Cellular signalling最新文献

{"title":"Inhibition of HDAC6 elicits anticancer effects on head and neck cancer cells through Sp1/SOD3/MKP1 signaling axis to downregulate ERK phosphorylation","authors":"Rukhsana Kausar ,&nbsp;Nga Thi Thanh Nguyen ,&nbsp;Truc Phan Hoang Le ,&nbsp;Jae Hyung Kim ,&nbsp;Sang Yoon Lee","doi":"10.1016/j.cellsig.2024.111587","DOIUrl":"10.1016/j.cellsig.2024.111587","url":null,"abstract":"<div><div>Oxidative stress caused by reactive oxygen species (ROS) and superoxides is linked to various cancer-related biological events. Extracellular superoxide dismutase (SOD3), an antioxidant enzyme that removes superoxides, contributes to redox homeostasis and has the potential to regulate tumorigenesis. Histone deacetylase 6 (HDAC6), a major HDAC isoform responsible for mediating the deacetylation of non-histone protein substrates, also plays a role in cancer progression. In this study, we examined the potential effects of HDAC6 inhibition on SOD3 expression in head and neck cancer (HNC) cells and its impact on cell proliferation, which remains unaddressed. We found that functional inactivation of HDAC6, through the use of chemical inhibitors such as tubastatin A (TubA), gene knockdown, or overexpression of an inactive mutant, strongly upregulated protein and mRNA levels of SOD3 in HNC cell lines FaDu and Detroit562. Mechanistically, TubA induced acetylation of the transcription factor Sp1 at Lys703, which consequently enhanced its binding to the SOD3 proximal promoter region and increased SOD3 expression. An acetylation-defective Sp1 mutant (K703R) was much less effective in inducing SOD3 expression compared to wild-type Sp1. TubA reduced intracellular ROS and superoxide levels, and this antioxidative effect was attenuated in SOD3 knockdown cells. Similar to the changes in ROS levels, HDAC6 inhibition as well as SOD3 overexpression suppressed cell proliferation and the stimulatory phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whereas SOD3 knockdown produced opposite effects in both resting and TubA-treated conditions. In addition, SOD3 overexpression prevented ROS-induced ERK1/2 phosphorylation and enhanced the protein stability of mitogen-activated protein kinase phosphatase 1 (MKP1), thereby counteracting ERK1/2 phosphorylation. We further showed that SOD3-mediated ERK1/2 dephosphorylation was moderated in MKP1 knockdown cells. Collectively, these results suggest that HDAC6 inhibition elicits anticancer effects on HNC cells by promoting Sp1 acetylation-dependent SOD3 upregulation, leading to MKP1 stabilization and subsequent ERK1/2 inactivation.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111587"},"PeriodicalIF":4.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP27 promotes glycolysis and hepatocellular carcinoma progression by stabilizing PFKFB3 through deubiquitination","authors":"Longhui Xie ,&nbsp;Dekun Song ,&nbsp;Zhengsheng Ouyang ,&nbsp;Yinkuan Ning ,&nbsp;Xintao Liu ,&nbsp;Lai Li ,&nbsp;Wangning Xia ,&nbsp;Yang Yang","doi":"10.1016/j.cellsig.2024.111585","DOIUrl":"10.1016/j.cellsig.2024.111585","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is associated with a dismal prognosis, primarily due to its high rates of metastasis and recurrence. Metabolic reprogramming, specifically enhanced glycolysis, is a prominent feature of cancer progression. This study identifies ubiquitin-specific peptidase 27 X-linked (USP27) as a significant regulator of glycolysis in HCC. We demonstrate that USP27 stabilizes PFKFB3, a key glycolytic enzyme, through deubiquitination, thereby increasing glycolytic activity and facilitating tumor progression. Furthermore, we reveal that CTCF, a well-known transcription factor, directly binds to the USP27 promoter and upregulates its expression, thereby establishing a connection between transcriptional regulation and metabolic reprogramming in HCC. Knockdown of USP27 or CTCF in HCC cells considerably decreased glycolysis and proliferation, while overexpression had the opposite effect. In vivo studies confirmed that USP27 knockdown suppresses HCC growth and metastasis. Our findings establish the CTCF/USP27/PFKFB3 axis as a novel mechanism driving HCC progression through glycolysis, indicating that targeting this pathway could offer new therapeutic opportunities. These results provide valuable insights into the molecular mechanisms underlying HCC and emphasize the potential of targeting USP27-mediated metabolic pathways as a strategy for cancer treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111585"},"PeriodicalIF":4.4,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of G protein subunit alpha i3 as a promising oncotarget of LUAD","authors":"Gaomeng Luo ,&nbsp;Wenxuan Hu ,&nbsp;Jian Yang ,&nbsp;Hao Ding ,&nbsp;Chun Xu ,&nbsp;Xin Tong ,&nbsp;Cheng Ding ,&nbsp;Jun Zhao","doi":"10.1016/j.cellsig.2024.111582","DOIUrl":"10.1016/j.cellsig.2024.111582","url":null,"abstract":"<div><div>Exploring new oncotargets essential for lung adenocarcinoma (LUAD) cell growth is important. Here the bioinformatical studies revealed that <em>Gαi3</em> expression is elevated in LUAD tissues and its overexpression correlates with poor survival of the patients. Moreover, overexpression of <em>Gαi3</em> mRNA and protein was detected in LUAD tissues of patients as well as in primary/immortalized LUAD cells. In both primary and immortalized LUAD cells, genetic silencing (by viral shRNA) or knockout (“KO”, through CRISPR/Cas9 method) of Gαi3 potently inhibited LUAD cell proliferation and mobility. The results of caspase-3 activity assay, caspase-9 activity assay, histone DNA ELISA, TUNEL nuclear staining and Annexin V staining showed that inhibition of Gαi3 expression promoted apoptosis. In addition, a significant decrease in mitochondrial membrane potential was found in Gαi3-deficient LUAD cells by JC-1 staining. Overexpression of Gαi3 strengthened the proliferation and migration of LUAD cell. Gene set enrichment analysis revealed that <em>Gαi3</em> was closely related to PI3k/Akt/mTOR, which we validated experimentally. Akt-S6K phosphorylation was downregulated following Gαi3 silencing or KO, but augmented after Gαi3 overexpression in primary LUAD cells. Restoring Akt-S6K phosphorylation by a S473D constitutively-active mutant Akt1 ameliorated Gαi3 KO-induced LUAD cell proliferation inhibition, migration suppression and apoptosis. <em>In vivo</em>, the growth of subcutaneous LUAD xenografts was largely inhibited after intratumoral injection of Gαi3 shRNA-expressing adeno-associated virus (AAV). Gαi3 downregulation, Akt-mTOR inhibition, proliferation inactivation and apoptosis were detected in the Gαi3 shRNA-treated LUAD xenografts. Together, targeting Gαi3 potently inhibited LUAD cell growth <em>in vitro</em> and <em>in vivo</em>.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111582"},"PeriodicalIF":4.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of ATF2 retards senescence induced by replication stress and pamidronate in mouse jaw bone marrow stem cells","authors":"Yuanyuan Li ,&nbsp;Yuxiu Lin ,&nbsp;Zhi Chen ,&nbsp;Wei Ji ,&nbsp;Huan Liu","doi":"10.1016/j.cellsig.2024.111579","DOIUrl":"10.1016/j.cellsig.2024.111579","url":null,"abstract":"<div><div>The aging process is associated with a loss of bone mass and an accumulation of senescent cells, which is under epigenetic control. Morphological and molecular analysis revealed a notable reduction in bone mass and alveolar crest height in aged mice, accompanied by increased levels of senescent mouse jaw bone marrow stem cells (mJBMSCs). To investigate whether specific transcription factors are involved, assay for transposase-accessible chromatin with sequencing (ATAC-seq) was performed on mJBMSCs isolated from 2-, 4-, 8-, and 20-month-old mice. In 20-month-old mJBMSCs, increased chromatin accessibility was observed alongside elevated expression of activating transcription factor 2 (ATF2) in both cells and alveolar bone. Silencing <em>Atf2</em> in mJBMSCs failed to reverse physiological aging, but delayed replication stress and pamidronate (PAM) induced senescence. The analysis of ATAC-seq and RNA sequencing indicated that the differentially expressed genes upregulated by PAM but downregulated by ATF2 deficiency were related to some key biological processes, including negative regulation of cell proliferation, inflammatory response, adipogenesis, and cellular senescence. The dual-luciferase assay was conducted to demonstrate that ATF2 enhances <em>Cdkn2a</em> transcription by binding to its promoter region. Our findings suggest significant chromatin alterations in aged mJBMSCs, positioning ATF2 as a potential target for combating externally induced senescence.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111579"},"PeriodicalIF":4.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aerobic plus resistance exercise attenuates skeletal muscle atrophy induced by dexamethasone through the HDAC4/FoxO3a pathway","authors":"Dehuan Liang ,&nbsp;Danni Wang ,&nbsp;Xinyue Zheng ,&nbsp;Heng Xiang ,&nbsp;Sujuan Liu ,&nbsp;Chunxia Yu ,&nbsp;Jiatong Tian ,&nbsp;Jianxiong Ma ,&nbsp;Yanmei Niu","doi":"10.1016/j.cellsig.2024.111581","DOIUrl":"10.1016/j.cellsig.2024.111581","url":null,"abstract":"<div><div>This study aimed to investigate the underlying mechanisms by which physical exercise mitigates muscle atrophy induced by Dexamethasone (Dex). A muscle atrophy model was established in the mouse C2C12 cell line and 8-week-old mice treated with Dex, with subsequent verification of phenotype and atrogene expression. The potential benefits of combined aerobic and resistance exercise in mitigating muscle atrophy were then examined. To elucidate the involvement of Histone deacetylase 4 (HDAC4) in the protective effects of exercise against muscle loss, a combination of RT-PCR, Western blotting, immunoprecipitation, and immunofluorescence staining techniques were employed. The upregulation of HDAC4 was observed following Dex-induced muscle atrophy in vitro and in vivo. Inhibition of HDAC4 in C2C12 cells resulted in an increase in myotube diameter and fusion index, along with a decrease in the expression of Atrogin-1 and MuRF1. Treatment with Tasquinimod, an HDAC4 inhibitor, effectively prevented muscle wasting and dysfunction in mice induced by Dex. After a 6-week exercise intervention, the Dex-Exercise group exhibited significant improvements in body fat level, hyperinsulinemia, muscle mass and function in comparison to the Dex-Sedentary group. Mechanistically, we discovered that HDAC4 bound to and deacetylated Forkhead box protein O 3a (FoxO3a) within the nucleus, leading to decreased phosphorylation of FoxO3a at Ser 253. This interaction subsequently facilitated the expression of downstream atrogene Atrogin-1 and MuRF1, resulting in muscle atrophy. Conversely, exercise was found to potentially mitigate muscle atrophy by inhibiting the HDAC4/FoxO3a pathway. These findings suggest that HDAC4 may be a potential therapeutic target for exercise to combat Dex-induced muscle atrophy.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111581"},"PeriodicalIF":4.4,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights into the relationship of mitochondrial metabolism and atherosclerosis","authors":"Zexun Wang ,&nbsp;Wangqing Sun ,&nbsp;Kai Zhang ,&nbsp;Xianjin Ke ,&nbsp;Zhongqun Wang","doi":"10.1016/j.cellsig.2024.111580","DOIUrl":"10.1016/j.cellsig.2024.111580","url":null,"abstract":"<div><div>Atherosclerotic cardiovascular and cerebrovascular diseases are the number one killer of human health. In view of the important role of mitochondria in the formation and evolution of atherosclerosis, our manuscript aims to comprehensively elaborate the relationship between mitochondria and the formation and evolution of atherosclerosis from the aspects of mitochondrial dynamics, mitochondria-organelle interaction (communication), mitochondria and cell death, mitochondria and vascular smooth muscle cell phenotypic switch, etc., which is combined with genome, transcriptome and proteome, in order to provide new ideas for the pathogenesis of atherosclerosis and the diagnosis and treatment of related diseases.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111580"},"PeriodicalIF":4.4,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probiotic DNA alleviates experimental airway allergy","authors":"Xiaorui Geng ,&nbsp;Yongjin Wu ,&nbsp;Zhiqiang Liu ,&nbsp;Jiangqi Liu ,&nbsp;Bailing Xie ,&nbsp;Le Liu ,&nbsp;Hanqing Zhang ,&nbsp;Lihua Mo ,&nbsp;Yu Liu ,&nbsp;Xianhai Zeng ,&nbsp;Pingchang Yang","doi":"10.1016/j.cellsig.2024.111578","DOIUrl":"10.1016/j.cellsig.2024.111578","url":null,"abstract":"<div><div><ul><li><span>•</span><span><div>Probiotic <em>Clostridium butyricum</em> DNA (CbDNA)-containing nasal instillations can attenuate experimental airway allergy</div></span></li><li><span>•</span><span><div>CbDNA has better effects on attenuating airway allergy than oral ingestion of live <em>C. butyricum</em></div></span></li><li><span>•</span><span><div>CbDNA increases the expression of SARM1 and induces activated Th2 cell apoptosis</div></span></li></ul></div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111578"},"PeriodicalIF":4.4,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt5a alleviates the symptoms of PCOS by modulating PI3K/AKT/mTOR pathway-mediated autophagy in granulosa cells","authors":"Yabo Ma ,&nbsp;Yuqin Ma ,&nbsp;Pengfei Li ,&nbsp;Fucheng Ma ,&nbsp;Miao Yu ,&nbsp;Jinrui Xu ,&nbsp;Yi Yang","doi":"10.1016/j.cellsig.2024.111575","DOIUrl":"10.1016/j.cellsig.2024.111575","url":null,"abstract":"<div><h3>Objective</h3><div>Polycystic ovary syndrome (PCOS) is a metabolic and endocrine disease that entails dysregulated ovulation, hyperandrogenism, and polycystic ovaries. While Wnt5a has been suggested to play key roles in follicular development and female fertility under normal conditions, its functions in the context of PCOS have yet to be established. This study was thus designed to explore the impact of Wnt5a on ovarian granulosa cell autophagy in PCOS, providing in vitro evidence in support of its role in this setting.</div></div><div><h3>Methods</h3><div>DHT-induced granulosa (KGN) cells were used as an in vitro model, and Wnt5a and autophagy-related protein levels in these cells were detected via Western blotting. Downregulating the expression of Wnt5a in KGN cells (by interference and inhibitor) was also performed, and Western blotting, RT-PCR, and immunofluorescence strategies were used to detect autophagy-related and PI3K/AKT/mTOR pathway-associated factors in this setting. In vivo<em>,</em> BOX5 was tested as a therapeutic inhibitor of Wnt5a in a murine model of DHEA-induced PCOS. Changes in ovarian morphology were detected through hematoxylin staining, while E2 and T hormone levels were quantified by ELISA, and autophagy-related factors in these animals were quantified through Western blotting, immunofluorescence, and immunohistochemistry.</div></div><div><h3>Results</h3><div>Wnt5a and autophagy-related protein levels rose significantly in DHT-induced KGN cells. Following downregulation of the Wnt5a in these cells, a significant decrease in autophagy-related factor levels was noted relative to the DHT group, together with significant increases in pathway-related factors. In mice, BOX5 treatment was sufficient to restore serum levels of androgen and to improve polycystic ovarian changes, while also suppressing the levels of autophagy-associated factors within ovarian granulosa cells.</div></div><div><h3>Conclusion</h3><div>Wnt5a downregulation suppresses autophagy in PCOS granulosa cells through the activation of the PI3K/AKT/mTOR pathway, in addition to remediating polycystic ovarian changes and normalizing serum levels of sex hormones.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111575"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fusion circRNA F-circEA1 facilitates EML4-ALK1 positive lung adenocarcinoma progression through the miR-4673/SMAD4/ADAR1 axis","authors":"Yinping Huo ,&nbsp;Dongmei Yuan ,&nbsp;Hongbing Liu ,&nbsp;Yong Song","doi":"10.1016/j.cellsig.2024.111571","DOIUrl":"10.1016/j.cellsig.2024.111571","url":null,"abstract":"<div><div>Circular RNA (circRNA) can sponge miRNA participate in the tumorigenesis and progression of various cancers. We substantiate for the first time that the fusion circular RNA (F-circRNA) F-circEA1 is involved in driving the echinoderm microtubule associated-protein like 4-anaplastic lymphoma kinase variant 1-positive (EML4-ALK1) lung adenocarcinoma (LUAD) progression and the expression of the parental gene EML4-ALK1, molecular mechanisms of F-circEA1 in the EML4-ALK1 LUAD remain unknown. Bioinformatics analysis showed that only miR-4673 can bind to F-circEA1 and bind to EML4-ALK1 3’-UTR to regulate the expression of EML4-ALK1. Notably, high miR-4673 expression exerted an inhibitory impact on the invasion, migration, and proliferation of EML4-ALK1-positive LUAD cells, and partially reversed the invasion, migration, and proliferation of F-cirEA1. F-circEA1 can sponge miR-4673, enhanced the recombinant mothers against decapentaplegic homolog 4 (SMAD4) expression, which is a downstream target of miR-4673. As a transcription factor, SMAD4 exhibits the ability to directly associate with EML4-ALK1 and adenosinedeaminase RNA editingenzyme 1 (ADAR1) promoter regions. Interestingly, it was also observed that the RNA editing enzyme ADAR1 facilitated the expression of F-circEA1, but inhibited the expression of miR-4673. The interplay between F-circEA1, miR-4673, SMAD4, and ADAR1 forms a feedback pathway that aids in regulating the progression of EML4-ALK variant 1-positive LUAD. This novel finding offers promising therapeutic ideas for the EML4-ALK variant 1-positive lung adenocarcinoma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111571"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor cells induce neural DKK1 expression to promote MDSC infiltration and subsequent T cell suppression","authors":"Ruoyan Liu ,&nbsp;Xiaotian Shi ,&nbsp;Shuangshuang Qian ,&nbsp;Zhonghao Sun ,&nbsp;Hao Dai ,&nbsp;Yongwei Wu ,&nbsp;Shihui Cao ,&nbsp;Jingtao Luo ,&nbsp;Ze Zhang","doi":"10.1016/j.cellsig.2024.111576","DOIUrl":"10.1016/j.cellsig.2024.111576","url":null,"abstract":"<div><div>Nerves are often overlooked as key components of the tumor microenvironment. However, the molecular mechanisms underlying the reciprocal interactions between tumors and nerves remain largely unknown. In this study, we analyzed data from The Cancer Genome Atlas (TCGA) and identified a significant association between DKK1 expression and poor prognosis, as well as a correlation between DKK1 expression and myeloid-derived suppressor cell (MDSC) infiltration in head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC), two cancer types characterized by pronounced tumor-nerve interactions. Based on these findings, we hypothesize that tumors may induce DKK1 expression in nerves, and that nerve-derived DKK1 may promote MDSC infiltration and immunosuppression. To test this hypothesis, we employed a combination of experimental approaches, including in vitro co-culture of trigeminal ganglia with tumor cells, multiplex immunohistochemistry, and in vivo administration of DKK1 neutralizing antibodies. Our results indicate that tumor cells significantly induce DKK1 expression in ganglia in co-culture experiments. Additionally, in vivo orthotopic tumor models revealed that DKK1 levels were markedly elevated in both the plasma and ganglia of tumor-bearing mice. Neutralization DKK1 in vivo led to a reduction in MDSC levels and impaired MDSC-mediated T cell suppression in both HNSCC and PDAC orthotopic models. Furthermore, conditional deletion of neuronal DKK1 elucidated its role in MDSC infiltration and immune suppression. Our findings establish a novel molecular axis in which tumor cells modulate the immune microenvironment by inducing the expression of secreted proteins in nerves, thereby enriching the research landscape of the tumor microenvironment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111576"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}