Experimental cell research最新文献_第6页

Phospholipase C δ1 affects integrin-mediated cell adhesion and migration by altering available phosphatidylinositol 4,5-bisphosphate levels 磷脂酶C δ1通过改变有效磷脂酰肌醇4,5-二磷酸水平影响整合素介导的细胞粘附和迁移。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-12 DOI: 10.1016/j.yexcr.2025.114857

Atsuko Yoneda , Ryosuke Fujinaka , Natsuki Tsuchiya , Saori Yaita , Sachi Suzuki , Yuu Kishi , Yoshikazu Nakamura , Reiko Satow , Kiyoko Fukami

Integrins are primary extracellular matrix receptors that play essential roles in homeostasis and development. Integrin activity is tightly regulated and is associated with conformational states. Although phosphatidylinositol 4,5-bisphosphate (PIP₂), produced by phosphatidylinositol 4-phosphate 5-kinases, is involved in integrin activation, it is unclear whether PIP₂-reducing enzymes affect integrin conformation and integrin-mediated cell behavior by altering PIP₂ levels. Herein, we showed that phospholipase C (PLC) δ1, a PIP₂-hydrolyzing enzyme, affected integrin-mediated cell adhesion and migration. In PLCδ1 null murine fibroblasts and PLCδ1 knockdown-human melanoma cells, integrin-mediated cell behavior and basal PIP₂ levels in the plasma membrane increased compared with those in control cells. PLCδ1 reduction led to increases in the extended conformation of integrin β1 ectodomain and the interaction between integrin and its activator/stabilizer talin in the absence of ligands. Overexpression of full-length-PLCδ1 or its pleckstrin homology domain but not their PIP₂-binding incompetent mutants inhibited the integrin-mediated cell behavior. To understand how altering plasma membrane PIP₂ levels affects integrin-mediated cell behavior, the catalytic domain of PIP₂ phosphatase was used. It reduced the basal levels of plasma membrane PIP₂, inhibited integrin-mediated cell migration, increased the closed conformation of the integrin β1 headpiece, and decreased integrin-talin interaction. These data suggested that the effects of PLCδ1 reduction were due to a PIP₂ increase and that the plasma membrane PIP₂ levels affected integrin conformation in the absence of ligands. Our results revealed that PLCδ1 finely tunes integrin-mediated cell adhesion and migration and integrin conformation by altering available PIP₂ levels in the plasma membrane.

整合素是主要的细胞外基质受体，在体内平衡和发育中起重要作用。整合素的活性受到严格调控，并与构象状态有关。虽然由磷脂酰肌醇4-磷酸5激酶产生的磷脂酰肌醇4,5-二磷酸（PIP2）参与整合素激活，但目前尚不清楚PIP2还原酶是否通过改变PIP2水平影响整合素构象和整合素介导的细胞行为。在此，我们发现磷脂酶C (PLC) δ1，一种pip2水解酶，影响整合素介导的细胞粘附和迁移。在PLCδ1缺失的小鼠成纤维细胞和PLCδ1敲低的人黑色素瘤细胞中，与对照细胞相比，整合素介导的细胞行为和质膜中基础PIP2水平增加。在没有配体的情况下，PLCδ1的还原导致整联素β1外结构域的延伸构象增加，以及整联素与其活化剂/稳定剂talin之间的相互作用增加。过表达全长plc δ1或其pleckstrin同源结构域，而不表达其pip2结合不能力突变体，可抑制整合素介导的细胞行为。为了了解改变质膜PIP2水平如何影响整合素介导的细胞行为，我们使用了PIP2磷酸酶的催化结构域。它降低了质膜PIP2的基础水平，抑制了整合素介导的细胞迁移，增加了整合素β1头部的封闭构象，降低了整合素-talin的相互作用。这些数据表明，PLCδ1降低的影响是由于PIP2的增加，并且在没有配体的情况下，质膜PIP2水平影响整合素的构象。我们的研究结果表明，PLCδ1通过改变质膜中可用的PIP2水平，精细地调节整合素介导的细胞粘附和迁移以及整合素构象。

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引用次数: 0

Extracellular vesicles from tumor-associated macrophages: Implications for tumor progression and emerging therapeutic strategies 来自肿瘤相关巨噬细胞的细胞外囊泡：肿瘤进展和新兴治疗策略的意义。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-11 DOI: 10.1016/j.yexcr.2025.114855

Carolinne Souza Amorim , João Alfredo Moraes , Mariana Renovato-Martins , Juliana Maria Motta

Extracellular vesicles (EVs) derived from tumor cells have been extensively explored over the past decades, as they represent a powerful means of communication that promotes tumor progression, including the formation of pre-metastatic niches and the consequent facilitation of successful metastatic dissemination. However, macrophages comprise a substantial population of non-tumoral cells within the tumor microenvironment and can either facilitate or inhibit tumor progression through the messages carried by their EVs. In this paper, we reviewed the literature on macrophage-derived EVs and their role in modulating tumor behavior, including development, metastasis, immune evasion, and chemoresistance. We begin by outlining the main categories of EVs and the subtypes of macrophage polarization, followed by a discussion of key aspects of macrophage-derived EVs across various tumor types. Finally, we examine emerging therapeutic strategies that utilize these EVs as potential tools in anticancer therapy.

在过去的几十年里，来自肿瘤细胞的细胞外囊泡（ev）已经被广泛探索，因为它们代表了一种促进肿瘤进展的强大通讯手段，包括转移前生态位的形成和随后成功转移传播的促进。然而，巨噬细胞由肿瘤微环境中的大量非肿瘤细胞组成，可以通过其ev携带的信息促进或抑制肿瘤进展。本文综述了巨噬细胞来源的内皮细胞及其在调节肿瘤行为中的作用，包括肿瘤的发生、转移、免疫逃避和化疗耐药性。我们首先概述了EVs的主要类别和巨噬细胞极化的亚型，然后讨论了各种肿瘤类型中巨噬细胞衍生的EVs的关键方面。最后，我们研究了利用这些ev作为抗癌治疗潜在工具的新兴治疗策略。

引用次数: 0

Overcoming multidrug resistance in cancer cells targeting ABC transporter ABCB1 with tyrosine kinase inhibitor: Olverembatinib 酪氨酸激酶抑制剂：Olverembatinib克服靶向ABC转运体ABCB1的癌细胞的多药耐药

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-11 DOI: 10.1016/j.yexcr.2025.114851

Bohan Zhang , Xiang Chen , Xingduo Dong , Yidong Li , Letao Bo , Harsh Patel , Brian Chou , Shanzhi Wang , Zhe-Sheng Chen

The overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) remains a primary challenge in overcoming multidrug resistance (MDR) in cancer cells. This study investigates the potential of olverembatinib, a third-generation tyrosine kinase inhibitor (TKI), to reverse ABCB1-mediated MDR and enhance the efficacy of chemotherapeutic drugs. Non-cytotoxic concentrations of olverembatinib significantly increased the sensitivity of ABCB1-overexpressing cells to paclitaxel and vincristine. Mechanistic analyses revealed that olverembatinib did not alter the expression or localization of ABCB1 but inhibited its drug efflux function, resulting in increased intracellular drug retention. Additionally, olverembatinib activated the ATPase activity of ABCB1 in a concentration-dependent manner and exhibited potent binding affinity to ABCB1 in docking simulations. These findings suggest that olverembatinib holds promise as a potent reversal agent for MDR, paving the way for its integration into novel combination chemotherapy regimens to improve cancer treatment outcomes.

atp结合盒B亚家族成员1 （ABCB1）的过表达仍然是克服癌细胞多药耐药（MDR）的主要挑战。本研究探讨了第三代酪氨酸激酶抑制剂（TKI） olverembatinib逆转abcb1介导的MDR和增强化疗药物疗效的潜力。无细胞毒性浓度的olverembatinib显著增加abcb1过表达细胞对紫杉醇和长春新碱的敏感性。机制分析显示，olverembatinib不改变ABCB1的表达或定位，但抑制其药物外排功能，导致细胞内药物潴留增加。此外，olverembatinib以浓度依赖的方式激活ABCB1的atp酶活性，并在对接模拟中显示出与ABCB1的有效结合亲和力。这些发现表明，olverembatinib有望成为一种有效的耐多药逆转药物，为其整合到新的联合化疗方案中以改善癌症治疗结果铺平了道路。

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引用次数: 0

Navigating the nexus: Dysregulation of non-coding RNAs in breast cancer under therapeutic interventions – Mechanisms and clinical implications 导航关系：治疗干预下乳腺癌非编码rna的失调-机制和临床意义。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-09 DOI: 10.1016/j.yexcr.2025.114854

Parisa Alirezae , Seyed Hossein Khoshraftar , Saba Hadi , Akbar Amirfiroozi , Mohammad M. Pourseif , Sima Mansoori-Derakhshan

Non-coding RNAs (ncRNAs)—including micro RNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs)—are key regulators of gene expression in the biological processes of breast cancer (BC) development. The dysregulation of these ncRNAs also contributes majorly to the initiation, progression, and treatment resistance of BC. This review summarizes the current understanding of how systemic therapeutic strategies (e.g. chemotherapy, endocrine therapy, targeted therapy, radiotherapy, and immunotherapy) can induce ncRNA changes which subsequently alter treatment responses. The underlying dysregulation of ncRNAs in BC occur through genetic events, epigenetic alterations, and complex transcriptional and post-transcriptional regulatory events, including competing endogenous RNA (ceRNA) networks. Some ncRNAs are important mediators of drug resistance (e.g. miR-21 in chemoresistance, HOTAIR in endocrine resistance, and ncRNAs regulated by ALKBH5 in HER2-targeted therapy resistance), modulating biological pathways such as apoptosis, DNA repair, and drug metabolism. The sensitivity of ncRNAs in biofluids make them appealing candidates for non-invasive biomarkers for diagnosis, prognosis, and real-time monitoring of response to treatment interventions. Despite the clear potential for ncRNAs to serve as therapeutic targets and as biomarkers in clinical management of BC, additional work is required to generate optimal delivery methods, achieve specificity, and standardize detection methods. Future studies, encompassing ‚multi-omics' strategies in BC research together with enhanced computational tools, will also be warranted to fully establish ncRNA discoveries into personalized BC care, and improved treatment outcomes for patient management through precision nanomedicine and liquid biopsy platforms.

非编码rna (ncRNAs)-包括微rna (miRNAs)，长ncRNAs （lncRNAs）和环状rna (circRNAs)-是乳腺癌（BC）发展生物学过程中基因表达的关键调控因子。这些ncrna的失调也主要导致了BC的发生、进展和治疗耐药性。本文综述了目前对全身治疗策略（如化疗、内分泌治疗、靶向治疗、放疗和免疫治疗）如何诱导ncRNA改变从而改变治疗反应的理解。BC中ncrna的潜在失调通过遗传事件、表观遗传改变以及复杂的转录和转录后调控事件发生，包括竞争性内源性RNA （ceRNA）网络。一些ncrna是重要的耐药介质（如miR-21在化疗耐药中，HOTAIR在内分泌耐药中，由ALKBH5调控的ncrna在her2靶向治疗耐药中），调节细胞凋亡、DNA修复和药物代谢等生物学途径。ncrna在生物体液中的敏感性使其成为诊断、预后和实时监测治疗干预反应的非侵入性生物标志物的有吸引力的候选者。尽管在BC的临床管理中，ncrna作为治疗靶点和生物标志物的潜力明显，但还需要进一步的工作来产生最佳的递送方法，实现特异性，并使检测方法标准化。未来的研究，包括BC研究中的“多组学”策略以及增强的计算工具，也将保证充分建立ncRNA发现到个性化BC护理中，并通过精确纳米医学和液体活检平台改善患者管理的治疗结果。

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引用次数: 0

Bioinformatics analysis of PLAUR and its oncogenic role of promoting colorectal cancer progression through the AKT/p53 signaling PLAUR的生物信息学分析及其通过AKT/p53信号通路促进结直肠癌进展的作用。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-05 DOI: 10.1016/j.yexcr.2025.114850

You Chen , Rui Ma , Chuyue Wang , Zhiying Yang , Ying Shi , Yingying Zhao , Xiaofen Pan , Bo Wang , Weili Wu , Ping Yuan

Cancer is a significant global health challenge, driving an urgent need to uncover novel therapeutic strategies, including for colorectal cancer (CRC). Elevated expression of the plasminogen activator, urokinase receptor (PLAUR) has been reported in several cancer types and is correlated with cancer progression. This study aims to evaluate the role of PLAUR in CRC and investigate its underlying mechanisms. We found that PLAUR expression was elevated across multiple cancer types, particularly in CRC, and consistently correlated with poor survival. Functional experiments in vitro and in vivo demonstrated that PLAUR knockdown inhibited tumor cell growth, triggering G1/S phase cell cycle arrest and apoptosis. Conversely, PLAUR overexpression facilitated malignant phenotypes. Mechanistically, PLAUR depletion activated the p53 pathway, which was associated with reduced phosphorylated AKT. PLAUR knockdown led to significant downregulation of phosphorylated AKT and upregulation of p53 and p21 in CRC cells, suggesting the involvement of the AKT/p53 pathway. Rescue experiments confirmed that PLAUR promotes malignant progression in colorectal cancer via the AKT/p53 pathway. In summary, these findings highlight the potential of PLAUR as a prospective prognostic indicator and a therapeutic target in CRC.

癌症是一个重大的全球健康挑战，迫切需要发现新的治疗策略，包括结肠直肠癌（CRC）。据报道，纤溶酶原激活剂尿激酶受体（PLAUR）在几种癌症类型中表达升高，并与癌症进展相关。本研究旨在评估PLAUR在CRC中的作用并探讨其潜在机制。我们发现PLAUR表达在多种癌症类型中升高，特别是在CRC中，并且始终与生存率低相关。体外和体内功能实验表明，PLAUR敲低可抑制肿瘤细胞生长，引发G1/S期细胞周期阻滞和凋亡。相反，PLAUR过表达促进了恶性表型。从机制上讲，PLAUR缺失激活了p53通路，这与磷酸化AKT的减少有关。PLAUR敲低导致CRC细胞中磷酸化AKT显著下调，p53和p21上调，提示参与了AKT/p53通路。援救实验证实PLAUR通过AKT/p53通路促进结直肠癌的恶性进展。总之，这些发现突出了PLAUR作为CRC的前瞻性预后指标和治疗靶点的潜力。

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引用次数: 0

MicroRNA-mediated metabolic control in HCC: From molecular networks to therapy 微rna介导的HCC代谢控制：从分子网络到治疗。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-03 DOI: 10.1016/j.yexcr.2025.114853

Dhuha D.M. Alrawi , Shahd rajab farhan , Ali G. Alkhathami , Chou-Yi Hsu , Zahraa Khudhair Abbas Al-Khafaji , Amr Ali Mohamed Abdelgawwad El-Sehrawy , Yasser Fakri Mustafa , Wael Nabil , Zuhair I. Al-Mashhadani

Hepatocellular carcinoma (HCC) is the most common histological subtype of primary liver cancer, accounting for nearly 80–90 % of all liver cancer cases. While ‘liver cancer’ refers broadly to all malignant tumors arising in the liver (including HCC, cholangiocarcinoma, and others), HCC specifically originates from hepatocytes. HCC is characterized by extensive metabolic reprogramming, including not only higher levels of aerobic glycolysis, de novo lipogenesis, and altered glutamine metabolism but also altered one-carbon metabolism. Enhanced metabolic adaptation markers, therefore, serve as key indicators of malignant transformation but also contribute to cancer progression by promoting cell proliferation, metastasis, immune modulation, and therapy evasion. Emerging evidence suggests microRNAs (miRNAs) can coordinate these metabolic adaptations by targeting key enzymes, transporters, transcription factors, signaling molecules, or pathways involved in metabolism. For instance, miR-122, miR-27a, miR-148a, and miR-4310 inhibit lipid accumulation and mitochondrial dysfunction, while miR-21, miR-103a, and miR-30b-5p promote glycolysis, lipogenesis, and anabolic metabolism. Long non-coding RNAs (lncRNAs) and exosomal miRNAs interact with these upstream regulators to form a heterogeneous network of non-coding RNAs. These networks participate in remodeling the tumor microenvironment, modulating the immune response, and facilitating metabolic adaptation in HCC. miRNAs are ideal for the potential stratification of HCC risk, prognosis, and therapeutic response, as they occupy key upstream positions in regulatory hierarchies and have been described as both biomarkers and potential metabolic switches. This study aims to elucidate the role of microRNAs in regulating metabolic pathways in HCC by delineating numerous miRNA-target interactions involved in glycolysis, lipid, amino acid, and nucleotide metabolism. This knowledge will enable us to identify novel diagnostic biomarkers and therapeutic targets for prognosis and to explore effective novel precision treatment strategies.

肝细胞癌（HCC）是原发性肝癌最常见的组织学亚型，占所有肝癌病例的近80-90%。“肝癌”泛指发生在肝脏的所有恶性肿瘤（包括HCC、胆管癌等），而HCC特异性地起源于肝细胞。HCC的特点是广泛的代谢重编程，不仅包括更高水平的有氧糖酵解、新生脂肪生成和谷氨酰胺代谢的改变，还包括单碳代谢的改变。因此，增强的代谢适应标记不仅是恶性转化的关键指标，而且还通过促进细胞增殖、转移、免疫调节和逃避治疗来促进癌症的进展。越来越多的证据表明，microRNAs （miRNAs）可以通过靶向关键酶、转运体、转录因子、信号分子或参与代谢的途径来协调这些代谢适应。例如，miR-122、miR-27a、miR-148a和miR-4310抑制脂质积累和线粒体功能障碍，而miR-21、miR-103a和miR-30b-5p促进糖酵解、脂肪生成和合成代谢。长链非编码rna （lncrna）和外泌体mirna与这些上游调控因子相互作用，形成非编码rna的异质网络。这些网络参与重塑肿瘤微环境，调节免疫反应，促进HCC的代谢适应。mirna是HCC风险、预后和治疗反应的潜在分层的理想选择，因为它们在调控层级中占据关键的上游位置，并且被描述为生物标志物和潜在的代谢开关。本研究旨在通过描述涉及糖酵解、脂质、氨基酸和核苷酸代谢的众多mirna -靶标相互作用，阐明microrna在调节HCC代谢途径中的作用。这些知识将使我们能够识别新的诊断生物标志物和预后治疗靶点，并探索有效的新型精确治疗策略。

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引用次数: 0

miR-98-3p/VEGFA axis mediates MALAT1-induced angiogenesis in ovarian tumors miR-98-3p/VEGFA轴介导malat1诱导的卵巢肿瘤血管生成。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-03 DOI: 10.1016/j.yexcr.2025.114844

Mengxin Zhang , Yu Zhang , Jiabao Xu, Wei Li, Mengjiao Hu, Wenhong Liu, Ye Xu, Fangfang Tao

The functional role of MicroRNA miR-98-3p in ovarian cancer is largely unexplored and its molecular mechanisms remain incompletely understood. In this study, we identified a novel regulatory axis involving MALAT1, miR-98-3p, and VEGFA in ovarian cancer angiogenesis. The study focuses on ovarian cancer-related proliferation and migration effects, primarily involving the angiogenesis effects of ovarian cancer. RNA sequencing following MALAT1 knockdown in HEY-T30 cells revealed significant alterations in several miRNAs, particularly miR-98-3p. Luciferase reporter assays confirmed direct binding between MALAT1 and miR-98-3p, establishing MALAT1 as a competing endogenous RNA (ceRNA) for miR-98-3p. Bioinformatic analysis and luciferase reporter assays further identified VEGFA as a direct target of miR-98-3p. Clinical database analysis demonstrated a positive correlation between MALAT1 and VEGFA expression, with elevated levels of both being significantly associated with poor overall survival in ovarian cancer patients. Functionally, both MALAT1 knockdown and miR-98-3p overexpression significantly impaired HUVEC tube formation, proliferation, and migration, which could be reversed by miR-98-3p inhibition. In vivo, miR-98-3p overexpression in subcutaneous xenografts resulted in reduced tumor volume, weight, vasculature, and blood perfusion, along with decreased expression of VEGFA, MMP2, and MMP9. These findings elucidate a MALAT1/miR-98-3p/VEGFA regulatory axis that modulates tumor angiogenesis in ovarian cancer, providing potential therapeutic targets for this malignancy.

MicroRNA miR-98-3p在卵巢癌中的功能作用在很大程度上未被探索，其分子机制仍不完全清楚。在这项研究中，我们发现了一个新的调控轴，涉及卵巢癌血管生成中的MALAT1、miR-98-3p和VEGFA。本研究的重点是卵巢癌相关的增殖和迁移效应，主要涉及卵巢癌的血管生成效应。在HEY-T30细胞中MALAT1敲低后的RNA测序显示，几种mirna，特别是miR-98-3p发生了显著变化。荧光素酶报告基因测定证实了MALAT1与miR-98-3p之间的直接结合，确立了MALAT1是miR-98-3p的竞争内源性RNA （ceRNA）。生物信息学分析和荧光素酶报告基因分析进一步确定VEGFA是miR-98-3p的直接靶点。临床数据库分析显示，MALAT1和VEGFA表达呈正相关，两者水平升高与卵巢癌患者总生存率低显著相关。在功能上，MALAT1敲低和miR-98-3p过表达均显著损害HUVEC管的形成、增殖和迁移，而miR-98-3p抑制可逆转这一过程。在体内，miR-98-3p在皮下异种移植物中的过表达导致肿瘤体积、重量、血管和血液灌注减少，同时VEGFA、MMP2和MMP9的表达降低。这些发现阐明了调节卵巢癌肿瘤血管生成的MALAT1/miR-98-3p/VEGFA调控轴，为这种恶性肿瘤提供了潜在的治疗靶点。

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引用次数: 0

MicroRNA-124–3p suppresses lung cancer by targeting ITGB1/PI3K/p-AKT signal transduction pathway MicroRNA-124-3p通过靶向ITGB1/PI3K/p-AKT信号转导通路抑制肺癌

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-03 DOI: 10.1016/j.yexcr.2025.114852

Ruiyun Han , Shunjuan Wang , Zhen Zhou , Dengliang Huang , Jing Hou , Meiyuan Tian , Rili Ge , Yanyan Ma

Worldwide, lung cancer is a leading cause of cancer-related death, and non-small cell lung cancer (NSCLC) represents the most common histological subtype. Numerous studies have demonstrated that microRNAs (miRNAs) play critical roles in NSCLC pathogenesis. microRNA-124–3p (miR-124–3p) has been identified as a tumor-associated miRNA, and we confirmed its downregulation in NSCLC cells. Functional assays showed that overexpression of miR-124–3p suppresses proliferation and migration of NSCLC cells, whereas its knockdown promotes these malignant phenotypes. A luciferase reporter assay revealed that miR-124–3p directly targets ITGB1 by binding to its 3′-UTR. Mechanistically, ITGB1 enhances PI3K expression and increases AKT phosphorylation, thereby activating the PI3K/AKT signaling pathway. Notably, miR-124–3p retained its tumor-suppressive effects even in A549 cells engineered to express the PIK3CA^H1047L mutation. Consistent with this, bioinformatics analysis demonstrated that miR-124–3p expression is significantly lower in tumor tissues than in adjacent normal lung and further decreases in advanced T stage (T3–T4) compared to early stage (T1–T2). These findings indicate that miR-124–3p inhibits NSCLC progression via the ITGB1/PI3K/p-AKT axis and remains functional despite PIK3CA activation, supporting its potential as a therapeutic candidate.

在世界范围内，肺癌是癌症相关死亡的主要原因，非小细胞肺癌（NSCLC）代表了最常见的组织学亚型。大量研究表明，microRNAs （miRNAs）在NSCLC的发病机制中起着至关重要的作用。microRNA-124-3p （miR-124-3p）已被确定为肿瘤相关的miRNA，我们证实其在NSCLC细胞中下调。功能分析显示，过表达miR-124-3p抑制NSCLC细胞的增殖和迁移，而敲低miR-124-3p则促进这些恶性表型。荧光素酶报告基因检测显示miR-124-3p通过结合ITGB1的3 ' -UTR直接靶向ITGB1。从机制上讲，ITGB1增强PI3K表达，增加AKT磷酸化，从而激活PI3K/AKT信号通路。值得注意的是，即使在表达PIK3CAH1047L突变的A549细胞中，miR-124-3p也保留了其肿瘤抑制作用。与此一致的是，生物信息学分析表明，miR-124-3p在肿瘤组织中的表达明显低于邻近正常肺组织，并且在晚期T期（T3-T4）比早期（T1-T2）进一步降低。这些发现表明，miR-124-3p通过ITGB1/PI3K/p-AKT轴抑制非小细胞肺癌的进展，尽管PIK3CA被激活，但miR-124-3p仍保持功能，支持其作为治疗候选药物的潜力。

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引用次数: 0

SLBP promotes lung adenocarcinoma progression by inhibiting ferroptosis and reprogramming glutamine metabolism via FADS2 interaction SLBP通过FADS2相互作用抑制铁下垂和重编程谷氨酰胺代谢促进肺腺癌进展。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-02 DOI: 10.1016/j.yexcr.2025.114849

Wei Yan , Pengfei Xu , Dan Xiao , Dong Hong , Huiqun Liu , Yigang Liu , Yaqi Wang , Tanxiu Chen , Anwen Liu

SLBP is significantly overexpressed in lung adenocarcinoma (LUAD) and correlates strongly with poor patient prognosis. Functional studies demonstrated that SLBP potently enhances proliferation, invasion, and metastasis of LUAD cells both in vitro and in vivo. Mechanistically, SLBP suppresses ferroptosis—a form of regulated cell death—by modulating key biochemical markers, including GSH, MDA, and Fe²⁺ levels, and it restores cell viability upon treatment with ferroptosis inducers. RNA-seq and biochemical analyses revealed that SLBP transcriptionally upregulates and stabilizes SLC7A11, a critical ferroptosis suppressor, thereby inhibiting lipid peroxidation and ferroptotic cell death. Additionally, immunopurification and mass spectrometry (IP-MS) identified FADS2 as a novel SLBP-interacting partner. SLBP binds to FADS2, promotes its expression, and drives metabolic reprogramming toward glutamine dependency, significantly altering choline and metal ion metabolism. This metabolic shift enhances cellular proliferation under nutrient stress. Crucially, SLBP-mediated proliferation was shown to be functionally dependent on FADS2, as FADS2 inhibition abrogates SLBP-driven growth without affecting SLBP levels. Collectively, these results uncover SLBP as a multifunctional oncoprotein that promotes LUAD progression through dual mechanisms: inhibiting ferroptosis via SLC7A11 and rewiring glutamine metabolism through FADS2, offering new potential targets for therapeutic intervention.

SLBP在肺腺癌（LUAD）中显著过表达，并与患者预后不良密切相关。功能研究表明，SLBP在体内和体外均能增强LUAD细胞的增殖、侵袭和转移。在机制上，SLBP通过调节关键生化标志物，包括GSH、MDA和Fe2+水平，抑制铁下垂（一种受调节的细胞死亡形式），并在铁下垂诱导剂治疗后恢复细胞活力。RNA-seq和生化分析显示，SLBP通过转录上调和稳定SLC7A11，从而抑制脂质过氧化和铁细胞死亡。此外，免疫纯化和质谱（IP-MS）鉴定FADS2是一种新的slbp相互作用伙伴。SLBP结合FADS2，促进其表达，并驱动代谢重编程向谷氨酰胺依赖，显著改变胆碱和金属离子代谢。这种代谢转变促进了营养胁迫下的细胞增殖。关键是，SLBP介导的增殖在功能上依赖于FADS2，因为FADS2抑制消除了SLBP驱动的生长，而不影响SLBP水平。总之，这些结果揭示了SLBP作为一种多功能癌蛋白，通过双重机制促进LUAD的进展：通过SLC7A11抑制铁凋亡，通过FADS2重新连接谷氨酰胺代谢，为治疗干预提供了新的潜在靶点。

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引用次数: 0

IL-33/ST2 signaling promotes intrahepatic cholangiocarcinoma through reprogramming macrophage polarization via MAPK pathway IL-33/ST2信号通过MAPK通路重编程巨噬细胞极化促进肝内胆管癌的发生。

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-12-02 DOI: 10.1016/j.yexcr.2025.114845

Aimaiti Yasen , Yichen Tang , Xiaomin Yang , Guohua Zuo , Jun Feng , Guoying Wang , Lu Zheng

Background

The role of IL-33/ST2 signaling in reprogramming macrophage polarization within the intrahepatic cholangiocarcinoma (ICC) microenvironment remains poorly understood. This study aimed to elucidate the mechanisms by which IL-33/ST2 signaling regulates macrophage polarization and its impact on ICC progression.

Methods

we overexpressed IL-33 in mouse macrophage J774A.1 cells and blocked IL-33/ST2 signaling using a ST2-neutralizing antibody. These macrophages were co-cultured with human ICC cells (HuCCT1 and RBE). Subcutaneous and orthotopic xenograft mouse models of ICC were established to assess the effects of ST2 blockade and adoptive transfer of differentially treated macrophages.

Results

IL-33 overexpression in J774A.1 cells significantly increased M2 macrophage marker expression, which was reversed by ST2 neutralization. This was associated with enhanced phosphorylation of ERK1, JNK, and P38, indicating MAPK pathway activation. Co-culture with IL-33-overexpressing macrophages promoted the invasion, migration and epithelial-mesenchymal transition (EMT) of ICC cells, effects that were attenuated by ST2 blockade. In vivo, ST2-neutralizing antibody inhibited ICC tumor growth, while infusion of M2 macrophages promoted it. Xenograft tumor tissues showed elevated expression of IL-33, ST2, M2 markers, and phosphorylated MAPK proteins, which were reduced upon ST2 neutralization.

Conclusion

IL-33/ST2 signaling drives ICC progression by promoting M2 macrophage polarization via the MAPK pathway. Targeting this axis may represent a novel therapeutic strategy for ICC.

背景：IL-33/ST2信号在肝内胆管癌（ICC）微环境中巨噬细胞极化重编程中的作用尚不清楚。本研究旨在阐明IL-33/ST2信号调控巨噬细胞极化及其对ICC进展的影响机制。方法：在小鼠巨噬细胞J774A.1细胞中过表达IL-33，并用ST2中和抗体阻断IL-33/ST2信号通路。这些巨噬细胞与人ICC细胞（HuCCT1和RBE）共培养。建立皮下和原位异种移植小鼠ICC模型，以评估ST2阻断和差异处理巨噬细胞过继转移的影响。结果：IL-33在J774A.1细胞中过表达可显著提高M2巨噬细胞标志物的表达，而ST2中和可逆转这种表达。这与ERK1、JNK和P38的磷酸化增强有关，表明MAPK通路激活。与过表达il -33的巨噬细胞共培养可促进ICC细胞的侵袭、迁移和上皮-间质转化（epithelial- mesenchal transition， EMT），而ST2阻断可减弱这种作用。体内st2中和抗体抑制ICC肿瘤生长，而M2巨噬细胞输注促进ICC肿瘤生长。异种移植肿瘤组织显示IL-33、ST2、M2标记物和磷酸化MAPK蛋白的表达升高，这些蛋白在ST2中和后降低。结论：IL-33/ST2信号通路通过MAPK通路促进M2巨噬细胞极化，从而驱动ICC进展。靶向这条轴可能是一种新的治疗ICC的策略。

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