PeriodicalIF":5.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11992884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}