Cell Communication and Signaling最新文献

{"title":"Unraveling the role of hypoxia-inducible factors in cutaneous melanoma: from mechanisms to therapeutic opportunities.","authors":"Arianna Bellazzo, Barbara Montico, Roberto Guerrieri, Francesca Colizzi, Agostino Steffan, Jerry Polesel, Elisabetta Fratta","doi":"10.1186/s12964-025-02173-4","DOIUrl":"https://doi.org/10.1186/s12964-025-02173-4","url":null,"abstract":"<p><p>Hypoxia is a common feature of solid malignancies, including cutaneous melanoma (CM). Hypoxia-inducible factor (HIF)-1α and HIF-2α orchestrate cellular responses to hypoxia and coordinate a transcriptional program that promote several aggressive features in CM, such as angiogenesis, epithelial-mesenchymal transition, metastasis formation, metabolic rewiring, and immune escape. BRAF^V600E, which is the most frequent mutation observed in CM patients, usually increases HIF-α signaling not only in hypoxia, but also in normoxic CM cells, enabling HIF-1α and HIF-2α to continuously activate downstream molecular pathways. In this review, we aim to provide a comprehensive overview of the intricate role and regulation of HIF-1α and HIF-2α in CM, with a brief focus on the complex interactions between HIF-α subunits and non-coding RNAs. We also discuss HIF-α-mediated cellular responses in normoxia along with the mechanisms that allow HIF-α subunits to maintain their stability under normal oxygen conditions. Finally, we resume available evidence on potential therapeutic approaches aimed at targeting HIF-1α and/or HIF-2α.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"177"},"PeriodicalIF":8.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11984274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060428","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":"REST contributes to renal fibrosis through inducing mitochondrial energy metabolism imbalance in tubular epithelial cells.","authors":"Yingxian Yang, Shuiqin Gong, Chun Zhou, Wang Xin, Shaozong Qin, Mengying Yao, Qigang Lan, Wenhao Liao, Jinghong Zhao, Yinghui Huang","doi":"10.1186/s12964-025-02166-3","DOIUrl":"10.1186/s12964-025-02166-3","url":null,"abstract":"<p><strong>Background: </strong>Renal fibrosis represents the final common pathological manifestation of chronic kidney disease (CKD), yet the underlying mechanism remains elusive, and there is still a lack of effective targeted therapeutic strategy. Although previous research indicated that repressor element 1-silencing transcription factor (REST) contributed to acute kidney injury (AKI) in renal tubular epithelial cells (RTECs), its specific contribution to renal fibrosis and associated mechanisms remains largely unexplored.</p><p><strong>Methods: </strong>Renal biopsies from CKD patients were collected to evaluate the expression of REST. Kidney-specific Rest conditional knockout (Cdh16-Cre/Rest^flox/flox) mice were generated and employed unilateral ureter obstruction (UUO) models to investigate the role of REST in renal fibrosis. RNA sequencing was performed to elucidate the mechanism. Mitochondrial function was evaluated by transmission electron microscopy (TEM), reactive oxygen species (ROS), oxygen consumption rates (OCR), extracellular acidifcation rate (ECAR) and adenosine triphosphate (ATP). The severity of renal fibrosis was assessed through Western blot, immunofluorescent staining and immumohistochemical staining. Bioinformatic prediction, dual luciferase reporter gene assay, point mutation and chromatin immunoprecipitation (ChIP) assay were utilized to clarify the molecular mechanism.</p><p><strong>Results: </strong>REST was significantly up-regulated in the kidney tissues from CKD patients, UUO-induced fibrotic mouse models and TGF-β1-incubated RTECs. Notably, kidney-specific knockout of Rest prominently alleviated renal fibrosis by improving mitochondrial energy metabolism and restoring fatty acid oxidation. Mechanically, REST disturbed mitochondrial energy metabolism through repressing the transcription of oxoglutarate dehydrogenase-like (OGDHL) via directly binding to its promotor region. Further, pharmacological inhibition of REST using the specific REST inhibitor, X5050, significantly ameliorated the progression of renal fibrosis both in vitro and in vivo.</p><p><strong>Conclusions: </strong>Our explorations revealed the upregulation of REST in renal fibrosis disrupts mitochondrial energy metabolism through transcriptionally suppressing OGDHL, which may act as a promising therapeutic target for renal fibrosis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"176"},"PeriodicalIF":8.2,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813051","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":"MCPIP3 orchestrates the balance of epidermal proliferation and differentiation.","authors":"Agata Lichawska-Cieslar, Weronika Szukala, Pawel Pilat, Leopold Eckhart, Jacek C Szepietowski, Jolanta Jura","doi":"10.1186/s12964-025-02184-1","DOIUrl":"10.1186/s12964-025-02184-1","url":null,"abstract":"<p><strong>Background: </strong>Monocyte chemoattractant protein-induced protein 3 (MCPIP3), also called Regnase-3 and encoded by the ZC3H12C gene, is a member of the MCPIP family of RNases. Previous studies showed that MCPIP1 in keratinocytes plays a pivotal role in the maintenance of skin integrity and immunological function. Given that the expression of MCPIP3, similar to that of MCPIP1, is increased in psoriatic lesions compared with uninvolved skin, a role of MCPIP3 in the regulation of keratinocyte and epidermal biology was hypothesized.</p><p><strong>Methods: </strong>This study aimed to investigate the specific function of the MCPIP3 protein in the skin. The expression pattern of MCPIP3 was studied in normal human epidermal keratinocytes (NHEKs) subjected to in vitro differentiation and upon stimulation with proinflammatory factors. Mice with keratinocyte-specific deletion of MCPIP3 (Mcpip3^loxP/loxPKrt14^Cre; MCPIP3^EKO) were generated and characterized. The response of the skin of MCPIP3^EKO mice to imiquimod (IMQ) and 12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated. The expression levels of key modulators of keratinocyte proliferation and differentiation were measured in MCPIP3^EKO model mice and in NHEKs transiently transfected with MCPIP3-specific siRNA. Reporter assays were used to identify direct targets of MCPIP3 nucleolytic activity.</p><p><strong>Results: </strong>In human keratinocytes, the expression of ZC3H12C/MCPIP3 was rapidly induced by stimulation with TPA, IL-17a, IL-36α, and TNF-α. Although mice with keratinocyte-specific deletion of MCPIP3 (MCPIP3^EKO) did not develop skin inflammation, they displayed abnormalities in skin morphology. Stimulation with IMQ and TPA exacerbated epidermal hyperplasia caused by keratinocyte-specific deficiency of MCPIP3 and led to abnormal epidermal differentiation. The expression levels of keratinocyte proliferation and differentiation markers, such as keratin-14, cyclin B1, involucrin, and the S100 calcium-binding proteins S100A7/A9, were increased in NHEKs in which MCPIP3 expression was silenced. MCPIP3 negatively regulates the level of cyclin B1 mRNA via direct nucleolytic cleavage within its 3' untranslated region.</p><p><strong>Conclusions: </strong>The MCPIP3 protein modulates the balance of keratinocyte proliferation and differentiation and functions as a regulator of epidermal morphology in vivo.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"175"},"PeriodicalIF":8.2,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813048","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 dynamics of chemoattractant receptors redistribution in the electrotaxis of 3T3 fibroblasts.","authors":"Jagoda Gorzkowska, Wiktoria Kozak, Sylwia Bobis-Wozowicz, Ivan Cherepashuk, Zbigniew Madeja, Sławomir Lasota","doi":"10.1186/s12964-025-02165-4","DOIUrl":"10.1186/s12964-025-02165-4","url":null,"abstract":"<p><strong>Background: </strong>Electrotaxis, the directed cell movement in direct current electric field (dcEF), is crucial for wound healing and development. We recently proposed a biphasic electrotaxis mechanism, where an initial rapid response is driven by ionic mechanisms, while redistribution of membrane components come into play during prolonged exposure to dcEF.</p><p><strong>Methods: </strong>To verify this hypothesis, we studied the redistribution dynamics of EGFR, PDGFRα/β, and TGFβR1 in dcEF. For this purpose, we utilized cells transfected with plasmids encoding fluorescently tagged receptors, which were exposed to dcEF in a custom-designed electrotactic chamber. Fluorescent images were captured using wide-field or TIRF microscopy, enabling precise quantitative analysis of receptor redistribution. Additionally, the functional significance of these selected receptors in electrotaxis was evaluated by silencing their expression using an siRNA library.</p><p><strong>Results: </strong>Although EGFR moved immediately to cathode after dcEF application, maximum distribution asymmetry was reached after 30-40 min. This process was more efficient at higher dcEF intensities, specifically, asymmetry was greater at 3 V/cm compared to 1 V/cm, consistent with the biphasic mechanism observed only under the stronger dcEF. Additionally, redistribution was more effective under alkaline conditions and near the cell base, but decreased when glass was coated with poly-L-lysine, indicating electroosmosis as a key factor. Importantly, EGFR redistribution did not correlate with the rapid reaction of 3T3 cells to dcEF reversal, which occurred within 1-2 min, when receptor orientation was not yet reversed. PDGFRα exhibited similar but less marked cathodal redistribution, while PDGFRβ and TGFβR1 did not redistribute. siRNA knockdown experiments confirmed the importance of EGFR and ErbB4 in the electrotaxis. EGFR's role was largely ligand-independent, and it had a significant impact on the response of 3T3 cells to dcEF during the first hour of the experiment, but was not involved in the fastest response, which was Kir-dependent.</p><p><strong>Conclusions: </strong>Our study suggests that EGFR redistribution may play a role in the early stages and partially contribute to the long-term electrotaxis of 3T3 fibroblasts. However, this mechanism alone does not fully explain rapid responses to dcEF orientation changes indicating a more complex, multimodal mechanism of electrotaxis in these cells.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"173"},"PeriodicalIF":8.2,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813053","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":"Toxoplasma gondii modulates immune responses and mitigates type 1 diabetes progression in a streptozotocin-induced rat model.","authors":"Kimia Moradi, Reyhaneh Moghaddami, Arshad Ghaffari-Nasab, Monir Khordadmehr, Abdol Sattar Pagheh, Hossein Mosajakhah, Sahar Rezaei, Esmaeil Gharepapagh, Mahdi Ahmadi, Mahbobeh Montazeri, Hossein Pazoki, Ehsan Ahmadpour","doi":"10.1186/s12964-025-02168-1","DOIUrl":"10.1186/s12964-025-02168-1","url":null,"abstract":"<p><p>Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. Emerging evidence suggests that infections, including Toxoplasma gondii (T. gondii), may modulate immune responses and influence disease outcomes. This study aimed to investigate the effects of T. gondii infection on the development of T1DM in a Streptozotocin (STZ)-induced rat model, with an emphasis on immune modulation, cytokine profiles, and organ inflammation. In rats experimentally infected with pathogenic and non-pathogenic Toxoplasma strains, diabetes was induced via STZ injection and compared to a control group. Blood glucose levels and the expression of IL-10, IL-1β, and TNF-α at both gene and protein levels were assessed. Histopathological examinations of the pancreas and kidneys were conducted, alongside small-animal PET scans to evaluate metabolic activity in these organs. The T. gondii-infected diabetic groups showed reduced blood glucose levels, increased IL-10, and decreased TNF-α and IL-1β levels compared to the STZ group. Histopathological and PET imaging analyses revealed improved pancreatic and renal tissues and reduced metabolic activity, indicating improvement effects associated with decreased inflammation and immune modulation. T. gondii infection seems to influence immune responses and slow the progression of T1DM in a rat model. These results suggest a potential therapeutic role for parasitic infections in autoimmune diseases, offering valuable insights into the complex relationship between infections, immune regulation, and metabolic health.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"172"},"PeriodicalIF":8.2,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813054","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":"Pulmonary mitochondrial DNA release and activation of the cGAS-STING pathway in Lethal Stx12 knockout mice.","authors":"Dan-Hua Liu, Fang Li, Run-Zhou Yang, Zhuanbin Wu, Xiao-Yan Meng, Sen-Miao Li, Wen-Xiu Li, Jia-Kang Li, Dian-Dian Wang, Rui-Yu Wang, Shu-Ang Li, Pei-Pei Liu, Jian-Sheng Kang","doi":"10.1186/s12964-025-02141-y","DOIUrl":"10.1186/s12964-025-02141-y","url":null,"abstract":"<p><p>STX12 (syntaxin12 or syntaxin13), a member of the SNARE protein family, plays a crucial role in intracellular vesicle transport and membrane fusion. Our previous research demonstrated that Stx12 knockout mice exhibit perinatal lethality with iron deficiency anemia. Despite its importance, the comprehensive physiological and pathological mechanism of STX12 remains largely unknown. Here, we revealed that STX12 deficiency causes the depolarization of mitochondrial membrane potential in zebrafish embryos and mouse embryonic fibroblasts. Additionally, the loss of STX12 decreased the levels of mitochondrial complex subunits, accompanied by mitochondrial DNA (mtDNA) release and activated cGAS-STING pathway and Type I interferon pathway in the lung tissue of Stx12^-/- mice. Additionally, we observed a substantial increase in cytokines and neutrophil infiltration within the lung tissues of Stx12 knockout mice, indicating severe inflammation, which could be a contributing factor for Stx12^-/- mortality. Various interventions have failed to rescue the lethal phenotype, suggesting that systemic effects may contribute to lethality. Further research is warranted to elucidate potential intervention strategies. Overall, our findings uncover the critical role of STX12 in maintaining mitochondrial function and mtDNA stability in pulmonary cells, and reveal that STX12 depletion results in pulmonary mtDNA release and activates mtDNA-dependent innate immunity.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"174"},"PeriodicalIF":8.2,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11980072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813049","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":"NEK8, a NIMA-family protein kinase at the core of the ciliary INV complex.","authors":"Joan Roig","doi":"10.1186/s12964-025-02143-w","DOIUrl":"10.1186/s12964-025-02143-w","url":null,"abstract":"<p><p>Here we describe the current knowledge about the ciliary kinase NEK8, highlighting what we know and what we don't know about its regulation, substrates and potential functions. We also review the literature about the pathological consequences of different NEK8 variants in patients of nephronophthisis, renal-hepatic-pancreatic dysplasia and autosomal dominant polycystic kidney disease, three different types of ciliopathies. NEK8 belongs to the NIMA family of serine/threonine protein kinases. Like its closest relative, NEK9, it contains a protein kinase and an RCC1 domain, but lacks the C-terminal region that is key for NEK9's regulation as a G2/M kinase. Importantly, NEK8 localizes to cilia as part of a multimeric protein complex that assembles in a fibrillar fashion at the proximal half of this signaling organelle, defining what is known as the INV compartment. NEK8 and its INV compartment partners inversin, ANKS6 and NPHP3 are necessary for left-right determination and the correct development of different organs such as the kidney, the heart and the liver. But the kinase substrates, regulatory mechanism and activating cues and thus the molecular basis of NEK8 important physiological roles remain elusive. We present the current findings regarding NEK8 and also highlight what we miss in order to progress towards the understanding of the kinase and the function of the INV complex at the cilia.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"170"},"PeriodicalIF":8.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797225","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":"Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies.","authors":"Siwei Wang, Lu Qin, Furong Liu, Zhanguo Zhang","doi":"10.1186/s12964-025-02169-0","DOIUrl":"10.1186/s12964-025-02169-0","url":null,"abstract":"<p><p>The cGAS-STING signaling pathway serves as a critical link between DNA sensing and innate immunity, and has tremendous potential to improve anti-tumor immunity by generating type I interferons. However, STING agonists have shown decreasing biotherapeutic efficacy in clinical trials. Tumor metabolism, characterized by aberrant nutrient utilization and energy production, is a fundamental hallmark of tumorigenesis. And modulating metabolic pathways in tumor cells has been discovered as a therapeutic strategy for tumors. As research concerning STING progressed, emerging evidence highlights its role in metabolic reprogramming, independent its immune function, indicating metabolic targets as a strategy for STING activation in cancers. In this review, we delve into the interplay between STING and multiple metabolic pathways. We also synthesize current knowledge on the antitumor functions of STING, and the metabolic targets within the tumor microenvironment (TME) that could be exploited for STING activation. This review highlights the necessity for future research to dissect the complex metabolic interactions with STING in various cancer types, emphasizing the potential for personalized therapeutic strategies based on metabolic profiling.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"171"},"PeriodicalIF":8.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11977922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804921","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":"Machine learning-based in-silico analysis identifies signatures of lysyl oxidases for prognostic and therapeutic response prediction in cancer.","authors":"Qingyu Xu, Ling Ma, Alexander Streuer, Eva Altrock, Nanni Schmitt, Felicitas Rapp, Alessa Klär, Verena Nowak, Julia Obländer, Nadine Weimer, Iris Palme, Melda Göl, Hong-Hu Zhu, Wolf-Karsten Hofmann, Daniel Nowak, Vladimir Riabov","doi":"10.1186/s12964-025-02176-1","DOIUrl":"10.1186/s12964-025-02176-1","url":null,"abstract":"<p><strong>Background: </strong>Lysyl oxidases (LOX/LOXL1-4) are crucial for cancer progression, yet their transcriptional regulation, potential therapeutic targeting, prognostic value and involvement in immune regulation remain poorly understood. This study comprehensively evaluates LOX/LOXL expression in cancer and highlights cancer types where targeting these enzymes and developing LOX/LOXL-based prognostic models could have significant clinical relevance.</p><p><strong>Methods: </strong>We assessed the association of LOX/LOXL expression with survival and drug sensitivity via analyzing public datasets (including bulk and single-cell RNA sequencing data of six datasets from Gene Expression Omnibus (GEO), Chinese Glioma Genome Atlas (CGGA) and Cancer Genome Atlas Program (TCGA)). We performed comprehensive machine learning-based bioinformatics analyses, including unsupervised consensus clustering, a total of 10 machine-learning algorithms for prognostic prediction and the Connectivity map tool for drug sensitivity prediction.</p><p><strong>Results: </strong>The clinical significance of the LOX/LOXL family was evaluated across 33 cancer types. Overexpression of LOX/LOXL showed a strong correlation with tumor progression and poor survival, particularly in glioma. Therefore, we developed a novel prognostic model for glioma by integrating LOX/LOXL expression and its co-expressed genes. This model was highly predictive for overall survival in glioma patients, indicating significant clinical utility in prognostic assessment. Furthermore, our analysis uncovered a distinct LOXL2-overexpressing malignant cell population in recurrent glioma, characterized by activation of collagen, laminin, and semaphorin-3 pathways, along with enhanced epithelial-mesenchymal transition. Apart from glioma, our data revealed the role of LOXL3 overexpression in macrophages and in predicting the response to immune checkpoint blockade in bladder and renal cancers. Given the pro-tumor role of LOX/LOXL genes in most analyzed cancers, we identified potential therapeutic compounds, such as the VEGFR inhibitor cediranib, to target pan-LOX/LOXL overexpression in cancer.</p><p><strong>Conclusions: </strong>Our study provides novel insights into the potential value of LOX/LOXL in cancer pathogenesis and treatment, and particularly its prognostic significance in glioma.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"169"},"PeriodicalIF":8.2,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788861","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":"HOXC6 promotes the metastasis of MSI-H CRC by interacting with M2 macrophages and inducing effector T cell exhaustion.","authors":"Lina Qi, Biting Zhou, Jiani Chen, Kailun Xu, Kailai Wang, Shu Zheng, Wangxiong Hu, Yanmei Yang","doi":"10.1186/s12964-025-02167-2","DOIUrl":"10.1186/s12964-025-02167-2","url":null,"abstract":"<p><p>We previously discovered that HOXC6 was the most significantly upregulated gene in right-sided colon cancer compared to left-sided colon cancer according to our previous study; however, the role of HOXC6 in microsatellite instability-high (MSI-H) tumors remains poorly understood. Here, multiple public datasets, and in-house cohorts were used to analyze the differential expression and prognostic role of HOXC6 in colorectal cancer (CRC). Immunohistochemistry and immunofluorescence were performed to evaluate the correlation between HOXC6 expression and M2 macrophage infiltration. CCK8 and Transwell assays were used to evaluate the proliferation and migration of tumor cells in vitro. BALB/c nude mice were utilized to construct a humanized immune system model to evaluate the efficacy of ruxolitinib in vivo. We found that HOXC6 was overexpressed in MSI-H CRC and associated with a poor prognosis. Upregulation of CCL2 by HOXC6 increased M2 macrophage infiltration. IL6 secreted by M2 macrophages induced the epithelial-mesenchymal transition of tumor cells by upregulating HOXC6. M2 macrophages promoted effector T cell exhaustion by downregulating 4-1BB. Thus, inhibition of the IL6/JAK pathway in M2 macrophages restored 4-1BB expression and T-cell cytotoxicity offering a promising therapeutic target for the treatment of HOXC6-overexpressing MSI-H CRC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"168"},"PeriodicalIF":8.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789430","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}