Cell Communication and Signaling最新文献

{"title":"PD-1 interactome in osteosarcoma: identification of a novel PD-1/AXL interaction conserved between humans and dogs.","authors":"Katarzyna Dziubek, Jakub Faktor, Kiran Bharat Lokhande, Ashish Shrivastava, Ines Papak, Elzbieta Chrusciel, Magdalena Pilch, Theodore Hupp, Natalia Marek-Trzonkowska, Ashutosh Singh, Maciej Parys, Sachin Kote","doi":"10.1186/s12964-024-01935-w","DOIUrl":"10.1186/s12964-024-01935-w","url":null,"abstract":"<p><p>The PD-1/PDL-1 immune checkpoint inhibitors revolutionized cancer treatment, yet osteosarcoma remains a therapeutic challenge. In some types of cancer, PD-1 receptor is not solely expressed by immune cells but also by cancer cells, acting either as a tumor suppressor or promoter. While well-characterized in immune cells, little is known about the role and interactome of the PD-1 pathway in cancer. We investigated PD-1 expression in human osteosarcoma cells and studied PD-1 protein-protein interactions in cancer. Using U2OS cells as a model, we confirmed PD-1 expression by western blotting and characterized its intracellular as well as surface localization through flow cytometry and immunofluorescence. High-throughput analysis of PD-1 interacting proteins was performed using a pull-down assay and quantitative mass spectrometry proteomic analysis. For validation and molecular modeling, we selected tyrosine kinase receptor AXL-a recently reported cancer therapeutic target. We confirmed the PD-1/AXL interaction by immunoblotting and proximity ligation assay (PLA). Molecular dynamics (MD) simulations uncovered binding affinities and domain-specific interactions between extracellular (ECD) and intracellular (ICD) domains of PD-1 and AXL. ECD complexes exhibited strong binding affinity, further increasing for the ICD complexes, emphasizing the role of ICDs in the interaction. PD-1 phosphorylation mutant variants (Y223F and Y248F) did not disrupt the interaction but displayed varying strengths and binding affinities. Using bemcentinib, a selective AXL inhibitor, we observed reduced binding affinity in the PD-1/AXL interaction, although it was not abrogated. To facilitate the future translation of this finding into clinical application, we sought to validate the interaction in canine osteosarcoma. Osteosarcoma spontaneously occurs at significantly higher frequency in dogs and shares close genetic and pathological similarities with humans. We confirmed endogenous expression of PD-1 and AXL in canine osteosarcoma cells, with PD-1/AXL interaction preserved in the dog cells. Also, the interacting residues remain conserved in both species, indicating an important biological function of the interaction. Our study shed light on the molecular basis of the PD-1/AXL interaction with the implication for its conservation across species, providing a foundation for future research aimed at improving immunotherapy strategies and developing novel therapeutic approaches.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"605"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856957","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":"Platelet-derived extracellular vesicles induced through different activation pathways drive melanoma progression by functional and transcriptional changes.","authors":"Zeynep Tavukcuoglu, Umar Butt, Alessandra V Sousa de Faria, Johannes Oesterreicher, Wolfgang Holnthoner, Saara Laitinen, Mari Palviainen, Pia R-M Siljander","doi":"10.1186/s12964-024-01973-4","DOIUrl":"10.1186/s12964-024-01973-4","url":null,"abstract":"<p><strong>Background: </strong>Beyond their conventional roles in hemostasis and wound healing, platelets have been shown to facilitate hematogenous metastasis by interacting with cancer cells. Depending on the activation route, platelets also generate different platelet-derived extracellular vesicles (PEVs) that may educate cancer cells in the circulation or within the tumor microenvironment. We engaged different platelet-activating receptors, including glycoprotein VI and C-type lectin-like receptor 2, to generate a spectrum of PEV types. This allowed us to investigate the differential capacity of PEVs to alter cancer hallmark functions such as proliferation, invasion, and pro-angiogenic potential using melanoma as a model. Additionally, we analyzed changes in the cell transcriptomes and cancer EV profiles.</p><p><strong>Methods: </strong>Two human melanoma cell lines (MV3 and A2058) with differential metastatic potential were studied in the 3D spheroid cultures. Human platelets were activated with collagen related peptide (CRP), fucoidan from Fucus vesiculosus (FFV), thrombin & collagen co-stimulus and Ca²⁺ ionophore, and PEVs were isolated by size-exclusion chromatography followed by ultrafiltration. Spheroids or cells were treated with PEVs and used in functional assays of proliferation, invasion, and endothelial tube formation as well as for the analysis of cancer EV production and their tetraspanin profiles. Differentially expressed genes and enriched signaling pathways in the PEV-treated spheroids were analyzed at 6 h and 24 h by RNA sequencing.</p><p><strong>Results: </strong>Among the studied PEVs, those generated by CRP and FFV exhibited the most pronounced effects on altering cancer hallmark functions. Specifically, CRP and FFV PEVs increased proliferation in both MV3 and A2058 spheroids. Distinct tetraspanin signatures of melanoma EVs were induced by all PEV types. While the PI3K-Akt and MAPK signaling pathways were activated by both CRP and FFV PEVs, they differently upregulated the immunomodulatory TGF-β and type-I interferon signaling pathways, respectively.</p><p><strong>Conclusions: </strong>Our study revealed both shared and distinct, cancer-promoting functions of PEVs, which contributed to the transcriptome and metastatic capabilities of the melanoma spheroids. Inhibiting the platelet receptors that modulate the PEVs' cancer-promoting properties may open up new strategies for identifying promising treatment targets for cancer therapy.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"601"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857051","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":"Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes.","authors":"Xiaowen Shi, Jianjiang Xu, Xin Zhong, Yuanyuan Qian, Liming Lin, Zimin Fang, Bozhi Ye, Yiting Lyu, Ran Zhang, Zhanxiong Zheng, Jibo Han","doi":"10.1186/s12964-024-01955-6","DOIUrl":"10.1186/s12964-024-01955-6","url":null,"abstract":"<p><p>Anthracycline antitumor drug doxorubicin (DOX) induces severe cardiotoxicity. Deubiquitinating enzymes (DUBs) are crucial for protein stability and function and play a significant role in cardiac pathophysiology. By comparing RNA sequencing datasets and conducting functional screening, we determined that Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a key regulator of DOX-induced cardiotoxicity. In this study, we aimed to explore the function and regulatory mechanisms of MYSM1 in DOX-induced cardiotoxicity. Genetic knockdown of MYSM1 significantly mitigated DOX-induced cardiomyopathy. Correspondingly, cardiomyocyte-specific knockdown of MYSM1 by AAV9 protected the heart from DOX-induced cardiotoxicity. Gain- and loss-of-function analysis verified that MYSM1 mediated DOX-induced cardiomyocyte injury in vitro. Through a Co-IP combined with LC-MS/MS analysis, we discovered that MYSM1 directly interacted with tripartite motif-containing protein 21 (TRIM21). Mechanistic investigations revealed that MYSM1 regulates the deubiquitination and the stability of TRIM21 via its MPN domain. Furthermore, MYSM1 exacerbated DOX-induced cardiotoxicity by enhancing ferroptosis. This study identified MYSM1 as a potential therapeutic target for DOX-induced cardiotoxicity and illustrated a MYSM1-TRIM21-ferroptosis axis in regulating DOX-induced cardiotoxicity.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"593"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856897","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":"HPV11 targeting KDM4A regulates the polarization of macrophage M₁ and promotes the development of nasal inverted papilloma.","authors":"Liying Zheng, Baoji Hu, Wenhao Yao, Kaisai Tian, Gaohan Zhu, Mingming Jin, Shuixian Huang, Xiaoping Chen, Yi Zhang","doi":"10.1186/s12964-024-01971-6","DOIUrl":"10.1186/s12964-024-01971-6","url":null,"abstract":"<p><p>The development of nasal inverted papilloma (NIP) is closely related to human papillomavirus (HPV) infection. Previous studies indicated that HPV11 shows the highest expression in NIP tissues. However, the mechanisms following its integration into host DNA require further clarification. In this study, high-throughput sequencing was employed to identify the HPV integration site KDM4A in HPV-positive specimens. The HPV11E6/E7 overexpression model was established in human nasal mucosal epithelial cells (HNE-pC), and the KDM4A gene was knocked out using CRISPR/Cas9 technology. Cell proliferation was assessed via CCK-8, colony formation, and EdU assays, while cell migration was evaluated through Transwell and wound healing assays. qRT-PCR and Western blot were used not only to analyze mRNA and protein expression in cells after HPV11E6/E7 overexpression and knockout of KDM4A but also to study the effect of the polarization of macrophages. A subcutaneous tumor model in nude mice validated the effects on proliferation and KDM4A knockout in vivo, with macrophage polarization types assessed via immunofluorescence staining. Results showed that HPV11E6/E7 overexpression significantly enhanced nasal epithelial cell proliferation and migration, along with promoting M₁ macrophage polarization. Knockout of KDM4A inhibited these effects and delayed the progression of macrophages toward M₁ polarization. Our findings suggest that low-risk HPV11 can drive the proliferation of nasal mucosa and regulate M₁ macrophage polarization via KDM4A, potentially contributing to NIP pathogenesis. Targeting inhibition of KDM4A expression may represent a viable therapeutic strategy for HPV-positive NIP.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"603"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856913","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":"PPARβ/δ upregulates the insulin receptor β subunit in skeletal muscle by reducing lysosomal activity and EphB4 levels.","authors":"Jue-Rui Wang, Javier Jurado-Aguilar, Emma Barroso, Ricardo Rodríguez-Calvo, Antoni Camins, Walter Wahli, Xavier Palomer, Manuel Vázquez-Carrera","doi":"10.1186/s12964-024-01972-5","DOIUrl":"10.1186/s12964-024-01972-5","url":null,"abstract":"<p><strong>Background: </strong>The increased degradation of the insulin receptor β subunit (InsRβ) in lysosomes contributes to the development of insulin resistance and type 2 diabetes mellitus. Endoplasmic reticulum (ER) stress contributes to insulin resistance through several mechanisms, including the reduction of InsRβ levels. Here, we examined how peroxisome proliferator-activated receptor (PPAR)β/δ regulates InsRβ levels in mouse skeletal muscle and C2C12 myotubes exposed to the ER stressor tunicamycin.</p><p><strong>Methods: </strong>Wild-type (WT) and Ppard^-/- mice, WT mice treated with vehicle or the PPARβ/δ agonist GW501516, and C2C12 myotubes treated with the ER stressor tunicamycin or different activators or inhibitors were used.</p><p><strong>Results: </strong>Ppard^-/- mice displayed reduced InsRβ protein levels in their skeletal muscle compared to wild-type (WT) mice, while the PPARβ/δ agonist GW501516 increased its levels in WT mice. Co-incubation of tunicamycin-exposed C2C12 myotubes with GW501516 partially reversed the decrease in InsRβ protein levels, attenuating both ER stress and the increase in lysosomal activity. In addition, the protein levels of the tyrosine kinase ephrin receptor B4 (EphB4), which binds to the InsRβ and facilitates its endocytosis and degradation in lysosomes, were increased in the skeletal muscle of Ppard^-/- mice, with GW501516 reducing its levels in the skeletal muscle of WT mice.</p><p><strong>Conclusions: </strong>Overall, these findings reveal that PPARβ/δ activation increases InsRβ levels by alleviating ER stress and lysosomal degradation.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"595"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857055","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":"Inflammasomes: potential therapeutic targets in hematopoietic stem cell transplantation.","authors":"Jieya Luo, Yunxia Zhou, Mingyang Wang, Junan Zhang, Erlie Jiang","doi":"10.1186/s12964-024-01974-3","DOIUrl":"10.1186/s12964-024-01974-3","url":null,"abstract":"<p><p>The realm of hematopoietic stem cell transplantation (HSCT) has witnessed remarkable advancements in elevating the cure and survival rates for patients with both malignant and non-malignant hematologic diseases. Nevertheless, a considerable number of patients continue to face challenges, including transplant-related complications, infection, graft failure, and mortality. Inflammasomes, the multi-protein complexes of the innate immune system, respond to various danger signals by releasing inflammatory cytokines and even mediating cell death. While moderate activation of inflammasomes is essential for immune defense and homeostasis maintenance, excessive activation precipitates inflammatory damage. The intricate interplay between HSCT and inflammasomes arises from their pivotal roles in immune responses and inflammation. This review examines the molecular architecture and composition of various types of inflammasomes, highlighting their activation and effector mechanisms within the context of the HSCT process and its associated complications. Additionally, we summarize the therapeutic implications of targeting inflammasomes and related factors in HSCT.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"596"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856926","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":"Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways.","authors":"Debojyoty Bandyopadhyay, Ellen T Tran, Ruchi A Patel, Matthew A Luetzen, Kevin Cho, Leah P Shriver, Gary J Patti, Mark A Varvares, David A Ford, Kyle S McCommis, Ratna B Ray","doi":"10.1186/s12964-024-01951-w","DOIUrl":"10.1186/s12964-024-01951-w","url":null,"abstract":"<p><p>One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"597"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856950","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":"Regulation of intestinal tissue‑resident memory T cells: a potential target for inflammatory bowel disease.","authors":"Xin Xia, Zhanjun Huang, Chengcheng Xu, Hailong Fu, Shengjun Wang, Jie Tian, Ke Rui","doi":"10.1186/s12964-024-01984-1","DOIUrl":"10.1186/s12964-024-01984-1","url":null,"abstract":"<p><p>Tissue-resident memory T (TRM) cells are populations which settle down in non-lymphoid tissues instead of returning to secondary lymph organs after the antigen presentation. These cells can provide rapid on-site immune protection as well as long-term tissue damage. It is reported that TRM cells from small intestine and colon exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional and functional heterogeneity. In this review, we focus on the reason why they lodge in intestinal tract, their developmental plasticity of going back to to circulation, as well as their regulators associated with retention, maintenance, exhaustion and metabolism. We also elaborate their role in the inflammatory bowel disease (IBD) and discuss the potential therapeutic strategies targeting TRM cells.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"610"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857058","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":"Adipose tissue protects against skin photodamage through CD151- and AdipoQ- EVs.","authors":"Yan-Wen Wang, Poh-Ching Tan, Qing-Feng Li, Xue-Wen Xu, Shuang-Bai Zhou","doi":"10.1186/s12964-024-01978-z","DOIUrl":"10.1186/s12964-024-01978-z","url":null,"abstract":"<p><p>To clarify the protective effects of subcutaneous adipose tissue (SAT) against photodamage, we utilized nude mouse skin with or without SAT. Skin and fibroblasts were treated with adipose tissue-derived extracellular vesicles (AT-EVs) or extracellular vesicles derived from adipose-derived stem cells (ADSC-EVs) to demonstrate that SAT protects the overlying skin from photodamage primarily through AT-EVs. Surprisingly, AT-EVs stimulated fibroblast proliferation more rapidly than ADSC-EVs did. The yield of AT-EVs from the same volume of AT was 200 times greater than that of ADSC-EVs. To compare the differences between AT-EVs and ADSC-EVs, we used a proximity barcoding assay (PBA) to analyze the surface proteins on individual particles of these two types of EVs. PBA analysis revealed that AT-EVs contain diverse subpopulations, with 83.42% expressing CD151, compared to only 1.98% of ADSC-EVs. Furthermore, AT-EVs are internalized more rapidly by cells than ADSC-EVs, as our study demonstrated that CD151-positive AT-EVs were endocytosed more quickly than their CD151-negative counterparts. Additionally, adiponectin in AT-EVs activated the AMPK pathway and inhibited the NF-κB pathway, enhancing fibroblast protection against photodamage. The significantly higher yield and faster acquisition of AT-EVs compared to ADSC-EVs underscore their potential for broader applications.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"594"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856846","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":"Transcriptional regulation of KCNA2 coding Kv1.2 by EWS::FLI1: involvement in controlling the YAP/Hippo signalling pathway and cell proliferation.","authors":"Maryne Dupuy, Anaïs Postec, Mathilde Mullard, Aurélie Chantôme, Philippe Hulin, Régis Brion, Maxime Gueguinou, Laura Regnier, Marie Potier-Cartereau, Bénédicte Brounais-Le Royer, Marc Baud'huin, Steven Georges, François Lamoureux, Benjamin Ory, Françoise Rédini, Christophe Vandier, Franck Verrecchia","doi":"10.1186/s12964-024-01981-4","DOIUrl":"10.1186/s12964-024-01981-4","url":null,"abstract":"<p><strong>Background: </strong>Ewing sarcoma (ES), the second main pediatric bone sarcoma, is characterised by a chromosomal translocation leading to the formation of fusion proteins like EWS::FLI1. While several studies have shown that potassium channels drive the development of many tumours, limited data exist on ES. This work therefore aimed to study the transcriptional regulation of KCNA2 and define the involvement of the Kv1.2 channel encoded by KCNA2 in a key function of ES development, cell proliferation.</p><p><strong>Methods: </strong>KCNA2 expression in patients and cell lines was measured via bioinformatic analysis (RNA-Seq). The presence of a functional Kv1.2 channel was shown using patch-clamp experiments. Molecular biology approaches were used after EWS::FLI1 silencing to study the transcriptional regulation of KCNA2. Proliferation and cell count assessment were performed using cell biology approaches. KCNA2 silencing (siRNA) and RNA-Seq were performed to identify the signalling pathways involved in the ability of KCNA2 to drive cell proliferation. The regulation of the Hippo signalling pathway by KCNA2 was studied by measuring Hippo/YAP target genes expression, while YAP protein expression was studied with Western-Blot and immunofluorescence approaches.</p><p><strong>Results: </strong>This research identified KCNA2 (encoding for a functional Kv1.2 channel) as highly expressed in ES biopsies and cell lines. The results indicated a correlation between KCNA2 expression and patient survival. The data also demonstrated that KCNA2/Kv1.2 is a direct target of EWS::FLI1, and identified the molecular mechanisms by which this chimeric protein regulates KCNA2 gene expression at the transcriptional level. Furthermore, the results indicated that KCNA2 expression and Kv1.2 activity regulate ES cell proliferation and that KCNA2 expression drives the Hippo/YAP signalling pathway. Using the specific Kv1.2 channel inhibitor (κ-Conotoxin), the results suggested that two complementary mechanisms are involved in this process, both dependently and independently of Kv1.2 functional channels at the plasma membrane.</p><p><strong>Conclusion: </strong>This study is the first to describe the involvement of KCNA2 expression and Kv1.2 channel in cancer development. The study also unveiled the involvement of KCNA2 in the regulation of the Hippo/YAP signalling cascade. Thus, this work suggests that KCNA2/Kv1.2 could be a potential therapeutic target in ES.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"602"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857068","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}