Cellular signalling最新文献_第5页

Aquaporin proteins: A promising frontier for therapeutic intervention in cerebral ischemic injury 水蒸发蛋白：大脑缺血损伤治疗干预的前沿领域。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-05 DOI: 10.1016/j.cellsig.2024.111452

Cerebral ischemic injury is characterized by reduced blood flow to the brain, remains a significant cause of morbidity and mortality worldwide. Despite improvements in therapeutic approaches, there is an urgent need to identify new targets to lessen the effects of ischemic stroke. Aquaporins, a family of water channel proteins, have recently come to light as promising candidates for therapeutic intervention in cerebral ischemic injury. There are 13 aquaporins identified, and AQP4 has been thoroughly involved with cerebral ischemia as it has been reported that modulation of AQP4 activity can offers a possible pathway for therapeutic intervention along with their role in pH, osmosis, ions, and the blood-brain barrier (BBB) as possible therapeutic targets for cerebral ischemia injury. The molecular pathways which can interacts with particular cellular pathways, participation in neuroinflammation, and possible interaction with additional proteins thought to be involved in the etiology of a stroke. Understanding these pathways offers crucial information on the diverse role of AQPs in cerebral ischemia, paving the door for the development of focused/targeted therapeutics.

脑缺血损伤的特点是脑部血流量减少，仍然是全球发病率和死亡率的重要原因。尽管治疗方法有所改进，但仍迫切需要找到新的靶点来减轻缺血性中风的影响。水通道蛋白家族中的水蒸发蛋白最近被发现有望成为治疗脑缺血损伤的候选靶点。目前已确定的水通道蛋白有 13 种，其中 AQP4 与脑缺血有密切关系，因为有报道称，调节 AQP4 的活性可为治疗干预提供一种可能的途径，同时它们在 pH 值、渗透、离子和血脑屏障（BBB）中的作用也是脑缺血损伤的可能治疗靶点。这些分子通路可与特定的细胞通路相互作用，参与神经炎症，并可能与其他被认为与中风病因有关的蛋白质相互作用。了解这些通路为了解 AQPs 在脑缺血中的不同作用提供了重要信息，为开发重点/靶向疗法铺平了道路。

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引用次数: 0

Octreotide protects against LPS-induced endothelial cell and lung injury 奥曲肽可防止 LPS 诱导的内皮细胞和肺损伤。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-05 DOI: 10.1016/j.cellsig.2024.111455

Growth hormone (GH) is a crucial regulator of growth, cell reproduction, and regeneration; and it is controlled by growth hormone-releasing hormone (GHRH) and somatostatin. Lipopolysaccharides (LPS) can compromise endothelial function, leading to increased inflammation and vascular leak. Octreotide (OCT) is an FDA-approved synthetic somatostatin analog (SSA) used to treat acromegaly and neuroendocrine tumors. The present study investigates the effects of OCT on LPS-induced injury in bovine and human lung endothelial cells, as well as in mouse lungs. Our in vitro observations suggest that OCT effectively counteracts LPS-induced endothelial leak, inflammation, and reactive oxygen species (ROS) generation. Furthermore, OCT reduces bronchoalveolar lavage fluid (BALF) protein concentration in an experimental model of Acute Lung Injury (ALI). Our study suggests that OCT mitigates LPS-induced endothelial cell and lung injury, suggesting that it may represent an exciting therapeutic possibility in diseases related to barrier dysfunction.

生长激素（GH）是生长、细胞繁殖和再生的重要调节剂，受生长激素释放激素（GHRH）和体生长激素控制。脂多糖（LPS）会损害内皮功能，导致炎症和血管渗漏增加。奥曲肽 (OCT) 是一种经 FDA 批准的合成体生长抑素类似物 (SSA)，用于治疗肢端肥大症和神经内分泌肿瘤。本研究调查了 OCT 对牛和人肺内皮细胞以及小鼠肺内 LPS 诱导损伤的影响。我们的体外观察结果表明，OCT 能有效对抗 LPS 诱导的内皮渗漏、炎症和活性氧（ROS）生成。此外，OCT 还能降低急性肺损伤（ALI）实验模型中支气管肺泡灌洗液（BALF）的蛋白质浓度。我们的研究表明，OCT 可减轻 LPS 诱导的内皮细胞和肺损伤，这表明它可能是治疗与屏障功能障碍有关的疾病的一种令人兴奋的方法。

引用次数: 0

Retraction notice to “MicroRNA-148a-3p enhances the effects of sevoflurane on hepatocellular carcinoma cell progression via ROCK1 repression” [Cellular Signalling 83 (2021) 109982] 关于 "MicroRNA-148a-3p 通过抑制 ROCK1 增强七氟烷对肝癌细胞进展的影响 "的撤稿通知 [Cellular Signalling 83 (2021) 109982]。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-05 DOI: 10.1016/j.cellsig.2024.111436

引用次数: 0

Resveratrol inhibits white adipose deposition by the ESR1-mediated PI3K/AKT signaling pathway 白藜芦醇通过 ESR1 介导的 PI3K/AKT 信号通路抑制白色脂肪沉积。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-04 DOI: 10.1016/j.cellsig.2024.111448

Excessive adipose accumulation is the primary cause of obesity. Resveratrol (RES), a natural polyphenolic compound, has garnered significant attention for its anti-obesity properties. However, the precise mechanisms by which RES influences fat deposition have not yet been explored. In this study, the aim was to identify the target proteins and associated pathways of RES in order to elucidate the mechanisms by which RES reduces fat deposition. In this study, mice were administered 400 mg/kg of RES via gavage for 12 weeks. We found that while 400 mg/kg RES had no impact on the growth of the mice, it significantly reduced the weight of various white adipose tissues, as well as the serum and liver concentrations of total cholesterol and triglycerides. Network pharmacology identified 15 potential targets of RES and highlighted the PI3K/AKT signaling pathway as a key pathway. Molecular docking and dynamic simulations suggested that ESR1 might be the target protein through which RES exerts its anti-fat deposition effects. In vitro experiments revealed that ESR1 promotes the proliferation and inhibits the differentiation of 3 T3-L1 adipocytes, and suppresses the PI3K/AKT signaling pathway. Silencing the ESR1 gene altered the ability of RES to inhibit cell differentiation via the PI3K/AKT pathway. Gene expression results in subcutaneous adipose tissue, epididymal fat tissue, and liver tissue of mice were consistent with observations in cells. In summary, RES reduces white fat deposition by directly targeting the ESR1 protein and inhibiting the PI3K/AKT signaling pathway. Our findings provide new insights into the potential use of RES in the prevention and treatment of obesity.

脂肪过度堆积是肥胖的主要原因。白藜芦醇（RES）是一种天然多酚化合物，因其抗肥胖特性而备受关注。然而，RES 影响脂肪沉积的确切机制尚未探明。本研究旨在确定 RES 的靶蛋白和相关途径，以阐明 RES 减少脂肪沉积的机制。在这项研究中，通过灌胃给小鼠服用每公斤 400 毫克的 RES，持续 12 周。我们发现，虽然每公斤 400 毫克的 RES 对小鼠的生长没有影响，但它能显著降低各种白色脂肪组织的重量，以及血清和肝脏中总胆固醇和甘油三酯的浓度。网络药理学确定了 RES 的 15 个潜在靶点，并强调 PI3K/AKT 信号通路是一个关键通路。分子对接和动态模拟表明，ESR1可能是RES发挥抗脂肪沉积作用的靶蛋白。体外实验发现，ESR1能促进3个T3-L1脂肪细胞的增殖和抑制分化，并抑制PI3K/AKT信号通路。沉默 ESR1 基因改变了 RES 通过 PI3K/AKT 途径抑制细胞分化的能力。小鼠皮下脂肪组织、附睾脂肪组织和肝组织中的基因表达结果与细胞中的观察结果一致。总之，RES通过直接靶向ESR1蛋白和抑制PI3K/AKT信号通路来减少白色脂肪沉积。我们的研究结果为RES在预防和治疗肥胖症方面的潜在应用提供了新的见解。

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引用次数: 0

The major vault protein integrates adhesion-driven signals to regulate collagen remodeling 主要拱顶蛋白整合了粘附驱动的信号，以调节胶原蛋白的重塑。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-04 DOI: 10.1016/j.cellsig.2024.111447

DDR1 interacts with fibrillar collagen and can affect β1 integrin-dependent signaling, but the mechanism that mediates functional interactions between these two different receptors is not defined. We searched for molecules that link DDR1 and β1 integrin-dependent signaling in response to collagen binding. The activation of DDR1 by binding to fibrillar collagen reduced by 5-fold, β1 integrin-dependent ERK phosphorylation that leads to MMP1 expression. In contrast, pharmacological inhibition of DDR1 or culturing cells on fibronectin restored ERK phosphorylation and MMP1 expression mediated by the β1 integrin. A phospho-site screen indicated that collagen-induced DDR1 activation inhibited β1 integrin-dependent ERK signaling by regulating autophosphorylation of focal adhesion kinase (FAK). Immunoprecipitation, mass spectrometry, and protein-protein interaction mapping showed that while DDR1 and FAK do not interact directly, the major vault protein (MVP) binds DDR1 and FAK depending on the substrate. MVP associated with DDR1 in cells expressing β1 integrin that were cultured on collagen. Knockdown of MVP restored ERK activation and MMP1 expression in DDR1-expressing cells cultured on collagen. Immunostaining of invasive cancers in human colon showed colocalization of DDR1 with MVP. These data indicate that MVP interactions with DDR1 and FAK contribute to the regulation of β1 integrin-dependent signaling pathways that drive collagen degradation.

DDR1 与纤维胶原相互作用，可影响β1整合素依赖性信号传导，但这两种不同受体之间功能性相互作用的介导机制尚未明确。我们寻找了连接 DDR1 和 b1 整合素依赖性信号转导与胶原蛋白结合的分子。与纤维胶原结合激活 DDR1 后，b1 整合素依赖的 ERK 磷酸化减少了 5 倍，而 ERK 磷酸化会导致 MMP1 的表达。相反，药物抑制 DDR1 或在纤维粘连蛋白上培养细胞可恢复 b1 整合素介导的 ERK 磷酸化和 MMP1 表达。磷酸化位点筛选表明，胶原诱导的 DDR1 激活通过调节焦点粘附激酶（FAK）的自身磷酸化，抑制了 β1 整合素依赖的 ERK 信号转导。免疫沉淀、质谱分析和蛋白质相互作用图谱显示，虽然DDR1和FAK不直接相互作用，但主要拱顶蛋白（MVP）会根据底物的不同与DDR1和FAK结合。在胶原蛋白上培养的表达 b1 整合素的细胞中，MVP 与 DDR1 相关。在胶原上培养的表达 DDR1 的细胞中，敲除 MVP 可恢复 ERK 的激活和 MMP1 的表达。人结肠浸润性癌症的免疫染色显示 DDR1 与 MVP 共定位。这些数据表明，MVP 与 DDR1 和 FAK 的相互作用有助于调节驱动胶原降解的 β1 整合素依赖性信号通路。

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引用次数: 0

New insights into prostate Cancer from the renin-angiotensin-aldosterone system. 肾素-血管紧张素-醛固酮系统对前列腺癌的新认识。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-04 DOI: 10.1016/j.cellsig.2024.111442

Prostate cancer is among the most common malignancies found in men, with multifactorial changes occurring altogether to disrupt the pathophysiology of this gland. The Renin-Angiotensin-Aldosterone System (RAAS) is an extensively studied pathway that has newly attributed fundamental roles in cancer biology that impact cell growth, migration, metastasis, and death. These processes are significantly influenced by various components of the RAAS, including prorenin, AT1R, AT2R, and Ang 1–7/Mas receptors. Although the pathophysiology of prostate cancer is complex, targeting the RAAS shows promise as a therapeutic approach. RAAS dysregulation is evident in prostate cancer, and treatments traditionally used for cardiovascular diseases are being explored for cancer therapy. The RAAS pathway has significant effects on the formation of new blood vessels (angiogenesis), the spread of cancer cells to other parts of the body (metastasis), and cell proliferation. In this pathway, angiotensin II and its receptors have crucial functions. Angiotensin II stimulates angiogenesis and cell proliferation through the AT1R, whereas the AT2R has the opposite effect by inhibiting cell growth. Additional pathways involving ACE2/Ang 1–7/Mas also provide potential targets for therapeutic intervention, mitigating the impact of the traditional ACE/Angiotensin II/AT1R pathway. The components of the RAAS influence multiple signalling pathways, such as Androgen Receptor (AR), NF-κB, and PI3K/AKT/mTOR, which enhances our understanding of how it contributes to the progression of prostate cancer. This also provides new possibilities for therapeutic interventions.

前列腺癌是男性最常见的恶性肿瘤之一，其病理生理学受到多种因素的共同影响。肾素-血管紧张素-醛固酮系统（RAAS）是一个被广泛研究的途径，它在癌症生物学中扮演着新的基本角色，影响着细胞的生长、迁移、转移和死亡。这些过程受到 RAAS 各种成分的重大影响，包括肾素原、AT1R、AT2R 和 Ang 1-7/Mas 受体。尽管前列腺癌的病理生理学十分复杂，但以 RAAS 为靶点的治疗方法前景看好。RAAS 失调在前列腺癌中非常明显，传统上用于心血管疾病的治疗方法正被用于癌症治疗。RAAS 通路对新血管的形成（血管生成）、癌细胞向身体其他部位的扩散（转移）和细胞增殖有重要影响。在这一途径中，血管紧张素 II 及其受体发挥着关键作用。血管紧张素 II 通过 AT1R 刺激血管生成和细胞增殖，而 AT2R 则通过抑制细胞生长产生相反的效果。涉及 ACE2/Ang 1-7/Mas 的其他途径也为治疗干预提供了潜在目标，减轻了传统 ACE/Angiotensin II/AT1R 途径的影响。RAAS 的成分会影响多种信号通路，如雄激素受体 (AR)、NF-κB 和 PI3K/AKT/mTOR，这加深了我们对 RAAS 如何导致前列腺癌进展的理解。这也为治疗干预提供了新的可能性。

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引用次数: 0

ZFHX2-AS1 interacts with DKC1 to regulate ARHGAP5 pseudouridylation and suppress ovarian cancer progression ZFHX2-AS1与DKC1相互作用，调控ARHGAP5假酰化并抑制卵巢癌的进展。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-03 DOI: 10.1016/j.cellsig.2024.111441

Ovarian cancer (OCa) remains a highly lethal disease, largely due to late-stage diagnosis and limited treatment options for recurrent metastatic tumors. Long non-coding RNAs (lncRNAs) have been recognized as key regulators of cancer hallmarks, yet their specific roles in driving OCa progression are not fully understood. In this study, we employed an integrated approach combining clinical correlation, functional assays, and mechanistic investigations to reveal that lncRNA ZFHX2-AS1 is significantly downregulated in OCa tissues and cells, with its reduced expression associated with poor clinical outcomes. Using in vitro and in vivo models, we demonstrated that overexpression of ZFHX2-AS1 suppresses OCa cell proliferation, migration and invasion, whereas ZFHX2-AS1 knockdown enhances these malignant phenotypes. Mechanistically, we defined that ZFHX2-AS1 interacts with and attenuates the enzymatic activity of the pseudouridine synthase DKC1, thereby reducing pseudouridylation and stabilizing the oncogenic ARHGAP5 mRNA. Re-expression of ARHGAP5 could partially reverse the tumor-suppressive effects of ZFHX2-AS1. Further, we found that ARHGAP5 promotes epithelial-mesenchymal transition (EMT) by regulating Rho GTPases activities, and that ZFHX2-AS1 inhibits EMT in OCa by downregulating ARHGAP5 expression and suppressing the Rho GTPase signaling pathway. Taken together, our findings identify ZFHX2-AS1 as a potent tumor suppressor in OCa, acting through the modulation of DKC1-mediated pseudouridylation of ARHGAP5 and the inhibition of the Rho GTPase pathway, thus offering a potential therapeutic target for combating OCa progression.

卵巢癌（OCa）仍然是一种致死率很高的疾病，这主要是由于晚期诊断和对复发性转移肿瘤的有限治疗方案造成的。长非编码 RNA（lncRNA）已被认为是癌症特征的关键调控因子，但它们在驱动卵巢癌进展中的具体作用尚未完全明了。在这项研究中，我们采用了一种将临床相关性、功能检测和机理研究相结合的综合方法，揭示了lncRNA ZFHX2-AS1在OCa组织和细胞中显著下调，其表达的减少与不良临床预后相关。我们利用体外和体内模型证明，ZFHX2-AS1 的过表达会抑制 OCa 细胞的增殖、迁移和侵袭，而 ZFHX2-AS1 的敲除会增强这些恶性表型。从机理上讲，我们确定 ZFHX2-AS1 与假尿苷合成酶 DKC1 相互作用并削弱其酶活性，从而减少假尿苷化并稳定致癌的 ARHGAP5 mRNA。ARHGAP5的再表达可部分逆转ZFHX2-AS1的肿瘤抑制作用。此外，我们还发现 ARHGAP5 可通过调节 Rho GTPase 的活性促进上皮-间质转化（EMT），而 ZFHX2-AS1 可通过下调 ARHGAP5 的表达和抑制 Rho GTPase 信号通路抑制 OCa 的 EMT。综上所述，我们的研究结果表明，ZFHX2-AS1通过调节DKC1介导的ARHGAP5假苷酸化和抑制Rho GTPase通路，是OCa中一种有效的肿瘤抑制因子，从而为抗击OCa进展提供了一个潜在的治疗靶点。

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引用次数: 0

Non-cyclic nucleotide EPAC1 activators suppress lipopolysaccharide-regulated gene expression, signalling and intracellular communication in differentiated macrophage-like THP-1 cells 非环核苷酸 EPAC1 激活剂可抑制分化巨噬细胞样 THP-1 细胞中脂多糖调控的基因表达、信号传导和细胞内通讯。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-03 DOI: 10.1016/j.cellsig.2024.111444

This study explores the anti-inflammatory effects of non-cyclic nucleotide EPAC1 activators, PW0577 and SY007, on lipopolysaccharide (LPS)-induced responses in differentiated THP-1 macrophage-like cells. Both activators were found to selectively activate EPAC1 in THP-1 macrophages, leading to the activation of the key down-stream effector, Rap1. RNA sequencing analysis of LPS-stimulated THP-1 macrophages, revealed that treatment with PW0577 or SY007 significantly modulates gene expression related to fibrosis and inflammation, including the suppression of NLRP3, IL-1β, and caspase 1 protein expression in LPS-stimulated cells. Notably, these effects were independent of p65 NFκB phosphorylation at Serine 536, indicating a distinct mechanism of action. The study further identified a shared influence of both activators on LPS signalling pathways, particularly impacting extracellular matrix (ECM) components and NFκB-regulated genes. Additionally, in a co-culture model involving THP-1 macrophages, vascular smooth muscle cells, and human coronary artery endothelial cells, EPAC1 activators modulated immune-vascular interactions, suggesting a broader role in regulating cellular communication between macrophages and endothelial cells. These findings enhance our understanding of EPAC1's role in inflammation and propose EPAC1 activators as potential therapeutic agents for treating inflammatory and fibrotic conditions through targeted modulation of Rap1 and associated signalling pathways.

本研究探讨了非环核苷酸 EPAC1 激活剂 PW0577 和 SY007 对分化的 THP-1 巨噬细胞样细胞中脂多糖（LPS）诱导反应的抗炎作用。研究发现，这两种激活剂都能选择性地激活 THP-1 巨噬细胞中的 EPAC1，从而激活关键的下游效应物 Rap1。对LPS刺激的THP-1巨噬细胞进行的RNA测序分析表明，PW0577或SY007能显著调节LPS刺激细胞中与纤维化和炎症相关的基因表达，包括抑制NLRP3、IL-1β和caspase 1蛋白的表达。值得注意的是，这些作用与 p65 NFκB 在丝氨酸 536 处的磷酸化无关，表明其作用机制与众不同。研究进一步确定了两种激活剂对 LPS 信号通路的共同影响，尤其是对细胞外基质（ECM）成分和 NFκB 调控基因的影响。此外，在涉及 THP-1 巨噬细胞、血管平滑肌细胞和人冠状动脉内皮细胞的共培养模型中，EPAC1 激活剂调节了免疫-血管相互作用，表明其在调节巨噬细胞和内皮细胞之间的细胞通讯中发挥着更广泛的作用。这些发现加深了我们对 EPAC1 在炎症中作用的理解，并提出 EPAC1 激活剂是通过靶向调节 Rap1 和相关信号通路治疗炎症和纤维化病症的潜在治疗药物。

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引用次数: 0

HNRNPD/MAD2L2 axis facilitates lung adenocarcinoma progression and is a potential prognostic biomarker HNRNPD/MAD2L2轴有助于肺腺癌的进展，是一种潜在的预后生物标志物。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-02 DOI: 10.1016/j.cellsig.2024.111443

Background

Although progress has been made in the treatment of LAUD, the survival rate for patients remains poor. An in-depth grasp of the molecular pathways implicated in LUAD progression is vital for improving diagnosis and treatment strategies. This study aims to explore novel molecular mechanisms driving LUAD progression and identify new potential prognostic biomarkers for LAUD patients.

Methods

Based on mass spectrometry analysis of human LUAD tissues, HNRNPD and MAD2L2 were identified as potential key proteins involved in LUAD progression. Subsequently, the interplay between HNRNPD and MAD2L2 was examined through dual-luciferase reporter assays, RNA-seq analysis, and various molecular biology techniques. Ultimately, the role of the HNRNPD/MAD2L2 axis in LUAD advancement and its potential as a prognostic indicator were investigated utilizing LUAD specimens, cell lines, and xenograft mouse models.

Results

In human LAUD tissues and cell lines, elevated levels of HNRNPD and MAD2L2 proteins were discovered. It was determined that HNRNPD binds to the MAD2L2 promoter, forming a regulatory axis at the transcriptional level. Subsequently, both in vitro and in vivo data demonstrated that the downregulation of the HNRNPD/MAD2L2 axis inhibited LUAD progression, while this effect could be rescued by MAD2L2 upregulation. Conversely, the upregulation of the HNRNPD/MAD2L2 axis facilitated LUAD progression, and this outcome could be reversed by MAD2L2 knockdown. Mechanistically, the downregulation of HNRNPD suppressed the promoter activity and transcription of MAD2L2, thus inhibiting the PI3K/HIF1α/ANGPTL4 pathway and tumor angiogenesis. Finally, it was confirmed that LUAD patients with high levels of both HNRNPD and MAD2L2 exhibited the poorest prognosis. Therefore, the HNRNPD/MAD2L2 axis has been identified as a potential predictive indicator for LUAD patients.

Conclusions

The HNRNPD/MAD2L2 axis facilitates LUAD progression and serves as a potential prognostic biomarker.

背景：尽管LAUD的治疗取得了进展，但患者的生存率仍然很低。深入了解LUAD进展的分子通路对于改善诊断和治疗策略至关重要。本研究旨在探索驱动LUAD进展的新型分子机制，并为LAUD患者确定新的潜在预后生物标志物：方法：基于对人类 LUAD 组织的质谱分析，HNRNPD 和 MAD2L2 被确定为参与 LUAD 进展的潜在关键蛋白。随后，通过双荧光素酶报告实验、RNA-seq分析和各种分子生物学技术研究了HNRNPD和MAD2L2之间的相互作用。最后，利用LUAD标本、细胞系和异种移植小鼠模型研究了HNRNPD/MAD2L2轴在LUAD进展中的作用及其作为预后指标的潜力：结果：在人类 LAUD 组织和细胞系中，发现 HNRNPD 和 MAD2L2 蛋白水平升高。结果：在人类 LAUD 组织和细胞系中发现 HNRNPD 和 MAD2L2 蛋白水平升高，并确定 HNRNPD 与 MAD2L2 启动子结合，在转录水平形成调控轴。随后，体外和体内数据都表明，下调 HNRNPD/MAD2L2 轴可抑制 LUAD 的进展，而上调 MAD2L2 则可挽救这种效应。相反，HNRNPD/MAD2L2 轴的上调促进了 LUAD 的进展，而这种结果可以通过敲除 MAD2L2 而逆转。从机制上讲，HNRNPD的下调抑制了MAD2L2的启动子活性和转录，从而抑制了PI3K/HIF1α/AGPTL4通路和肿瘤血管生成。最后，研究证实，HNRNPD和MAD2L2水平均较高的LUAD患者预后最差。因此，HNRNPD/MAD2L2轴被认为是LUAD患者的潜在预测指标：结论：HNRNPD/MAD2L2 轴促进了 LUAD 的进展，是一种潜在的预后生物标志物。

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引用次数: 0

Single-cell analysis reveals that TCF7L2 facilitates the progression of ccRCC via tumor-associated macrophages 单细胞分析表明，TCF7L2 通过肿瘤相关巨噬细胞促进了 ccRCC 的进展。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-02 DOI: 10.1016/j.cellsig.2024.111453

Background

Tumor-associated macrophages (TAMs) play an important role in the recurrence and progression of clear cell renal cell carcinoma (ccRCC). However, the specified mechanism has not been elucidated.

Methods

Single-cell and transcriptome analysis were applied to characterize the heterogeneity of TAMs. SCENIC would infer regulators of different subsets of TAMs. The CellChat algorithm was used to infer macrophage-tumor interaction networks, whereas pseudo-time traces were used to parse cell evolution and dynamics.

Results

In this study, single-cell transcriptomic data of ccRCC were analyzed. Notably, the macrophages were clustered to select the cluster with a tendency toward M2-type TAM, which has an impact on the occurrence and metastasis of ccRCC. This macrophage cluster was defined as “TAM2”. And this study revealed that TCF7L2 as a potential transcription factor regulating TAM2 transcriptional heterogeneity and differentiation. Pseudotime traces showed TCF7L2 trajectories during TAM2 cell cluster development. In addition, the results of cell interaction showed that TAM2 had the highest number and strength of interactions with cancer cells and endothelial cells. In vitro experiments, this study found that TCF7L2 was highly expressed in TAMs and promoted the polarization of macrophages to M2-type macrophages. And then overexpression of TCF7L2 in macrophages markedly promoted ccRCC invasion and proliferation.

Conclusion

TCF7L2 could play a key role in the progression of ccRCC via enhancing TAMs recruitment and M2-type polarization.

背景：肿瘤相关巨噬细胞（TAMs）在透明细胞肾细胞癌（ccRCC）的复发和进展中发挥着重要作用。然而，其具体机制尚未阐明：方法：应用单细胞和转录组分析来描述TAMs的异质性。SCENIC 将推断 TAMs 不同亚群的调节因子。CellChat算法用于推断巨噬细胞与肿瘤的相互作用网络，而伪时间轨迹则用于解析细胞的进化和动态：本研究分析了ccRCC的单细胞数据。结果：该研究分析了ccRCC的单细胞数据。值得注意的是，对巨噬细胞进行了聚类，筛选出倾向于M2型TAM的集群，这对ccRCC的发生和转移有影响。该巨噬细胞群被定义为 "TAM2"。这项研究发现，TCF7L2 是调控 TAM2 转录异质性和分化的潜在转录因子。伪时间轨迹显示了TCF7L2在TAM2细胞簇发育过程中的轨迹。此外，细胞相互作用的结果表明，TAM2 与癌细胞和内皮细胞相互作用的次数和强度最高。在体外实验中，本研究发现 TCF7L2 在 TAMs 中高表达，并能促进巨噬细胞极化为 M2 型巨噬细胞。结论：TCF7L2可在ccRCC中发挥重要作用：结论：TCF7L2可通过增强TAMs招募和M2型极化在ccRCC的进展中发挥关键作用。

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引用次数: 0