Experimental cell research最新文献

{"title":"Small leucine zipper protein negatively regulates liver fibrosis by suppressing the expression of plasminogen activator inhibitor-1","authors":"Hyeryung Kang ,&nbsp;Suhyun Kim ,&nbsp;Sungyeon Park ,&nbsp;Sila Han,&nbsp;Minsoo Kang,&nbsp;Sujin Kwon,&nbsp;Jesang Ko","doi":"10.1016/j.yexcr.2024.114258","DOIUrl":"10.1016/j.yexcr.2024.114258","url":null,"abstract":"<div><div>Liver fibrosis, which is caused by viral infection, toxic exposure, and autoimmune diseases, is a chronic liver disease. Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor of tissue-type plasminogen activator (tPA) and urokinase plasminogen activator, which convert plasminogen into plasmin. Therefore, PAI-1 suppresses fibrinolysis by blocking plasmin synthesis and is involved in liver fibrosis via extracellular matrix deposition. Small leucine zipper protein (sLZIP) acts as a transcription factor and plays critical roles in many cellular processes. However, the role of sLZIP in liver fibrosis remains unclear. In this study, we investigated the role of sLZIP in regulating PAI-1 transcription and liver fibrosis. sLZIP knockdown enhanced the expression of PAI-1 at the mRNA and protein levels. sLZIP knockdown also increased PAI-1 secretion and suppressed blood clot lysis by blocking tPA activity. Moreover, conditioned medium derived from sLZIP knockdown cells downregulated the expression of matrix metalloprotease (MMP)-2 and MMP-9 in the presence of tPA in hepatic stellate cells (HSCs). Liver-specific sLZIP knockout mice showed deteriorated liver fibrosis compared to control mice in a bile duct ligation-induced fibrosis model. These findings demonstrate that sLZIP functions as a negative regulator of liver fibrosis by suppressing PAI-1 transcription and HSC activation.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114258"},"PeriodicalIF":3.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMGA1 stimulates cancer stem-like features and sensitivity to monensin in gastric cancer","authors":"Diana Pádua ,&nbsp;Paula Figueira ,&nbsp;António Pombinho ,&nbsp;Inês Monteiro ,&nbsp;Carlos Filipe Pereira ,&nbsp;Raquel Almeida ,&nbsp;Patrícia Mesquita","doi":"10.1016/j.yexcr.2024.114257","DOIUrl":"10.1016/j.yexcr.2024.114257","url":null,"abstract":"<div><p>Gastric cancer represents a serious health problem worldwide, with insufficient molecular biomarkers and therapeutic options. Consequently, several efforts have been directed towards finding specific disease markers in order to develop new therapies capable of defeating gastric cancer. Attention has been pointed to cancer stem cells (CSCs) as they are primarily responsible for tumor initiation and recurrence, making them essential therapeutic targets. Using the SORE6-GFP reporter system, based on the expression of SOX2 and/or OCT4 to drive GFP expression, we isolated gastric cancer stem-like cells (SORE6+ cells) enriched in several molecules, including SOX2, C-MYC, KLF4, HIF-1α, NOTCH1 and HMGA1. Here, we explored the previously undisclosed link of HMGA1 with gastric CSCs. Our results indicated that HMGA1 can activate a transcriptional program that includes SOX2, C-MYC, and KLF4 and endows cells with CSC features. We further showed that chemical induction of gastric CSCs using ciclopirox (CPX) can be mediated by HMGA1. Finally, we showed that HMGA1 GFP+ cells were sensitive to monensin confirming the selective activity of this drug over CSCs. Thus, HMGA1 is a key player in the cellular reprogramming of gastric non-CSCs to cancer stem-like cells.</p></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114257"},"PeriodicalIF":3.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014482724003483/pdfft?md5=c82bf770a387203534a2debdcd6d8f43&pid=1-s2.0-S0014482724003483-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142241595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipoxin A4 modulates the PKA/CREB and NF-κB signaling pathway to mitigate chondrocyte catabolism and apoptosis in temporomandibular joint osteoarthritis","authors":"Palati Tuerxun ,&nbsp;Takkun Ng ,&nbsp;Jiadong Sun ,&nbsp;Farong Ou ,&nbsp;Xiaoshi Jia ,&nbsp;Ke Zhao ,&nbsp;Ping Zhu","doi":"10.1016/j.yexcr.2024.114249","DOIUrl":"10.1016/j.yexcr.2024.114249","url":null,"abstract":"<div><p>Temporomandibular joint osteoarthritis (TMJ-OA) is characterized by the degradation of the extracellular matrix (ECM) in cartilage and the apoptosis of chondrocytes, which is caused by inflammation and disruptions of chondrocyte metabolism and inflammation. Lipoxin A4 (LXA4), a specialized pro-resolving mediator, has been shown to inhibit inflammation and regulate the balance between ECM synthesis and degradation. However, the therapeutic effects of LXA4 on TMJ-OA and its underlying mechanisms remain unclear. Interleukin-1 beta (IL-1β)-induced chondrocyte and surgically induced TMJ-OA rat models were established in this study. The viability of chondrocytes treated with LXA4 was evaluated with the cell counting kit-8 (CCK-8) assay, while protein levels were assessed by western blot analysis, and the apoptosis rate was evaluated with terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) staining. Histological analysis was conducted to evaluate the impact of LXA4 on cartilage degradation in TMJ-OA rat models. In vitro, the qRT-PCR and western blot analysis demonstrated that LXA4 facilitated the upregulation of collagen proteins (Collagen II) and decreased expression of matrix metalloproteinases (MMP-3, and MMP-13) associated with ECM modulation. LXA4 enhanced the TMJ-OA chondrocyte viability and decreased apoptotic rate. In vivo, histology and immunohistochemistry (IHC) analysis revealed that intraperitoneal injection of LXA4 contributed to the amelioration of chondrocyte injuries and deceleration of TMJ-OA. Transcriptomic sequencing revealed that cAMP signaling pathway was up-regulated and NF-κB signaling pathway was down-regulated in LXA4 treated group. LXA4 inhibited the phosphorylation of P65 and inhibitor of nuclear factor kappa B (IκBα) proteins while enhancing the phosphorylation PKA and CREB. This study demonstrates the potential of LXA4 as a therapeutic agent for suppressing chondrocyte catabolism and apoptosis by increasing PKA/CREB activity and decreasing NF-κB signaling.</p></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114249"},"PeriodicalIF":3.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SOX9 promotes hypoxic pulmonary hypertension through stabilization of DPP4 in pulmonary artery smooth muscle cells","authors":"Yan-Zi Guo ,&nbsp;Han-Yu Cui ,&nbsp;Ming-Yuan Cai ,&nbsp;Di Wang ,&nbsp;Wei-Ping Deng ,&nbsp;Chang-Ping Hu","doi":"10.1016/j.yexcr.2024.114254","DOIUrl":"10.1016/j.yexcr.2024.114254","url":null,"abstract":"<div><p>Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling (PVR), primarily due to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This study aimed to investigate the role and molecular mechanism of SOX9 in hypoxic PH in rats. The findings revealed that SOX9 was upregulated in the pulmonary arteries and PASMCs of hypoxia-exposed rats. SOX9 knockdown inhibited hypoxia-induced proliferation and migration of PASMCs, reduced PVR, and subsequently alleviated hypoxia-induced PH in rats, suggesting that SOX9 plays a critical role in PH. Further investigation demonstrated that SOX9 interacted with DPP4, preventing its ubiquitin degradation in hypoxia-exposed PASMCs. DPP4 knockdown inhibited hypoxia-induced PASMC proliferation and migration, and administration of the DPP4 inhibitor sitagliptin (5 mg/kg) significantly reduced PVR and alleviated hypoxia-induced PH in rats, indicating that SOX9 contributes to PH by stabilizing DPP4. The results also showed that hypoxia induced YAP1 expression and dephosphorylation, leading to YAP1 nuclear localization. YAP1 knockdown promoted the degradation of HIF-1α in hypoxia-exposed PASMCs and inhibited hypoxia-induced proliferation and migration of PASMCs. Additionally, HIF-1α, as a transcription factor, promoted SOX9 expression by binding to the SOX9 promoter in hypoxia-exposed PASMCs. In conclusion, hypoxia promotes the proliferation and migration of PASMCs through the regulation of the YAP1/HIF-1α/SOX9/DPP4 signaling pathway, leading to PH in rats. These findings suggest that SOX9 may serve as a potential prognostic marker and therapeutic target for PH.</p></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114254"},"PeriodicalIF":3.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PANoptosis is a prominent cell death feature in thoracic aortic aneurysm or dissection","authors":"Xu Xu ,&nbsp;Yaxin Zhu ,&nbsp;Yuting Niu ,&nbsp;Yufei Chen ,&nbsp;Siyang Fan ,&nbsp;Dingkun Lu ,&nbsp;Ruixia Xu ,&nbsp;Xiaohan Fan","doi":"10.1016/j.yexcr.2024.114247","DOIUrl":"10.1016/j.yexcr.2024.114247","url":null,"abstract":"<div><p>Thoracic aortic aneurysm and dissection (TAAD) is a devastating macrovascular disease, and its pathogenic mechanisms have not been well clarified. This study aimed to investigate the role of PANoptosis, which is newly defined programmed cell death (PCD) and characterized by pyroptosis, apoptosis, and necroptosis, in the pathogenesis of TAAD. We found that the expression of initiator factor Z-DNA binding protein 1 (ZBP1) and PANoptosis-related genes were upregulated in the β-aminopropionitrile (BAPN) + Angiotensin II (Ang II)-induced TAAD mice. Ang II stimuli enhanced the expression of ZBP1, promoted the generation of bioactive GSDMD (Gasdermin D) fragments, the cleavage of Caspase 3, and increased the phosphorylation of mixed lineage kinase domain-like pseudokinase (MLKL) in human aortic vascular smooth muscle cells (HASMCs), indicating the activation of hallmarks for PANoptosis. Moreover, ZBP1-mediated PANoptosis occurs in the aortic tissues of TAAD patients. These results highlight the significant role of PANoptosis in TAAD pathogenesis, suggesting ZBP1 and other PANoptosis-related genes as potential therapeutic targets for this condition.</p></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114247"},"PeriodicalIF":3.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142241594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT1 mediates the inflammatory response of macrophages and regulates the TIMP3/ADAM17 pathway in atherosclerosis","authors":"Dong Jia ,&nbsp;Wei Ping ,&nbsp;Meng Wang ,&nbsp;Dan Wang ,&nbsp;Liguo Zhang ,&nbsp;Yang Cao","doi":"10.1016/j.yexcr.2024.114253","DOIUrl":"10.1016/j.yexcr.2024.114253","url":null,"abstract":"<div><h3>Objective</h3><p>Macrophage polarization and the resulting phenotype have versatile roles in atherosclerosis. The study aims to decipher the role of SIRT1 in regulating macrophage phenotypes and atherosclerosis development.</p></div><div><h3>Methods</h3><p>Two mouse lines of SIRT1^△Mac/ApoE^−/− and SIRT1^fl/fl/ApoE^−/− were fed with high-fat diet to generate atherosclerotic lesion. Mouse peritoneal macrophages were isolated and transfected with SIRT1-overexpressing vector or vector-null.</p></div><div><h3>Results</h3><p>The SIRT1^△Mac/ApoE^−/− mice exhibited greater atherosclerotic lesions, stronger immunofluorescence staining for M1-like macrophage marker, iNOS, and weaker immunofluorescence staining for M2-like macrophage marker, Arginase-1, than the SIRT1^fl/fl/ApoE^−/− littermates. The gene expressions of M1 markers (IL-1β, IL-6, and iNOS) were increased and those of M2 markers (IL-10 and Arg-1) decreased in both aortic roots and peritoneal macrophages from SIRT1^△Mac/ApoE^−/− mice, whereas SIRT1 overexpression rectified the changes in M1/M2 expression. A declined expression of TIMP3 with an increased expression of ADAM17 was noted in SIRT1^△Mac/ApoE^−/− macrophages, whereas SIRT1 overexpression rescued TIMP3 expression and inhibited ADAM17 expression.</p></div><div><h3>Conclusion</h3><p>Our data suggest that SIRT1 deficiency may promote macrophage M1 polarization and regulate the TIMP3/ADAM17 pathway thus favoring atherosclerosis development, indicating an anti-atherosclerotic role of macrophage SIRT1.</p></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114253"},"PeriodicalIF":3.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014482724003446/pdfft?md5=b42bd5c50c1aa66c5a76ffc605a111d2&pid=1-s2.0-S0014482724003446-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAM83D promotes the progression of 4NQO-induced esophageal carcinoma via inhibiting FBWX7","authors":"Jinjin Li ,&nbsp;Jianbing Tian ,&nbsp;Ming Ma ,&nbsp;Zhiruo Qin ,&nbsp;Bingji Cao ,&nbsp;Jiangshuo Yang ,&nbsp;Xuexiao Wang ,&nbsp;Xingxiao Yang","doi":"10.1016/j.yexcr.2024.114252","DOIUrl":"10.1016/j.yexcr.2024.114252","url":null,"abstract":"<div><p>The present study aimed to explore the expression and regulatory role of FAM83D in the different developmental stages of esophageal squamous cell carcinoma (ESCC) to determine the effect of FAM83D on the proliferation, migration, and invasion of ESCC cells and to elucidate its underlying molecular mechanism. Immunohistochemistry (IHC) analysis revealed that the expression of FAM83D was obviously elevated in ESCC tissues compared to adjacent normal tissues. Furthermore, the FAM83D levels was positively correlated with tumor size, TNM stage, T stage, and N stage, while it was negatively correlated with FBXW7 expression, Karnofsky Performance Status (KPS) score, and survival rate. Subsequently, ESCC cell lines with low FAM83D expression were constructed using RNA interference technology to investigate the impact of FAM83D on the biological behavior of ESCC cells. Silencing of FAM83D inhibited the proliferation and migration of ESCC cells but promoted apoptosis. Furthermore, a reduction in FAM83D expression may also induce cell cycle arrest at the G0/G1 phase and regulate the expression of proteins related to epithelial-mesenchymal transition (EMT), the cell cycle, and apoptosis. Further research indicated that silencing FAM83D led to the upregulation of FBXW7 expression. These results suggested that FAM83D may exert its effects on ESCC by downregulating FBXW7. Additionally, using a 4NQO solution in the drinking water to establish an ESCC mouse model, IHC analysis revealed that FAM83D expression levels were positively correlated with the pathological grade of esophageal lesions in the mice and negatively correlated with the expression levels of FBXW7 and E-cadherin. The above results demonstrated that FAM83D may facilitate the progression of ESCC by negatively regulating FBXW7 expression and that FAM83D could represent a promising therapeutic target for ESCC.</p></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114252"},"PeriodicalIF":3.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking Trehalose's versatility: A comprehensive Journey from biosynthesis to therapeutic applications","authors":"Amandeep Kaur,&nbsp;Sukhwinder Singh,&nbsp;Sukesh Chander Sharma","doi":"10.1016/j.yexcr.2024.114250","DOIUrl":"10.1016/j.yexcr.2024.114250","url":null,"abstract":"<div><p>For over forty years, a sugar of rare configuration known as trehalose (two molecules of glucose linked at their 1-carbons), has been recognised for more than just its roles as a storage compound. The ability of trehalose to protect an extensive range of biological materials, for instance cell lines, tissues, proteins and DNA, has sparked considerable interest in the biotechnology and pharmaceutical industries. Currently, trehalose is now being investigated as a promising therapeutic candidate for human use, as it has shown potential to reduce disease severity in various experimental models. Despite its diverse biological effects, the precise mechanism underlying this observation remain unclear. Therefore, this review delves into the significance of trehalose biosynthesis pathway in the development of novel drug, investigates the inhibitors of trehalose synthesis and evaluates the binding efficiency of T6P with TPS1. Additionally, it also emphasizes the knowledge about the protective effect of trehalose on modulation of autophagy, combating viral infections, addressing the conditions like cancer and neurodegenerative diseases based on the recent advancement. Furthermore, review also highlight the trehalose's emerging role as a surfactant in delivering monoclonal antibodies that will further broadening its potential application in biomedicines.</p></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114250"},"PeriodicalIF":3.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142172572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired incorporation of fibronectin into the extracellular matrix during aging exacerbates the senescent state of dermal cells","authors":"Luce Perié ,&nbsp;Cynthia Houël ,&nbsp;Anne Zambon ,&nbsp;Christelle Guere ,&nbsp;Katell Vié ,&nbsp;Johanne Leroy-Dudal ,&nbsp;Charlotte Vendrely ,&nbsp;Rémy Agniel ,&nbsp;Franck Carreiras ,&nbsp;Cédric R. Picot","doi":"10.1016/j.yexcr.2024.114251","DOIUrl":"10.1016/j.yexcr.2024.114251","url":null,"abstract":"<div><p>Fibronectin (Fn) is a ubiquitous extracellular matrix (ECM) glycoprotein that acts as an ECM scaffold organizer and is essential in many biological functions, including tissue repair, differentiation or cancer dissemination. Evidence suggests that the amount of Fn changes during aging. However, how these changes influence the aging process remains unclear. This study aims to understand Fn influence on cell aging. First, we assess the relative level of Fn abundance in both different biopsies of skin donors and replicative senescence cellular model. In skin biopsies, we observed that Fn level decreases with aging in the reticular dermis, while its expression remains relatively stable in the papillary dermis, likely to sustain the dermis-epidermis junction. During replicative senescence, in BJ skin fibroblasts, while intracellular Fn increases, we found that secretion and Fn fibrils formation are less effective. Reduced Fn fibrils leads to disorganization of the ECM. This could be explained by the expression of different Fn isoforms observed in the secretome of senescent cells. Surprisingly, the knockdown of Fn delays the onset of senescence while cultivating cells onto a Fn-coated support promotes it. Taken together, these new insights on the role of Fn during aging may emerge new therapeutic strategies on aged-related diseases.</p></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114251"},"PeriodicalIF":3.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomal miR-155-5p drives ibrutinib resistance in B-cell lymphoma","authors":"Bon Park ,&nbsp;Myung Eun Choi ,&nbsp;Kyung Ju Ryu ,&nbsp;Chaehwa Park ,&nbsp;Minki Choi ,&nbsp;Sang Eun Yoon ,&nbsp;Won Seog Kim ,&nbsp;Hyeon Ho Kim ,&nbsp;Jung Yong Hong ,&nbsp;Seok Jin Kim","doi":"10.1016/j.yexcr.2024.114248","DOIUrl":"10.1016/j.yexcr.2024.114248","url":null,"abstract":"<div><p>Ibrutinib, a Bruton Tyrosine Kinase (BTK) inhibitor, has shown effectiveness against various B-cell lymphoid malignancies. However, prolonged usage can induce resistance, affecting treatment outcomes. The oncogenic microRNA, miR-155-5p, is associated with poor prognosis in B-cell lymphomas, prompting our investigation into the mechanism of acquired ibrutinib resistance in these cells. We generated ibrutinib-resistant OCI-Ly1 cells (OCI-Ly1-IbtR) through continuous exposure to 1 μM and 2 μM of ibrutinib. We conducted microRNA profiling of OCI-Ly1-IbtR and isolated exosomes via ultracentrifugation. Comparative studies of microRNA levels in cells and exosomes, as well as exploration of targets of up-regulated microRNAs in OCI-Ly1-IbtR, were performed. Target validation involved transfection of candidate microRNAs, and co-culture experiments utilized OCI-Ly1 cells with exosomes from OCI-Ly1-IbtR. Elevated levels of miR-155-5p were observed in OCI-Ly1-IbtR and its exosomes, correlating with AKT and NF-κB activation. Transfection of miR-155-5p induced AKT/NF-κB pathway activation in OCI-Ly1, resulting in ibrutinib resistance, enhanced colony formation, and sustained BTK activity. Primary cell lines from ibrutinib-refractory B-cell lymphoma patients exhibited similar signaling protein activation. Target evaluation identified KDM5B and DEPTOR as miR-155-5p targets, confirmed by downregulation after transfection. We observed KDM5B and DEPTOR enrichment in Ago2 during ibrutinib resistance and miR-155-5p transfection. Co-culture experiments demonstrated exosome-mediated transfer of miR-155-5p, inducing ibrutinib resistance and KDM5B/DEPTOR downregulation in OCI-Ly1. Our findings suggest that miR-155-5p overexpression is associated with AKT and NF-κB pathway activation in ibrutinib-resistant cells, proposing a potential role for acquired miR-155-5p upregulation in B-cell lymphoma ibrutinib resistance.</p></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"442 2","pages":"Article 114248"},"PeriodicalIF":3.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}