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Integrating bulk and single-cell transcriptomics to elucidate the role and potential mechanisms of autophagy in aging tissue. 整合体细胞和单细胞转录组学,阐明自噬在衰老组织中的作用和潜在机制。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-16 DOI: 10.1007/s13402-024-00996-w
Zhenhua Zhu, Linsen Li, Youqiong Ye, Qing Zhong

Purpose: Autophagy is frequently observed in tissues during the aging process, yet the tissues most strongly correlated with autophagy during aging and the underlying regulatory mechanisms remain inadequately understood. The purpose of this study is to identify the tissues with the highest correlation between autophagy and aging, and to explore the functions and mechanisms of autophagy in the aging tissue microenvironment.

Methods: Integrated bulk RNA-seq from over 7000 normal tissue samples, single-cell sequencing data from blood samples of different ages, more than 2000 acute myeloid leukemia (AML) bulk RNA-seq, and multiple sets of AML single-cell data. The datasets were analysed using various bioinformatic approaches.

Results: Blood tissue exhibited the highest positive correlation between autophagy and aging among healthy tissues. Single-cell resolution analysis revealed that in aged blood, classical monocytes (C. monocytes) are most closely associated with elevated autophagy levels. Increased autophagy in these monocytes correlated with a higher proportion of C. monocytes, with hypoxia identified as a crucial contributing factor. In AML, a representative myeloid blood disease, enhanced autophagy was accompanied by an increased proportionof C. monocytes. High autophagy levels in monocytes are associated with pro-inflammatory gene upregulation and Reactive Oxygen Species (ROS) accumulation, contributing to tissue aging.

Conclusion: This study revealed that autophagy is most strongly correlated with aging in blood tissue. Enhanced autophagy levels in C. monocytes demonstrate a positive correlation with increased secretion of pro-inflammatory factors and elevated production of ROS, which may contribute to a more rapid aging process. This discovery underscores the critical role of autophagy in blood aging and suggests potential therapeutic targets to mitigate aging-related health issues.

目的:自噬在衰老过程中经常在组织中被观察到,然而衰老过程中与自噬相关性最强的组织及其潜在的调控机制仍未被充分了解。本研究旨在确定自噬与衰老相关性最高的组织,并探索自噬在衰老组织微环境中的功能和机制:整合了7000多份正常组织样本的大量RNA-seq数据、不同年龄段血液样本的单细胞测序数据、2000多份急性髓性白血病(AML)的大量RNA-seq数据以及多组AML单细胞数据。这些数据集采用了各种生物信息学方法进行分析:结果:在健康组织中,血液组织显示出自噬与衰老之间最高的正相关性。单细胞分辨率分析显示,在衰老的血液中,经典单核细胞(C. monocytes)与自噬水平升高的关系最为密切。这些单核细胞自噬水平的升高与 C. 单核细胞比例的升高有关,而缺氧被认为是一个重要的促成因素。在具有代表性的骨髓性血液疾病急性髓性白血病中,自噬的增强伴随着C. 单核细胞比例的增加。单核细胞的高自噬水平与促炎基因上调和活性氧(ROS)积累有关,从而导致组织老化:这项研究表明,自噬与血液组织的衰老关系最为密切。C.单核细胞自噬水平的提高与促炎因子分泌的增加和 ROS 生成的增加呈正相关,这可能会导致更快的衰老过程。这一发现强调了自噬在血液衰老中的关键作用,并提出了缓解衰老相关健康问题的潜在治疗目标。
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引用次数: 0
ALKBH4 functions as a hypoxia-responsive tumor suppressor and inhibits metastasis and tumorigenesis. ALKBH4 是一种低氧反应性肿瘤抑制因子,可抑制转移和肿瘤发生。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-14 DOI: 10.1007/s13402-024-01004-x
Ji-Lin Chen, Pei-Hua Peng, Han-Tsang Wu, Dar-Ren Chen, Ching-Yun Hsieh, Jeng-Shou Chang, Joseph Lin, Huan-Yu Lin, Kai-Wen Hsu

Purpose: The human AlkB homolog (ALKBH) dioxygenase superfamily plays a crucial role in gene regulation and is implicated in cancer progression. Under hypoxic conditions, hypoxia-inducible factors (HIFs) dynamically regulate methylation by controlling various dioxygenases, thereby modulating gene expression. However, the role of hypoxia-responsive AlkB dioxygenase remains unclear.

Methods: The molecular events were examined using real-time PCR and Western blot analysis. Tumor cell aggressiveness was evaluated through migration, invasion, MTT, trypan blue exclusion, and colony formation assays. In vivo metastatic models and xenograft experiments were conducted to evaluate tumor progression.

Results: Here, we examined the expression of the ALKBH superfamily under hypoxic conditions and found that ALKBH4 expression was negatively regulated by hypoxia. Knockdown of ALKBH4 enhanced the epithelial-mesenchymal transition (EMT), cell migration, invasion, and growth in vitro. The silencing of ALKBH4 enhanced metastatic ability and tumor growth in vivo. Conversely, overexpression of ALLKBH4 reversed these observations. Furthermore, overexpression of ALKBH4 significantly reversed hypoxia/HIF-1α-induced EMT, cell migration, invasion, tumor metastasis, and tumorigenicity. Notably, high expression of ALKBH4 was associated with better outcomes in head and neck cancer and breast cancer patients. Enrichment analysis also revealed that ALKBH4 was negatively enriched in hypoxia-related pathways. Clinically, a negative correlation between ALKBH4 and HIF-1α protein expression has been observed in tissues from both head and neck cancers and breast cancers.

Conclusion: These findings collectively suggest that ALKBH4 acts as a tumor suppressor and holds therapeutic potential for hypoxic tumors.

目的:人类 AlkB 同源物(ALKBH)二加氧酶超家族在基因调控中起着至关重要的作用,并与癌症进展有关。在缺氧条件下,缺氧诱导因子(HIFs)通过控制各种二氧酶动态调节甲基化,从而调控基因表达。然而,缺氧反应性 AlkB 二氧酶的作用仍不清楚:方法:使用实时 PCR 和 Western 印迹分析对分子事件进行检测。通过迁移、侵袭、MTT、胰蓝排除和集落形成试验评估肿瘤细胞的侵袭性。体内转移模型和异种移植实验用于评估肿瘤进展:结果:我们研究了缺氧条件下ALKBH超家族的表达,发现ALKBH4的表达受缺氧负调控。敲除 ALKBH4 可增强上皮-间质转化(EMT)、细胞迁移、侵袭和体外生长。沉默 ALKBH4 会增强转移能力和体内肿瘤生长。相反,过表达 ALLKBH4 则会逆转这些观察结果。此外,过表达 ALKBH4 能显著逆转缺氧/HIF-1α 诱导的 EMT、细胞迁移、侵袭、肿瘤转移和致瘤性。值得注意的是,ALKBH4的高表达与头颈癌和乳腺癌患者更好的预后有关。富集分析还显示,ALKBH4 在缺氧相关通路中负富集。临床上,在头颈癌和乳腺癌组织中观察到ALKBH4与HIF-1α蛋白表达呈负相关:这些发现共同表明,ALKBH4 是一种肿瘤抑制因子,具有治疗缺氧性肿瘤的潜力。
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引用次数: 0
Targeting the Notch-Furin axis with 2-hydroxyoleic acid: a key mechanism in glioblastoma therapy. 用 2-hydroxyoleic acid 靶向 Notch-Furin 轴:胶质母细胞瘤治疗的关键机制。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-14 DOI: 10.1007/s13402-024-00995-x
Raquel Rodríguez-Lorca, Ramón Román, Roberto Beteta-Göbel, Manuel Torres, Victoria Lladó, Pablo V Escribá, Paula Fernández-García

Purpose: Glioblastomas (GBMs) are highly treatment-resistant and aggressive brain tumors. 2OHOA, which is currently running a phase IIB/III clinical trial for newly diagnosed GBM patients, was developed in the context of melitherapy. This therapy focuses on the regulation of the membrane's structure and organization with the consequent modulation of certain cell signals to revert the pathological state in several disorders. Notch signaling has been associated with tumorigenesis and cell survival, potentially driving the pathogenesis of GBM. The current study aims to determine whether 2OHOA modulates the Notch pathway as part of its antitumoral mechanism.

Methods: 2OHOA's effect was evaluated on different components of the pathway by Western blot, Q-PCR, and confocal microscopy. Notch receptor processing was analyzed by subcellular fractionation and colocalization studies. Furin activity was evaluated under cleavage of its substrate by fluorescence assays and its binding affinity to 2OHOA was determined by surface plasmon resonance.

Results: We found that 2OHOA inhibits Notch2 and Notch3 signaling by dual mechanism. Notch2 inhibition is unleashed by impairment of its processing through the inactivation of furin activity by physical association. Instead, Notch3 is transcriptionally downregulated leading to a lower activation of the pathway. Moreover, we also found that HES1 overexpression highlighted the relevance of this pathway in the 2OHOA pharmacological efficacy.

Conclusion: These findings report that the inhibition of Notch signaling by 2OHOA plays a role in its anti-tumoral activity, an effect that may be driven through direct inhibition of furin, characterizing a novel target of this bioactive lipid to treat GBM.

目的:胶质母细胞瘤(GBM)是一种高度耐药的侵袭性脑肿瘤。2OHOA 目前正在进行 IIB/III 期临床试验,用于治疗新确诊的 GBM 患者。这种疗法的重点是调节膜的结构和组织,从而调节某些细胞信号,以恢复多种疾病的病理状态。Notch信号与肿瘤发生和细胞存活有关,可能是GBM发病机制的驱动因素。本研究旨在确定 2OHOA 是否调节 Notch 通路,作为其抗肿瘤机制的一部分。通过亚细胞分馏和共聚焦研究分析了Notch受体的处理过程。通过荧光测定评估了Furin在其底物裂解过程中的活性,并通过表面等离子共振测定了其与2OHOA的结合亲和力:结果:我们发现2OHOA通过双重机制抑制Notch2和Notch3信号传导。Notch2的抑制作用是通过物理结合使呋喃活性失活,从而影响其处理过程。相反,Notch3 的转录下调导致该通路的激活降低。此外,我们还发现 HES1 的过表达突出了该通路在 2OHOA 药效中的相关性:这些研究结果表明,2OHOA 对 Notch 信号转导的抑制在其抗肿瘤活性中发挥了作用,这种作用可能是通过直接抑制呋喃来实现的。
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引用次数: 0
Tumour cell-released autophagosomes promote lung metastasis by upregulating PD-L1 expression in pulmonary vascular endothelial cells in breast cancer. 肿瘤细胞释放的自噬体通过上调乳腺癌肺血管内皮细胞中PD-L1的表达促进肺转移
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-07 DOI: 10.1007/s13402-024-00994-y
Xu-Ru Wang, Xiao-He Zhou, Xiao-Tong Sun, Yu-Qing Shen, Yu-Yang Wu, Cheng-Dong Wu, Feng-Jiao Zhu, Yi-Ting Wei, Jin-Peng Chen, Jing Chen, Shi-Ya Zheng, Li-Xin Wang

Purpose: Establishing an immunosuppressive premetastatic niche (PMN) in distant organs is crucial for breast cancer metastasis. Vascular endothelial cells (VECs) act as barriers to transendothelial cell migration. However, the immune functions of PMNs remain unclear. Tumour cell-released autophagosomes (TRAPs) are critical modulators of antitumour immune responses. Herein, we investigated the mechanism through which TRAPs modulate the immune function of pulmonary VECs in lung PMN in breast cancer.

Methods: Immortalised mouse pulmonary microvascular endothelial cells were incubated with TRAPs in vitro. RNA sequencing, flow cytometry, and western blotting were employed to assess immunosuppressive function and mechanism. In vivo, TRAP-trained and autophagy-deficient tumour mice were used to detect immunosuppression, and high-mobility group box 1 (HMGB1)-deficient TRAP-trained and TLR4 knockout mice were utilised to investigate the underlying mechanisms of pulmonary VECs. Additionally, the efficacy of anti-programmed cell death ligand-1 (PD-L1) immunotherapy was evaluated in early tumour-bearing mice.

Results: HMGB1 on TRAPs surfaces stimulated VECs to upregulate PD-L1 via a TLR4-MyD88-p38/STAT3 signalling cascade that depended on the cytoskeletal movement of VECs. Importantly, PD-L1 on TRAP-induced VECs can inhibit T cell function, promote lung PMN immunosuppression, and result in more pronounced lung metastasis. Treatment with anti-PD-L1 reduces lung metastasis in early stage tumour-bearing mice.

Conclusions: These findings revealed a novel role and mechanism of TRAP-induced immunosuppression of pulmonary VECs in lung PMN. TRAPs and their surface HMGB1 are important therapeutic targets for reversing immunosuppression, providing a new theoretical basis for the treatment of early stage breast cancer using an anti-PD-L1 antibody.

目的:在远处器官建立免疫抑制性转移前生态位(PMN)对乳腺癌转移至关重要。血管内皮细胞(VEC)是跨内皮细胞迁移的屏障。然而,PMN 的免疫功能仍不清楚。肿瘤细胞释放的自噬体(TRAPs)是抗肿瘤免疫反应的关键调节因子。在此,我们研究了TRAPs调节乳腺癌肺PMN中肺VECs免疫功能的机制:方法:将固定化的小鼠肺微血管内皮细胞与 TRAPs 在体外培养。采用 RNA 测序、流式细胞术和 Western 印迹法评估免疫抑制功能和机制。在体内,利用TRAP训练小鼠和自噬缺陷肿瘤小鼠检测免疫抑制,并利用高移动性基团框1(HMGB1)缺陷TRAP训练小鼠和TLR4基因敲除小鼠研究肺血管内皮细胞的潜在机制。此外,还在早期肿瘤小鼠中评估了抗程序性细胞死亡配体-1(PD-L1)免疫疗法的疗效:结果:TRAPs表面的HMGB1通过TLR4-MyD88-p38/STAT3信号级联刺激VECs上调PD-L1,该信号级联依赖于VECs的细胞骨架运动。重要的是,TRAP 诱导的 VECs 上的 PD-L1 可抑制 T 细胞功能,促进肺 PMN 免疫抑制,并导致更明显的肺转移。抗PD-L1可减少早期肿瘤小鼠的肺转移:这些发现揭示了TRAP诱导的肺VECs免疫抑制在肺PMN中的新作用和机制。TRAP及其表面的HMGB1是逆转免疫抑制的重要治疗靶点,为使用抗PD-L1抗体治疗早期乳腺癌提供了新的理论基础。
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引用次数: 0
Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFβ and Hedgehog signal pathway. 黄芪皂苷IV通过TGFβ和刺猬信号通路抑制EREG/ErbB/ERK,从而逆转了非小细胞肺癌对紫杉醇的耐药性。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-07 DOI: 10.1007/s13402-024-00999-7
Wenhao Xiu, Yujia Zhang, Dongfang Tang, Sau Har Lee, Rui Zeng, Tingjie Ye, Hua Li, Yanlin Lu, Changtai Qin, Yuxi Yang, Xiaofeng Yan, Xiaoling Wang, Xudong Hu, Maoquan Chu, Zhumei Sun, Wei Xu

Purpose: Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug.

Method: The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance.

Results: ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFβ and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC.

Conclusions: These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFβ, Hedgehog axis.

目的:紫杉醇是治疗晚期非小细胞肺癌(NSCLC)的一线化疗药物,但它经常引起获得性耐药性,导致治疗失败。因此,筛选并鉴定可使耐药癌细胞对化疗药物重新敏感的紫杉醇耐药性逆转剂的机制至关重要:方法:采用细胞活力、成球和异种移植试验评估 ASIV 逆转紫杉醇耐药性的能力。免疫组化、细胞因子应用、小干扰RNA、小分子抑制剂和RNA-seq等方法被用于表征ASIV抑制epiregulin(EREG)和下游信号转导以逆转taxol耐药性的分子机制:结果:ASIV通过抑制NSCLC中球形细胞的干性相关基因逆转了紫杉醇耐药。机制探索发现,ASIV促进了EREG的K48连接多泛素化和降解。此外,化疗药物也会触发EREG。因此,EREG与ErbB受体结合并激活ERK信号,从而调控干性相关基因的表达。抑制EREG/ErbB/ERK可抑制干性相关基因,从而逆转对紫杉醇的耐药性。最后,研究人员观察到,TGFβ和刺猬信号是EREG/ErbB/ERK的下游,可以使用抑制剂来逆转NSCLC对紫杉醇的耐药性:这些研究结果表明,ASIV抑制EREG可通过EREG/ErbB/ERK-TGFβ和Hedgehog轴抑制NSCLC的干性,从而逆转紫杉醇耐药性。
{"title":"Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFβ and Hedgehog signal pathway.","authors":"Wenhao Xiu, Yujia Zhang, Dongfang Tang, Sau Har Lee, Rui Zeng, Tingjie Ye, Hua Li, Yanlin Lu, Changtai Qin, Yuxi Yang, Xiaofeng Yan, Xiaoling Wang, Xudong Hu, Maoquan Chu, Zhumei Sun, Wei Xu","doi":"10.1007/s13402-024-00999-7","DOIUrl":"https://doi.org/10.1007/s13402-024-00999-7","url":null,"abstract":"<p><strong>Purpose: </strong>Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug.</p><p><strong>Method: </strong>The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance.</p><p><strong>Results: </strong>ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFβ and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC.</p><p><strong>Conclusions: </strong>These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFβ, Hedgehog axis.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mitochondria in tumor immune surveillance and tumor therapies targeting mitochondria. 肿瘤免疫监视中的线粒体和针对线粒体的肿瘤疗法。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-07 DOI: 10.1007/s13402-024-01000-1
Lvyuan Li, Yi Zhang, Qiling Tang, Chunyu Wu, Mei Yang, Yan Hu, Zhaojian Gong, Lei Shi, Can Guo, Zhaoyang Zeng, Pan Chen, Wei Xiong

Mitochondria play a central role in cellular energy production and metabolic regulation, and their function has been identified as a key factor influencing tumor immune responses. This review provides a comprehensive overview of the latest advancements in understanding the role of mitochondria in tumor immune surveillance, covering both innate and adaptive immune responses. Specifically, it outlines how mitochondria influence the function of the tumor immune system, underscoring their crucial role in modulating immune cell behavior to either promote or inhibit tumor development and progression. Additionally, this review highlights emerging drug interventions targeting mitochondria, including novel small molecules with significant potential in cancer therapy. Through an in-depth analysis, it explores how these innovative strategies could improve the efficacy and outlook of tumor treatment.

线粒体在细胞能量产生和代谢调节中发挥着核心作用,其功能已被确定为影响肿瘤免疫反应的关键因素。本综述全面概述了在了解线粒体在肿瘤免疫监视中的作用方面取得的最新进展,包括先天性免疫反应和适应性免疫反应。具体来说,它概述了线粒体如何影响肿瘤免疫系统的功能,强调了线粒体在调节免疫细胞行为以促进或抑制肿瘤发生和发展方面的关键作用。此外,这篇综述还重点介绍了针对线粒体的新兴药物干预措施,包括在癌症治疗中具有巨大潜力的新型小分子药物。通过深入分析,本综述探讨了这些创新策略如何改善肿瘤治疗的疗效和前景。
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引用次数: 0
Unveiling therapeutic avenues targeting xCT in head and neck cancer. 揭示针对头颈部癌症 xCT 的治疗途径。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-03 DOI: 10.1007/s13402-024-00997-9
Jaewang Lee, Jong-Lyel Roh

Head and neck cancer (HNC) remains a major global health burden, prompting the need for innovative therapeutic strategies. This review examines the role of the cystine/glutamate antiporter (xCT) in HNC, specifically focusing on how xCT contributes to cancer progression through mechanisms such as redox imbalance, ferroptosis, and treatment resistance. The central questions addressed include how xCT dysregulation affects tumor biology and the potential for targeting xCT to enhance treatment outcomes. We explore recent developments in xCT-targeted current and emerging therapies, including xCT inhibitors and novel treatment modalities, and their role in addressing therapeutic challenges. This review aims to provide a comprehensive analysis of xCT as a therapeutic target and to outline future directions for research and clinical application.

头颈癌(HNC)仍然是全球主要的健康负担,因此需要创新的治疗策略。这篇综述探讨了胱氨酸/谷氨酸拮抗剂(xCT)在HNC中的作用,特别关注xCT如何通过氧化还原失衡、铁变态反应和耐药性等机制促进癌症进展。研究的核心问题包括 xCT 失调如何影响肿瘤生物学以及靶向 xCT 提高治疗效果的潜力。我们探讨了以 xCT 为靶点的现有疗法和新兴疗法的最新进展,包括 xCT 抑制剂和新型治疗模式,以及它们在应对治疗挑战方面的作用。本综述旨在全面分析作为治疗靶点的xCT,并概述未来的研究和临床应用方向。
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引用次数: 0
IRE1α inhibitor enhances paclitaxel sensitivity of triple-negative breast cancer cells. IRE1α抑制剂可增强三阴性乳腺癌细胞对紫杉醇的敏感性。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-01 Epub Date: 2024-06-18 DOI: 10.1007/s13402-024-00961-7
Min Wu, Lin Zhang, Lifu Pi, Layang Liu, Siyu Wang, Yujie Wu, Hongli Pan, Mingyao Liu, Zhengfang Yi

Purpose: Breast cancer is the most commonly diagnosed cancer in women, and triple-negative breast cancer (TNBC) accounts for approximately 15%-20% of all breast cancers. TNBC is highly invasive and malignant. Due to the lack of relevant receptor markers, the prognosis of TNBC is poor and the five-year survival rate is low. Paclitaxel is the first-line drug for the treatment of TNBC, which can inhibit cell mitosis. However, many patients develop drug resistance during treatment, leading to chemotherapy failure. Therefore, finding new therapeutic combinations to overcome TNBC drug resistance can provide new strategies for improving the survival rate of TNBC patients.

Methods: Cell viability assay, RT-qPCR, Colony formation assay, Western blot, and Xenogeneic transplantation methods were used to investigate roles and mechanisms of IRE1α/XBP1s pathway in the paclitaxel-resistant TNBC cells, and combined paclitaxel and IRE1α inhibitor in the treatment of TNBC was examined in vitro and in vivo.

Results: We found activation of UPR in paclitaxel-resistant cells, confirming that IRE1α/XBP1 promotes paclitaxel resistance in TNBC. In addition, we demonstrated that the combination of paclitaxel and IRE1α inhibitors can synergistically inhibit the proliferation of TNBC tumors both in vitro and in vivo,suggesting that IRE1α inhibitors combined with paclitaxel may be a new treatment option for TNBC.

Conclusions: In this study, we demonstrated the important role of IRE1α signaling in mediating paclitaxel resistance and identified that combination therapies targeting IRE1α signaling could overcome paclitaxel resistance and enhance chemotherapy efficacy.

目的:乳腺癌是女性最常确诊的癌症,而三阴性乳腺癌(TNBC)约占所有乳腺癌的 15%-20%。TNBC 具有高度侵袭性和恶性。由于缺乏相关的受体标志物,TNBC 的预后较差,五年生存率较低。紫杉醇是治疗 TNBC 的一线药物,可抑制细胞有丝分裂。然而,许多患者在治疗过程中会产生耐药性,导致化疗失败。因此,寻找克服TNBC耐药性的新疗法组合可为提高TNBC患者生存率提供新策略:方法:采用细胞活力检测、RT-qPCR、集落形成检测、Western blot和异种移植等方法研究IRE1α/XBP1s通路在紫杉醇耐药TNBC细胞中的作用和机制,并在体外和体内观察紫杉醇和IRE1α抑制剂联合治疗TNBC的效果:结果:我们发现紫杉醇耐药细胞中的UPR被激活,证实IRE1α/XBP1促进了TNBC对紫杉醇的耐药。此外,我们还证明了紫杉醇与IRE1α抑制剂联合使用可协同抑制TNBC肿瘤在体外和体内的增殖,这表明IRE1α抑制剂与紫杉醇联合使用可能是治疗TNBC的一种新选择:本研究证实了IRE1α信号传导在介导紫杉醇耐药中的重要作用,并发现针对IRE1α信号传导的联合疗法可以克服紫杉醇耐药并提高化疗疗效。
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引用次数: 0
Characterization and proteomic analysis of plasma-derived small extracellular vesicles in locally advanced rectal cancer patients. 局部晚期直肠癌患者血浆衍生小细胞外囊泡的特征和蛋白质组学分析
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-01 Epub Date: 2024-08-20 DOI: 10.1007/s13402-024-00983-1
Haiyan Chen, Yimin Fang, Siqi Dai, Kai Jiang, Li Shen, Jian Zhao, Kanghua Huang, Xiaofeng Zhou, Kefeng Ding

Background: Neoadjuvant chemoradiotherapy (nCRT) stands as a pivotal therapeutic approach for locally advanced rectal cancer (LARC), yet the absence of a reliable biomarker to forecast its efficacy remains a challenge. Thus, this study aimed to assess whether the proteomic compositions of small extracellular vesicles (sEVs) might offer predictive insights into nCRT response among patients with LARC, while also delving into the proteomic alterations within sEVs post nCRT.

Methods: Plasma samples were obtained from LARC patients both pre- and post-nCRT. Plasma-derived sEVs were isolated utilizing the TIO2-based method, followed by LC-MS/MS-based proteomic analysis. Subsequently, pathway enrichment analysis was performed to the Differentially Expressed Proteins (DEPs). Additionally, ROC curves were generated to evaluate the predictive potential of sEV proteins in determining nCRT response. Public databases were interrogated to identify sEV protein-associated genes that are correlated with the response to nCRT in LARC.

Results: A total of 16 patients were enrolled. Among them, 8 patients achieved a pathological complete response (good responders, GR), while the remaining 8 did not achieve a complete response (poor responders, PR). Our analysis of pretreatment plasma-derived sEVs revealed 67 significantly up-regulated DEPs and 9 significantly down-regulated DEPs. Notably, PROC (AUC: 0.922), F7 (AUC: 0.953) and AZU1 (AUC: 0.906) demonstrated high AUC values and significant differences (P value < 0.05) in discriminating between GR and PR patients. Furthermore, a signature consisting of 5 sEV protein-associated genes (S100A6, ENO1, MIF, PRDX6 and MYL6) was capable of predicting the response to nCRT, yielding an AUC of 0.621(95% CI: 0.454-0.788). Besides, this 5-sEV protein-associated gene signature enabled stratification of patients into low- and high-risk group, with the low-risk group demonstrating a longer overall survival in the testing set (P = 0.048). Moreover, our investigation identified 11 significantly up-regulated DEPs and 31 significantly down-regulated DEPs when comparing pre- and post-nCRT proteomic profiles. GO analysis unveiled enrichment in the regulation of phospholipase A2 activity.

Conclusions: Differential expression of sEV proteins distinguishes between GR and PR patients and holds promise as predictive markers for nCRT response and prognosis in patients with LARC. Furthermore, our findings highlight substantial alterations in sEV protein composition following nCRT.

背景:新辅助化放疗(noadjuvant chemoradiotherapy,nCRT)是局部晚期直肠癌(local advanced rectal cancer,LARC)的关键治疗方法,但缺乏预测其疗效的可靠生物标志物仍是一项挑战。因此,本研究旨在评估小细胞外囊泡(sEVs)的蛋白质组组成是否能预测LARC患者的nCRT反应,同时深入研究nCRT后sEVs内的蛋白质组变化:方法:从 LARC 患者中获取 nCRT 前和 nCRT 后的血浆样本。利用基于 TIO2 的方法分离血浆中的 sEV,然后进行基于 LC-MS/MS 的蛋白质组学分析。随后,对差异表达蛋白(DEPs)进行了通路富集分析。此外,还生成了 ROC 曲线,以评估 sEV 蛋白在确定 nCRT 反应方面的预测潜力。对公共数据库进行了查询,以确定与 LARC nCRT 反应相关的 sEV 蛋白相关基因:结果:共有16名患者入组。结果:共有 16 名患者入选,其中 8 名患者获得了病理完全反应(良好反应者,GR),其余 8 名患者未获得完全反应(不良反应者,PR)。我们对治疗前血浆衍生的 sEVs 进行了分析,发现 67 个 DEPs 显著上调,9 个 DEPs 显著下调。值得注意的是,PROC(AUC:0.922)、F7(AUC:0.953)和 AZU1(AUC:0.906)显示出较高的 AUC 值和显著差异(P 值 结论):sEV 蛋白的差异表达可区分 GR 和 PR 患者,有望成为 LARC 患者 nCRT 反应和预后的预测标志物。此外,我们的研究结果还强调了 nCRT 后 sEV 蛋白组成的实质性改变。
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引用次数: 0
Interferon Gamma Inducible Protein 30: from biological functions to potential therapeutic target in cancers. 伽马干扰素诱导蛋白 30:从生物学功能到癌症的潜在治疗靶点。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1007/s13402-024-00979-x
Sen Zhang, Liwen Ren, Wan Li, Yizhi Zhang, Yihui Yang, Hong Yang, Fang Xu, Wanxin Cao, Xiaoxue Li, Xu Zhang, Guanhua Du, Jinhua Wang

Interferon Gamma Inducible Protein 30 (IFI30), also known as Gamma-Interferon-Inducible Lysosomal Thiol Reductase (GILT), is predominantly found in lysosomes and the cytoplasm. As the sole enzyme identified to catalyze disulfide bond reduction in the endocytic pathway, IFI30 contributes to both major histocompatibility complex (MHC) class I-restricted antigen cross-presentation and MHC class II-restricted antigen processing by decreasing the disulfide bonds of endocytosed proteins. Remarkably, emerging research has revealed that IFI30 is involved in tumorigenesis, tumor development, and the tumor immune response. Targeting IFI30 may provide new strategies for cancer therapy and improve the prognosis of patients. This review provided a comprehensive overview of the research progress on IFI30 in tumor progression, cellular redox status, autophagy, tumor immune response, and drug sensitivity, with a view to providing the theoretical basis for pharmacological intervention of IFI30 in tumor therapy, particularly in immunotherapy.

伽马干扰素诱导蛋白 30(IFI30)又称伽马干扰素诱导溶酶体硫醇还原酶(GILT),主要存在于溶酶体和细胞质中。IFI30 是目前发现的唯一能在内吞途径中催化二硫键还原的酶,它能通过减少内吞蛋白的二硫键,促进主要组织相容性复合体(MHC)Ⅰ类限制的抗原交叉呈递和 MHC Ⅱ类限制的抗原加工。值得注意的是,新的研究发现,IFI30 参与了肿瘤发生、肿瘤发展和肿瘤免疫反应。以 IFI30 为靶点可为癌症治疗提供新策略,并改善患者的预后。本综述全面概述了IFI30在肿瘤进展、细胞氧化还原状态、自噬、肿瘤免疫反应和药物敏感性等方面的研究进展,以期为IFI30在肿瘤治疗尤其是免疫治疗中的药物干预提供理论依据。
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Cellular Oncology
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