Cellular signalling最新文献_第7页

Wnt5a alleviates the symptoms of PCOS by modulating PI3K/AKT/mTOR pathway-mediated autophagy in granulosa cells Wnt5a通过调节颗粒细胞中PI3K/AKT/mTOR通路介导的自噬来缓解PCOS的症状。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-12-20 DOI: 10.1016/j.cellsig.2024.111575

Yabo Ma , Yuqin Ma , Pengfei Li , Fucheng Ma , Miao Yu , Jinrui Xu , Yi Yang

Objective

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.

Methods

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, 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.

Results

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.

Conclusion

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.

目的：多囊卵巢综合征（PCOS）是一种代谢和内分泌疾病，包括排卵失调、雄激素过多和多囊卵巢。虽然Wnt5a被认为在正常情况下对卵泡发育和女性生育能力起关键作用，但其在PCOS中的功能尚未确定。因此，本研究旨在探讨Wnt5a对PCOS患者卵巢颗粒细胞自噬的影响，并提供体外证据支持其在此情况下的作用。方法：以dht诱导的颗粒细胞（KGN）为体外模型，采用Western blotting检测细胞中Wnt5a及自噬相关蛋白水平。我们还通过干扰和抑制剂下调KGN细胞中Wnt5a的表达，并使用Western blotting、RT-PCR和免疫荧光策略检测自噬相关因子和PI3K/AKT/mTOR通路相关因子。在体内，BOX5在dhea诱导的PCOS小鼠模型中作为Wnt5a的治疗抑制剂进行了测试。采用苏木精染色检测卵巢形态学变化，ELISA检测E2、T激素水平，Western blotting、免疫荧光、免疫组织化学检测自噬相关因子。结果：dht诱导的KGN细胞中Wnt5a及自噬相关蛋白水平显著升高。在这些细胞中下调Wnt5a后，与DHT组相比，自噬相关因子水平显著降低，通路相关因子水平显著升高。在小鼠中，BOX5处理足以恢复血清雄激素水平，改善多囊卵巢的变化，同时也抑制卵巢颗粒细胞内自噬相关因子的水平。结论：Wnt5a下调可通过激活PI3K/AKT/mTOR通路抑制PCOS颗粒细胞的自噬，并可修复多囊卵巢病变，使血清性激素水平正常化。

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引用次数: 0

Fusion circRNA F-circEA1 facilitates EML4-ALK1 positive lung adenocarcinoma progression through the miR-4673/SMAD4/ADAR1 axis 融合circRNA F-circEA1通过miR-4673/SMAD4/ADAR1轴促进EML4-ALK1阳性肺腺癌的进展。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-12-20 DOI: 10.1016/j.cellsig.2024.111571

Yinping Huo , Dongmei Yuan , Hongbing Liu , Yong Song

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.

环状RNA （circRNA）可以海绵miRNA参与各种癌症的发生和进展。我们首次证实融合环状RNA (F-circRNA) F-circEA1参与驱动棘皮微管相关蛋白样4-间变性淋巴瘤激酶1阳性（EML4-ALK1）肺腺癌（LUAD）的进展和亲本基因EML4-ALK1的表达，但F-circEA1在EML4-ALK1 LUAD中的分子机制尚不清楚。生物信息学分析表明，只有miR-4673可以结合F-circEA1和EML4-ALK1 3'-UTR来调节EML4-ALK1的表达。值得注意的是，miR-4673的高表达对eml4 - alk1阳性LUAD细胞的侵袭、迁移和增殖有抑制作用，并部分逆转F-cirEA1的侵袭、迁移和增殖。F-circEA1可以海绵miR-4673，增强重组母细胞抗十肢瘫痪同源物4 （SMAD4）的表达，SMAD4是miR-4673的下游靶点。作为一种转录因子，SMAD4表现出与EML4-ALK1和腺苷脱氨酶RNA编辑酶1 （ADAR1）启动子区域直接结合的能力。有趣的是，我们还观察到RNA编辑酶ADAR1促进F-circEA1的表达，但抑制miR-4673的表达。F-circEA1、miR-4673、SMAD4和ADAR1之间的相互作用形成了一个反馈通路，有助于调节EML4-ALK变异体1阳性LUAD的进展。这一新发现为EML4-ALK变异1阳性肺腺癌提供了有希望的治疗思路。

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引用次数: 0

Tumor cells induce neural DKK1 expression to promote MDSC infiltration and subsequent T cell suppression 肿瘤细胞诱导神经DKK1表达，促进MDSC浸润和随后的T细胞抑制。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-12-20 DOI: 10.1016/j.cellsig.2024.111576

Ruoyan Liu , Xiaotian Shi , Shuangshuang Qian , Zhonghao Sun , Hao Dai , Yongwei Wu , Shihui Cao , Jingtao Luo , Ze Zhang

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.

神经作为肿瘤微环境的关键组成部分常常被忽视。然而，肿瘤和神经之间相互作用的分子机制在很大程度上仍然未知。在这项研究中，我们分析了来自癌症基因组图谱（TCGA）的数据，发现了DKK1表达与预后不良之间的显著关联，以及DKK1表达与头颈部鳞状细胞癌（HNSCC）和胰腺导管腺癌（PDAC）中髓源性抑制细胞（MDSC）浸润之间的相关性，这两种癌症类型的特征是肿瘤-神经相互作用明显。基于这些发现，我们推测肿瘤可能诱导DKK1在神经中的表达，神经源性DKK1可能促进MDSC浸润和免疫抑制。为了验证这一假设，我们采用了多种实验方法，包括体外三叉神经节与肿瘤细胞共培养、多重免疫组化和体内给药DKK1中和抗体。在共培养实验中，肿瘤细胞显著诱导神经节中DKK1的表达。此外，体内原位肿瘤模型显示，DKK1水平在荷瘤小鼠的血浆和神经节中均显著升高。在HNSCC和PDAC原位模型中，体内中和DKK1导致MDSC水平降低和MDSC介导的T细胞抑制受损。此外，神经元DKK1的条件缺失阐明了其在MDSC浸润和免疫抑制中的作用。我们的发现建立了一个新的分子轴，肿瘤细胞通过诱导神经分泌蛋白的表达来调节免疫微环境，从而丰富了肿瘤微环境的研究领域。

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引用次数: 0

Mechanism underlying CDC20 affecting epithelial ovarian cancer biological behavior by regulating BAG6 ubiquitination CDC20通过调控BAG6泛素化影响上皮性卵巢癌生物学行为的机制

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-12-20 DOI: 10.1016/j.cellsig.2024.111577

Xiaocui Zhang, Fangfang Bi, Qing Yang

Epithelial ovarian cancer (EOC) endangers women's life and health. It is reported that cell division cycle 20 (CDC20) plays a role in EOC, but its underlying mechanisms remain unclear. Additionally, the involvement of bcl-2-associated athanogen-6 (BAG6) in EOC has not been previously reported. This study demonstrated that CDC20 was highly expressed in EOC and exhibited oncogenic properties through both in vitro and in vivo molecular biology experiments. In contrast, BAG6 was low expressed and functioned as a tumor suppressor. Both CDC20 and BAG6 were found to correlate with patient stage. Notably, the degradation of BAG6, mediated by CDC20 via ubiquitin-proteasome pathway, was shown to enhance the malignant biological behavior of EOC. Furthermore, the interaction between CDC20 and BAG6 was dependent on the WD40 domain of CDC20 and the D-box of BAG6. These findings provided valuable insights into the molecular mechanisms of EOC and established a theoretical basis for novel therapeutic targets in clinical treatment.

上皮性卵巢癌（EOC）危害妇女的生命和健康。据报道，细胞分裂周期20 （CDC20）在EOC中起作用，但其潜在机制尚不清楚。此外，bcl-2相关的缺氧原-6 （BAG6）参与EOC的研究此前未见报道。本研究通过体外和体内分子生物学实验证明，CDC20在EOC中高表达，并表现出致癌特性。相比之下，BAG6低表达并作为肿瘤抑制因子发挥作用。CDC20和BAG6均与患者分期相关。值得注意的是，CDC20通过泛素-蛋白酶体途径介导的BAG6降解被证明可以增强EOC的恶性生物学行为。此外，CDC20与BAG6的相互作用依赖于CDC20的WD40结构域和BAG6的D-box。这些发现为EOC的分子机制提供了有价值的见解，并为临床治疗新的治疗靶点奠定了理论基础。

引用次数: 0

ALKBH5 promotes cardiac fibroblasts pyroptosis after myocardial infarction through Notch1/NLRP3 pathway ALKBH5通过Notch1/NLRP3途径促进心肌梗死后心肌成纤维细胞焦亡。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-12-20 DOI: 10.1016/j.cellsig.2024.111574

Liu-Gen Cui , Shu-Hui Wang , Sumra Komal , Jian-Jian Yin , Miao-Miao Zhai , Yue-Jiao Zhou , Qing-Wen Yu , Cong Wang , Pei Wang , Zhi-Mo Wang , Aliza Muhammad Zafar , Muhammad Shakeel , Li-Rong Zhang , Sheng-Na Han

Through bioinformatics screening, we previously found that AlkB homolog 5 (ALKBH5) expression, an m⁶A demethylase, was higher in patients with heart failure than in the normal population. This study aimed to investigate the molecular mechanisms by which ALKBH5 regulates heart failure. We established a myocardial infarction (MI)-induced heart failure model in rats in vivo and an in vitro hypoxia model using rat primary cardiac fibroblasts (RCFs). M⁶A sequencing, RNA immunoprecipitation assay, RNA pull-down assay, proximity ligation assay, gain-of-function and loss-of-function experiments, and transcriptomic analysis were performed to confirm the pyroptosis-promoting effects of ALKBH5. The effects of two small-molecule inhibitors (ZINC78774792 and ZINC00546946) on ALKBH5 expression were examined. The expression of m⁶A demethyltransferase ALKBH5 was significantly elevated in hypoxia-induced RCFs. Transcriptional profiling revealed Notch receptor 1 (Notch1) as an m⁶A modification target of ALKBH5, and Notch1 mRNA m⁶A modifications were increased in ALKBH5-deficient RCFs. Moreover, Notch1 and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) are associated. ALKBH5 knockdown alleviated hypoxia-induced RCF cell pyroptosis by inhibiting Notch1, NLRP3 inflammasome activation, and pyroptosis-associated protein (N-GSDMD), whereas ALKBH5 overexpression had the opposite effect. Targeting ALKBH5 with two small-molecule inhibitors (ZINC78774792 and ZINC00546946) reduced hypoxia-induced RCF pyroptosis, and ZINC00546946 alleviated cell pyroptosis after myocardial infarction in mice. Our results indicate that ALKBH5 promotes cardiac fibroblast pyroptosis after myocardial infarction through the Notch1/NLRP3 pathway. Therefore, inhibiting ALKBH5 may be a strategy for treating cardiovascular diseases.

通过生物信息学筛选，我们之前发现AlkB同源物5 (ALKBH5)，一种m6A去甲基化酶，在心力衰竭患者中的表达高于正常人群。本研究旨在探讨ALKBH5调控心力衰竭的分子机制。我们利用大鼠原代心脏成纤维细胞（rcf）建立了大鼠心肌梗死（MI）诱导的体内心力衰竭模型和体外缺氧模型。通过M6A测序、RNA免疫沉淀实验、RNA下拉实验、邻近连接实验、功能获得和功能丧失实验以及转录组学分析来证实ALKBH5的促焦作用。研究了两种小分子抑制剂ZINC78774792和ZINC00546946对ALKBH5表达的影响。缺氧诱导的rcf中m6A去甲基转移酶ALKBH5的表达显著升高。转录谱分析显示，Notch受体1 （Notch1）是ALKBH5的m6A修饰靶点，Notch1 mRNA m6A修饰在ALKBH5缺陷rcf中增加。此外，Notch1与NOD-、LRR-和pyrin domain containing protein 3 （NLRP3）相关。ALKBH5敲低可通过抑制Notch1、NLRP3炎性体激活和焦亡相关蛋白（N-GSDMD）减轻缺氧诱导的RCF细胞焦亡，而ALKBH5过表达则具有相反的作用。两种小分子抑制剂（ZINC78774792和ZINC00546946）靶向ALKBH5可降低小鼠缺氧诱导的RCF焦亡，ZINC00546946可减轻小鼠心肌梗死后细胞焦亡。我们的研究结果表明，ALKBH5通过Notch1/NLRP3途径促进心肌梗死后心肌成纤维细胞焦亡。因此，抑制ALKBH5可能是治疗心血管疾病的一种策略。

{"title":"ALKBH5 promotes cardiac fibroblasts pyroptosis after myocardial infarction through Notch1/NLRP3 pathway","authors":"Liu-Gen Cui , Shu-Hui Wang , Sumra Komal , Jian-Jian Yin , Miao-Miao Zhai , Yue-Jiao Zhou , Qing-Wen Yu , Cong Wang , Pei Wang , Zhi-Mo Wang , Aliza Muhammad Zafar , Muhammad Shakeel , Li-Rong Zhang , Sheng-Na Han","doi":"10.1016/j.cellsig.2024.111574","DOIUrl":"10.1016/j.cellsig.2024.111574","url":null,"abstract":"<div><div>Through bioinformatics screening, we previously found that AlkB homolog 5 (ALKBH5) expression, an m<sup>6</sup>A demethylase, was higher in patients with heart failure than in the normal population. This study aimed to investigate the molecular mechanisms by which ALKBH5 regulates heart failure. We established a myocardial infarction (MI)-induced heart failure model in rats in vivo and an in vitro hypoxia model using rat primary cardiac fibroblasts (RCFs). M<sup>6</sup>A sequencing, RNA immunoprecipitation assay, RNA pull-down assay, proximity ligation assay, gain-of-function and loss-of-function experiments, and transcriptomic analysis were performed to confirm the pyroptosis-promoting effects of ALKBH5. The effects of two small-molecule inhibitors (ZINC78774792 and ZINC00546946) on ALKBH5 expression were examined. The expression of m<sup>6</sup>A demethyltransferase ALKBH5 was significantly elevated in hypoxia-induced RCFs. Transcriptional profiling revealed Notch receptor 1 (Notch1) as an m<sup>6</sup>A modification target of ALKBH5, and Notch1 mRNA m<sup>6</sup>A modifications were increased in ALKBH5-deficient RCFs. Moreover, Notch1 and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) are associated. ALKBH5 knockdown alleviated hypoxia-induced RCF cell pyroptosis by inhibiting Notch1, NLRP3 inflammasome activation, and pyroptosis-associated protein (N-GSDMD), whereas ALKBH5 overexpression had the opposite effect. Targeting ALKBH5 with two small-molecule inhibitors (ZINC78774792 and ZINC00546946) reduced hypoxia-induced RCF pyroptosis, and ZINC00546946 alleviated cell pyroptosis after myocardial infarction in mice. Our results indicate that ALKBH5 promotes cardiac fibroblast pyroptosis after myocardial infarction through the Notch1/NLRP3 pathway. Therefore, inhibiting ALKBH5 may be a strategy for treating cardiovascular diseases.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111574"},"PeriodicalIF":4.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876256","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}

引用次数: 0

METTL3-mediated m6A modifications of NLRP3 accelerate alveolar bone resorption through enhancing macrophage pyroptosis mettl3介导的NLRP3的m6A修饰通过增强巨噬细胞焦亡加速牙槽骨吸收。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-12-19 DOI: 10.1016/j.cellsig.2024.111572

Qiudong Yang , Junhong Xiao , Yuqi Liu , Zhengkun Yang , Chuan Wang , Jiahui Sun , Huiyi Wang , Heyu Liu , Xiaoxuan Wang , Li Ma , Xin Huang , Zhengguo Cao

Periodontitis (PD) is twice as prevalent in diabetics compared to nondiabetics, and diabetes-associated PD is characterized by increased inflammation and aggravated tissue damage. Pyroptosis has recently been implicated in diabetes-associated PD; however, the underlying mechanisms remain largely unknown, resulting in a lack of effective treatments. In this study, we investigated the role of methyltransferase-like 3 (METTL3) in macrophage pyroptosis and found that it inhibits the osteogenic differentiation of osteoblasts via pyroptotic macrophages in a diabetes-associated periodontitis mouse model. Further analysis and validation revealed that nod-like receptor family pyrin domain-containing 3 (NLRP3) is a target of METTL3, with its mRNA stability regulated through a binding of insulin-like growth factor 2 binding protein 3 (IGF2BP3)-dependent pathway. Additionally, local injection of adeno-associated virus 9 (AAV9) demonstrated that METTL3 deficiency in macrophages significantly ameliorates periodontal inflammation and alveolar bone loss in diabetes-associated PD mice. Collectively, our findings indicate that METTL3-mediated modulation of NLRP3 expression is a crucial factor in macrophage pyroptosis during diabetes-associated PD progression. This suggests that the METTL3/IGF2BP3/NLRP3 axis is a novel and promising target for the improvement of periodental inflammation and alveolar bone loss in diabetes-associated PD.

牙周炎（PD）在糖尿病患者中的发病率是非糖尿病患者的两倍，糖尿病相关PD的特征是炎症增加和组织损伤加重。最近发现焦亡与糖尿病相关的PD有关；然而，潜在的机制仍然很大程度上是未知的，导致缺乏有效的治疗。在本研究中，我们在糖尿病相关性牙周炎小鼠模型中研究了甲基转移酶样3 （METTL3）在巨噬细胞热噬中的作用，发现它通过热噬巨噬细胞抑制成骨细胞的成骨分化。进一步的分析和验证表明，nod样受体家族pyrin domain-containing 3 （NLRP3）是METTL3的靶点，其mRNA稳定性通过胰岛素样生长因子2结合蛋白3 （IGF2BP3）依赖途径调控。此外，局部注射腺相关病毒9 （AAV9）表明，巨噬细胞中METTL3缺失可显著改善糖尿病相关PD小鼠的牙周炎症和牙槽骨丢失。总的来说，我们的研究结果表明，mettl3介导的NLRP3表达调节是糖尿病相关PD进展中巨噬细胞焦亡的关键因素。这表明METTL3/IGF2BP3/NLRP3轴是改善糖尿病相关PD患者牙周炎症和牙槽骨丢失的一个新的、有希望的靶点。

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引用次数: 0

Identification of AXL as a novel positive regulator of lipid raft in gastric cancer AXL在胃癌中作为一种新的正调节因子的鉴定。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-12-19 DOI: 10.1016/j.cellsig.2024.111573

Zhi Yang , Chuanfu Ren , Ziyun He , Banxin Luo , Xin Chen , En Xu , Wenxian Guan , Xuefeng Xia

Lipid rafts are highly heterogeneous and dynamic microdomains involved in molecule trafficking and signaling transduction. This study investigates the role of lipid rafts in gastric cancer and their key regulators. Analyzing FFPE samples from 111 gastric cancer patients, we found that high lipid raft levels predict poor prognosis. Modulating these levels in gastric cancer cell lines significantly impacted cell proliferation, migration, and invasion. Weighted Gene Co-expression Network Analysis identified AXL as a hub gene associated with lipid rafts. AXL knockdown experiments revealed its interaction with Caveolin-1, a caveolae lipid raft protein, which regulates lipid raft levels and promotes AKT and ERK signaling, enhancing cancer development and metastasis. In vivo tumorigenesis assays and survival analyses further supported these findings. This study underscores the significance of lipid rafts in gastric cancer and identifies AXL as a novel regulator, offering new insights into the molecular mechanisms of cancer progression and suggesting potential therapeutic targets.

脂筏是高度异质性和动态的微结构域，参与分子运输和信号转导。本研究探讨脂筏在胃癌中的作用及其关键调控因子。通过分析111例胃癌患者的FFPE样本，我们发现高脂筏水平预示着不良预后。在胃癌细胞系中调节这些水平可以显著影响细胞的增殖、迁移和侵袭。加权基因共表达网络分析发现AXL是与脂筏相关的枢纽基因。AXL敲低实验发现其与小泡脂筏蛋白Caveolin-1相互作用，调节脂筏水平，促进AKT和ERK信号传导，促进肿瘤的发生和转移。体内肿瘤发生试验和生存分析进一步支持了这些发现。本研究强调了脂筏在胃癌中的重要性，并确定了AXL作为一种新的调节因子，为癌症进展的分子机制提供了新的见解，并提出了潜在的治疗靶点。

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引用次数: 0

Corrigendum to “Iron depletion suppresses mTORC1-directed signalling in intestinal Caco-2 cells via induction of REDD1” [Cellular Signalling, 28: (2016) 412–424] “铁缺乏通过诱导REDD1抑制肠道Caco-2细胞mtorc1定向信号传导”的更正[细胞信号传导，28(2016)412-424]。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-12-17 DOI: 10.1016/j.cellsig.2024.111567

Ailsa Watson , Christopher Lipina , Harry J. McArdle , Peter M. Taylor , Harinder S. Hundal

引用次数: 0

Platelet inhibition by hypochlorous acid involves cAMP signalling 次氯酸抑制血小板与cAMP信号有关。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-12-16 DOI: 10.1016/j.cellsig.2024.111568

Lorna O'Donoghue , Dishon Hiebner , Roopesh Krishnankutty , Ingmar Schoen , Alex von Kriegsheim , Albert Smolenski

Hypochlorous acid (HOCl), made by neutrophil-derived myeloperoxidase, has been suggested to inhibit platelets, however, the mechanisms involved have not been described. Here we confirm that HOCl exposure changes platelet morphology and inhibits platelet spreading and aggregation. HOCl effects could be reversed by glutathione suggesting a role for cysteine oxidation. Mass spectrometry-based proteomics of HOCl-exposed platelets revealed oxidised cysteine residues in 37 proteins including adenylate cyclase 6 and Rap1B. Adenylate cyclase is involved in the inhibitory cAMP pathway triggered by endothelium-derived prostacyclin and Rap1 is a small G protein required for integrin αIIbβ3 activation and platelet aggregation. We show that HOCl exposure stimulates cAMP production and phosphorylation of the cAMP-dependent protein kinase substrate VASP in platelets and transfected HEK293T cells. In addition, HOCl inhibited Rap1-GTP formation. These data suggest that HOCl inhibits platelets at least in part through the cAMP pathway and by regulating Rap1. Thus, this study provides new insights into HOCl mediated crosstalk between neutrophils and platelets.

由中性粒细胞衍生的髓过氧化物酶产生的次氯酸（HOCl）被认为可以抑制血小板，然而，其机制尚未被描述。本研究证实HOCl暴露会改变血小板形态，抑制血小板的扩散和聚集。HOCl效应可被谷胱甘肽逆转，提示其与半胱氨酸氧化有关。基于质谱的hocl暴露血小板蛋白质组学显示37个蛋白中有氧化的半胱氨酸残基，包括腺苷酸环化酶6和Rap1B。腺苷酸环化酶参与内皮源性前列环素触发的抑制性cAMP通路，Rap1是整合素αIIbβ3活化和血小板聚集所需的小G蛋白。我们发现，暴露于HOCl刺激血小板和转染HEK293T细胞中cAMP的产生和cAMP依赖性蛋白激酶底物VASP的磷酸化。此外，HOCl抑制Rap1-GTP的形成。这些数据表明，HOCl至少部分通过cAMP途径和调节Rap1抑制血小板。因此，这项研究为HOCl介导的中性粒细胞和血小板之间的串扰提供了新的见解。

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引用次数: 0

Disulfiram/Cu targeting FOXO6 modulates sensitivity of hepatocellular carcinoma to lenvatinib via disrupt choline metabolic 双硫仑/铜靶向FOXO6通过破坏胆碱代谢调节肝癌对lenvatinib的敏感性。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-12-16 DOI: 10.1016/j.cellsig.2024.111563

Shiyi Wu , Jialu Weng , Yating Pan , Zhikai Wen , Jing Zeng , Yunwei Lou , Songjian Tong , Pan Liao , Na Li , Zhijie Yu , Jinglin Xia

Disulfiram/Cu(DSF/Cu) has a known pharmacokinetic and safety profile, exerting a strong antitumor effect. Oral tyrosine kinase inhibitors including lenvatinib are approved as first-line therapy for treating advanced unresectable hepatocellular carcinoma (HCC). These patients still have limited survival due to drug resistance. Disulfiram/Cu and lenvatinib are the promising antitumor treatments. In this study, we studied whether Disulfiram/Cu increased lenvatinib sensitivity in HCC cells. Moreover, the potential drug targets of Disulfiram/Cu and associated mechanisms were explored. We mainly investigated Autophagic flux was determined via immunofluorescence analysis and confocal microscopy. p-PI3K, p-AKT, p62, LC3B, FOXO6, and CHKA proteins associated with autophagy were detected by immunoblotting. In addition, antitumour activity of Disulfiram/Cu in combination with lenvatinib was examined in vivo through construction of the nude mouse transplant tumor model. Furthermore, our results show disulfiram/Cu combined with lenvatinib exerted the synergistic impact on treating HCC in vitro. Mechanistically, transcriptome combined with metabolome reveals Disulfiram/Cu targeting FOXO6 induction of autophagy mediated inhibits cell growth in hepatocellular carcinoma by downregulating CHKα for inhibiting AKT pathway activation while blocking choline metabolic reprogramming in HCC. These effects mostly explain the tumor-promoting effect of FOXO6 on HCC. In general, the results illustrate the mechanistic associations between metabolites and tumor cell malignant phenotype, contributing to developing new anti-HCC pharmacological treatments by Inhibiting FOXO6 for disrupting choline metabolic pathway.

双硫仑/铜（DSF）具有已知的药代动力学和安全性，具有很强的抗肿瘤作用。口服酪氨酸激酶抑制剂（包括lenvatinib）被批准作为治疗晚期不可切除肝细胞癌（HCC）的一线疗法。由于耐药，这些患者的生存期仍然有限。双硫仑/铜和lenvatinib是很有前途的抗肿瘤药物。在这项研究中，我们研究了双硫仑/铜是否会增加HCC细胞对lenvatinib的敏感性。此外，还探讨了双硫仑/铜的潜在药物靶点及其相关机制。我们主要通过免疫荧光分析和共聚焦显微镜检测自噬通量。免疫印迹法检测与自噬相关的p-PI3K、p-AKT、p62、LC3B、FOXO6和CHKA蛋白。此外，通过构建裸鼠移植瘤模型，检测双硫仑/铜联合lenvatinib的体内抗肿瘤活性。此外，我们的研究结果表明，双硫仑/铜联合lenvatinib在体外治疗HCC方面具有协同作用。机制上，转录组学和代谢组学结合发现，双硫仑/铜靶向FOXO6诱导自噬，通过下调CHKα抑制AKT通路激活，阻断肝癌中胆碱代谢重编程，从而抑制肝癌细胞生长。这些作用在很大程度上解释了FOXO6对HCC的促瘤作用。总的来说，这些结果说明了代谢物与肿瘤细胞恶性表型之间的机制关联，有助于通过抑制FOXO6破坏胆碱代谢途径来开发新的抗hcc药物治疗。

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