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NDR1/FBXO11 promotes phosphorylation-mediated ubiquitination of β-catenin to suppress metastasis in prostate cancer NDR1/FBXO11 促进磷酸化介导的 β-catenin 泛素化,从而抑制前列腺癌的转移
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.7150/ijbs.98907
Zuodong Xuan, Chen Chen, Huimin Sun, Kunao Yang, Jinxin Li, Meilin Fu, Yang Bai, Zeyuan Zheng, Yue Zhao, Chunlan Xu, Bin Liu, Tian Li, Chen Shao
Background: Prostate cancer progression hinges on β-catenin's stability and activity, a key factor in epithelial-mesenchymal transition (EMT) and metastasis. This study delves into NDR1-dependent phosphorylation's impact on β-catenin via FBXO11, an E3 ubiquitin ligase, in prostate cancer cells./nMethods: Human prostate cancer cell lines underwent various in vitro assays, including real-time PCR, Western blotting, immunoprecipitation, immunofluorescence, and protein stability assays, to explore β-catenin's interactions and post-translational modifications. NDR1 modulation's in vivo efficacy was assessed using a nude mice lung metastasis model. Small-molecule screening identified a potential NDR1 activator, aNDR1, tested for its effects on metastasis via in vitro and in vivo assays./nResults: NDR1 phosphorylated β-catenin at Ser33/37, facilitating its interaction with FBXO11. This led to FBXO11-mediated ubiquitination and cytoplasmic degradation of β-catenin, while the NDR1-FBXO11 complex impeded β-catenin nuclear translocation by inducing JNK2 ubiquitination. Thus, NDR1 and FBXO11 jointly regulate β-catenin activity in prostate cancer cells through dual phosphorylation-driven ubiquitination, potentially suppressing EMT. Reduced NDR1 expression inhibited FBXO11 and β-catenin phosphorylation, diminishing β-catenin and JNK2 ubiquitination, promoting EMT and enhancing prostate cancer cell metastasis. The inhibitory effects of aNDR1 on prostate cancer metastasis were validated./nConclusion: The NDR1/FBXO11 axis outlines a non-canonical β-catenin degradation pathway crucial in regulating EMT and prostate cancer cell metastasis. NDR1 activation, particularly with aNDR1, could offer a promising therapeutic avenue against prostate cancer metastasis.
背景:前列腺癌的进展取决于β-catenin的稳定性和活性,而β-catenin是上皮-间质转化(EMT)和转移的关键因素。本研究通过前列腺癌细胞中的E3泛素连接酶FBXO11,探讨了NDR1依赖性磷酸化对β-catenin的影响。方法:对人类前列腺癌细胞系进行各种体外检测,包括实时PCR、Western印迹、免疫沉淀、免疫荧光和蛋白质稳定性检测,以探讨β-catenin的相互作用和翻译后修饰。利用裸鼠肺转移模型评估了 NDR1 调节的体内疗效。小分子筛选确定了一种潜在的 NDR1 激活剂 aNDR1,并通过体外和体内试验测试了其对转移的影响:NDR1使β-catenin在Ser33/37处磷酸化,促进其与FBXO11的相互作用。这导致了 FBXO11 介导的 β-catenin 泛素化和胞质降解,而 NDR1-FBXO11 复合物通过诱导 JNK2 泛素化阻碍了 β-catenin 的核转位。因此,NDR1和FBXO11通过双重磷酸化驱动的泛素化共同调节前列腺癌细胞中β-catenin的活性,从而可能抑制EMT。减少 NDR1 的表达可抑制 FBXO11 和 β-catenin 的磷酸化,减少 β-catenin 和 JNK2 的泛素化,促进 EMT 并增强前列腺癌细胞的转移。aNDR1对前列腺癌转移的抑制作用得到了验证:NDR1/FBXO11轴勾勒出了一条非经典β-catenin降解途径,对调控EMT和前列腺癌细胞转移至关重要。激活 NDR1(尤其是与 aNDR1 一起激活)可为前列腺癌转移提供一种前景广阔的治疗途径。
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引用次数: 0
RUNX1-MUC13 Interaction Activates Wnt/β-Catenin Signaling Implications for Colorectal Cancer Metastasis RUNX1-MUC13 相互作用激活 Wnt/β-Catenin 信号转导对结直肠癌转移的影响
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.7150/ijbs.98396
Xinyi Chen, Jingyao Tu, Mu Yang, Yuan Wang, Bo Liu, Hong Qiu, Xianglin Yuan
Background: Colorectal cancer (CRC) remains a significant global health challenge, often characterized by late-stage metastasis and poor prognosis. The Runt-related transcription factor 1 (RUNX1) plays a dual role as both an oncogene and a tumor suppressor in various cancers, including CRC. However, the specific regulatory mechanisms of RUNX1 in CRC, particularly its direct roles, are not fully understood./nObjective: This study aimed to investigate the role of RUNX1 in CRC progression and its interaction with Mucin 13 (MUC13) as a potential regulatory target./nMethods: RUNX1 expression was analyzed in CRC tissues and cell lines compared to controls. In vitro and in vivo assays were conducted to assess the effects of RUNX1 overexpression and knockdown on cell behavior. ChIP-seq and RNA-seq analyses were performed to identify RUNX1 targets, with a focus on MUC13./nResults: RUNX1 expression was significantly upregulated in CRC tissues and cells, correlating with advanced pathological characteristics and poor patient outcomes. RUNX1 overexpression enhanced CRC cell proliferation, migration, invasion, and G2/M phase arrest, while its knockdown had the opposite effects. MUC13 was identified as a direct transcriptional target of RUNX1, with its expression contributing to the activation of the Wnt/β-catenin signaling pathway. Disruption of MUC13 partially reversed the malignant phenotypes induced by RUNX1./nConclusion: RUNX1 promotes CRC progression by upregulating MUC13 and activating the Wnt/β-catenin pathway. This RUNX1-MUC13 axis represents a potential therapeutic target for managing CRC.
背景:结直肠癌(CRC)仍然是全球健康面临的重大挑战,其特点通常是晚期转移和预后不良。Runt 相关转录因子 1(RUNX1)在包括 CRC 在内的多种癌症中扮演着致癌基因和肿瘤抑制因子的双重角色。然而,RUNX1 在 CRC 中的具体调控机制,尤其是其直接作用尚未完全明了:本研究旨在探讨 RUNX1 在 CRC 进展中的作用及其与作为潜在调控靶点的粘蛋白 13(MUC13)的相互作用:与对照组相比,分析了 RUNX1 在 CRC 组织和细胞系中的表达。进行了体外和体内试验,以评估 RUNX1 过表达和敲除对细胞行为的影响。进行了 ChIP-seq 和 RNA-seq 分析,以确定 RUNX1 的靶点,重点是 MUC13:RUNX1在CRC组织和细胞中的表达明显上调,与晚期病理特征和患者预后不良相关。RUNX1 的过表达增强了 CRC 细胞的增殖、迁移、侵袭和 G2/M 期停滞,而其敲除则产生相反的效果。研究发现,MUC13是RUNX1的直接转录靶标,其表达有助于激活Wnt/β-catenin信号通路。阻断MUC13可部分逆转RUNX1诱导的恶性表型:RUNX1通过上调MUC13和激活Wnt/β-catenin通路促进了CRC的进展。RUNX1-MUC13 轴是治疗 CRC 的潜在靶点。
{"title":"RUNX1-MUC13 Interaction Activates Wnt/β-Catenin Signaling Implications for Colorectal Cancer Metastasis","authors":"Xinyi Chen, Jingyao Tu, Mu Yang, Yuan Wang, Bo Liu, Hong Qiu, Xianglin Yuan","doi":"10.7150/ijbs.98396","DOIUrl":"https://doi.org/10.7150/ijbs.98396","url":null,"abstract":"<b>Background:</b> Colorectal cancer (CRC) remains a significant global health challenge, often characterized by late-stage metastasis and poor prognosis. The Runt-related transcription factor 1 (RUNX1) plays a dual role as both an oncogene and a tumor suppressor in various cancers, including CRC. However, the specific regulatory mechanisms of RUNX1 in CRC, particularly its direct roles, are not fully understood./n<b>Objective:</b> This study aimed to investigate the role of RUNX1 in CRC progression and its interaction with Mucin 13 (MUC13) as a potential regulatory target./n<b>Methods:</b> RUNX1 expression was analyzed in CRC tissues and cell lines compared to controls. <i>In vitro</i> and <i>in vivo</i> assays were conducted to assess the effects of RUNX1 overexpression and knockdown on cell behavior. ChIP-seq and RNA-seq analyses were performed to identify RUNX1 targets, with a focus on MUC13./n<b>Results:</b> RUNX1 expression was significantly upregulated in CRC tissues and cells, correlating with advanced pathological characteristics and poor patient outcomes. RUNX1 overexpression enhanced CRC cell proliferation, migration, invasion, and G2/M phase arrest, while its knockdown had the opposite effects. MUC13 was identified as a direct transcriptional target of RUNX1, with its expression contributing to the activation of the Wnt/β-catenin signaling pathway. Disruption of MUC13 partially reversed the malignant phenotypes induced by RUNX1./n<b>Conclusion:</b> RUNX1 promotes CRC progression by upregulating MUC13 and activating the Wnt/β-catenin pathway. This RUNX1-MUC13 axis represents a potential therapeutic target for managing CRC.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"2 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258118","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
AFM41a: A Novel PAD2 Inhibitor for Sepsis Treatment-Efficacy and Mechanism. AFM41a:用于败血症治疗的新型 PAD2 抑制剂--疗效与机制
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.97166
Tao Dong, Leonard Barasa, Xin Yu, Wenlu Ouyang, Liujiazi Shao, Chao Quan, Su He Wang, Jifeng Zhang, Morgan Salmon, Allan Tsung, Hasan B Alam, Jianjie Ma, Paul R Thompson, Yongqing Li

Pseudomonas aeruginosa (PA) infection can cause pneumonia and sepsis by activating peptidyl-arginine deiminase (PAD) and triggering the formation of neutrophil extracellular traps (NETs). Our previous research has elucidated the crucial role of PAD2 in regulating CitH3 production and NETosis signaling following bacterial infection. Therefore, targeting PAD2 with selective inhibitors holds promise for treating PA-induced sepsis. Here, we compare the structure and function of two PAD2 inhibitors, AFM32a and AFM41a, and investigate their biological effects in mice subjected with PA. We analyze their impact on PAD2 inhibition, macrophage polarization, and other host defense mechanisms against PA-induced sepsis utilizing both in vivo and in vitro approaches. Our findings demonstrate that both PAD2 inhibitors (AFM32a and AFM41a) and Pad2 deficiency substantially enhance protection against PA-induced sepsis, with AFM41a showing superior efficacy over AFM32a. This protective effect is marked by improved survival rates, reduced bacterial growth in mice subjected to PA infection, and the promotion of M2 macrophage polarization coupled with enhanced autophagic activity. Our results advocate for targeting PAD2 as an effective strategy to bolster host defenses against PA infection. Utilizing AFM41a to promote M2 macrophage polarization and autophagy offers promising avenues for the treatment of PA infection and the improvement of sepsis outcomes.

铜绿假单胞菌(PA)感染可通过激活肽基精氨酸脱氨酶(PAD)和触发中性粒细胞胞外捕获物(NET)的形成而引起肺炎和败血症。我们之前的研究阐明了 PAD2 在细菌感染后调控 CitH3 生成和 NETosis 信号传导中的关键作用。因此,以 PAD2 为靶点的选择性抑制剂有望治疗 PA 诱导的败血症。在此,我们比较了两种 PAD2 抑制剂 AFM32a 和 AFM41a 的结构和功能,并研究了它们对 PA 小鼠的生物效应。我们利用体内和体外方法分析了它们对 PAD2 抑制、巨噬细胞极化和其他宿主防御机制的影响。我们的研究结果表明,PAD2 抑制剂(AFM32a 和 AFM41a)和 Pad2 缺乏都能显著增强对 PA 诱导的败血症的保护作用,其中 AFM41a 比 AFM32a 表现出更优越的疗效。这种保护作用的显著特点是提高了存活率,减少了受 PA 感染的小鼠体内的细菌生长,促进了 M2 巨噬细胞的极化并增强了自噬活性。我们的研究结果表明,靶向 PAD2 是增强宿主防御 PA 感染的有效策略。利用 AFM41a 促进 M2 巨噬细胞极化和自噬为治疗 PA 感染和改善败血症预后提供了很好的途径。
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引用次数: 0
Transcription Factor E2F4 Promote Proliferation, Migration, and Invasion of Gastric Cancer Cells by transcriptionally activating DSCC1 转录因子 E2F4 通过转录激活 DSCC1 促进胃癌细胞增殖、迁移和侵袭
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.7150/ijbs.99590
Shantanu Baral, Yantao Yu, Qiannan Sun, Mingrui Jiang, Ruiqi Li, Yifan Cheng, Arawker Mubeen Hussein, Youquan Shi, Yongjun Jiang, Dong Tang, Sen Wang, Daorong Wang
Gastric cancer (GC) ranks as the fifth most common cancer and the fourth leading cause of cancer-related deaths globally. Despite advancements in molecular profiling, the mechanisms driving GC proliferation and metastasis remain unclear. This study identifies Early 2 Factor 4 (E2F4) as a key transcription factor that promotes GC cell proliferation, migration, and invasion by upregulating DNA Replication and Sister Chromatid Cohesion 1 (DSCC1) expression. Bioinformatics and transcription factor analyses revealed E2F4 as a significant regulator of DSCC1. Functional assays confirmed E2F4's role in enhancing GC cell malignancy in vitro and in vivo. Knockdown and overexpression experiments demonstrated that E2F4 positively regulates DSCC1 at the transcriptional level, with ChIP-qPCR and dual luciferase reporter assays validating the binding sites on the DSCC1 promoter. These findings highlight the E2F4-DSCC1 axis as a potential therapeutic target to mitigate GC progression.
胃癌(GC)是全球第五大常见癌症,也是导致癌症相关死亡的第四大原因。尽管分子图谱分析取得了进展,但胃癌增殖和转移的驱动机制仍不清楚。本研究发现,早期2因子4(E2F4)是一种关键的转录因子,它通过上调DNA复制和姐妹染色单体内聚1(DSCC1)的表达,促进GC细胞的增殖、迁移和侵袭。生物信息学和转录因子分析显示,E2F4 是 DSCC1 的重要调节因子。功能测试证实了 E2F4 在体外和体内增强 GC 细胞恶性程度的作用。基因敲除和过表达实验表明,E2F4 在转录水平上对 DSCC1 起着积极的调控作用,ChIP-qPCR 和双荧光素酶报告实验验证了 DSCC1 启动子上的结合位点。这些发现凸显了 E2F4-DSCC1 轴是缓解 GC 进展的潜在治疗靶点。
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引用次数: 0
Pharmacological manipulation of TRPC5 by kaempferol attenuates metastasis of gastrointestinal cancer via inhibiting calcium involved in the formation of filopodia 山奈酚对TRPC5的药理调控可通过抑制钙离子参与形成丝状体来减轻胃肠癌的转移
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 DOI: 10.7150/ijbs.87829
Suyun Yu, Rui Deng, Wei Wang, Defang Zou, Liang He, Zhonghong Wei, Yanhong Pan, Xiaoman Li, Yuanyuan Wu, Aiyun Wang, Wenxing Chen, Yang Zhao, Yin Lu
The thermo-sensory receptor, transient receptor potential channel 5 (TRPC5), a non-selective calcium ion (Ca2+)-permeable ion channel, has been implicated in cancer initiation and progression. However, its specific role in gastrointestinal cancer remains unclear. This study demonstrates that TRPC5 is significantly overexpressed in gastrointestinal tumors and is inversely associated with patient prognosis. TRPC5 overexpression triggers a substantial elevation in intracellular Ca2+ levels ([Ca2+]i), driving actin cytoskeleton reorganization and facilitating filopodia formation. Furthermore, kaempferol, a compound sourced from traditional Chinese medicine, is identified as a TRPC5 inhibitor that effectively suppresses its activity, thereby impeding gastrointestinal cancer metastasis. These findings underscore the potential of TRPC5 as a therapeutic target for metastasis inhibition, with kaempferol emerging as a promising natural inhibitor that could be optimized for clinical use in preventing cancer metastasis.
热感觉受体瞬时受体电位通道 5(TRPC5)是一种非选择性钙离子(Ca2+)渗透离子通道,它与癌症的发生和发展有关。然而,它在胃肠癌中的具体作用仍不清楚。本研究表明,TRPC5 在胃肠道肿瘤中显著过表达,并与患者的预后成反比。TRPC5 过表达会引发细胞内 Ca2+ 水平([Ca2+]i)大幅升高,从而推动肌动蛋白细胞骨架重组,促进丝状体形成。此外,山奈酚(一种源自传统中药的化合物)被确定为 TRPC5 抑制剂,可有效抑制其活性,从而阻碍胃肠癌转移。这些发现强调了TRPC5作为转移抑制治疗靶点的潜力,山奈酚是一种很有前景的天然抑制剂,可优化用于临床预防癌症转移。
{"title":"Pharmacological manipulation of TRPC5 by kaempferol attenuates metastasis of gastrointestinal cancer via inhibiting calcium involved in the formation of filopodia","authors":"Suyun Yu, Rui Deng, Wei Wang, Defang Zou, Liang He, Zhonghong Wei, Yanhong Pan, Xiaoman Li, Yuanyuan Wu, Aiyun Wang, Wenxing Chen, Yang Zhao, Yin Lu","doi":"10.7150/ijbs.87829","DOIUrl":"https://doi.org/10.7150/ijbs.87829","url":null,"abstract":"The thermo-sensory receptor, transient receptor potential channel 5 (TRPC5), a non-selective calcium ion (Ca<sup>2+</sup>)-permeable ion channel, has been implicated in cancer initiation and progression. However, its specific role in gastrointestinal cancer remains unclear. This study demonstrates that TRPC5 is significantly overexpressed in gastrointestinal tumors and is inversely associated with patient prognosis. TRPC5 overexpression triggers a substantial elevation in intracellular Ca<sup>2+</sup> levels ([Ca<sup>2+</sup>]i), driving actin cytoskeleton reorganization and facilitating filopodia formation. Furthermore, kaempferol, a compound sourced from traditional Chinese medicine, is identified as a TRPC5 inhibitor that effectively suppresses its activity, thereby impeding gastrointestinal cancer metastasis. These findings underscore the potential of TRPC5 as a therapeutic target for metastasis inhibition, with kaempferol emerging as a promising natural inhibitor that could be optimized for clinical use in preventing cancer metastasis.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"23 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258116","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
Single-Cell RNA-Sequencing Identifies Bone Marrow-Derived Progenitor Cells as a Main Source of Extracellular Matrix-Producing Cells Across Multiple Organ-Based Fibrotic Diseases. 单细胞 RNA 序列测定发现骨髓衍生的祖细胞是多种器官纤维化疾病细胞外基质生成细胞的主要来源。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-16 eCollection Date: 2024-01-01 DOI: 10.7150/ijbs.98839
Yu Zhong, Biao Wei, Wenbiao Wang, Junzhe Chen, Wenjing Wu, Liying Liang, Xiao-Ru Huang, Cheuk-Chun Szeto, Xueqing Yu, David J Nikolic-Paterson, Hui-Yao Lan

Fibrosis is characterized by the aberrant deposition of extracellular matrix (ECM) due to dysregulated tissue repair responses, imposing a significant global burden on fibrosis-related diseases. Although alpha-smooth muscle actin (α-SMA/ACTA2)-expressing myofibroblasts are considered as key player in fibrogenesis, the origin of ECM-producing cells remains controversial. To address this issue, we integrated and analyzed large-scale single-cell transcriptomic datasets from patients with distinct fibrotic diseases involving the heart, lung, liver, or kidney. Unexpectedly, not all ACTA2-expressing cells were ECM-producing cells identified by expressing collagen genes; instead, the majority of ECM-producing cells were myofibroblasts and fibroblasts derived from circulating bone marrow precursor, and to a lesser extent from local pericytes and vascular smooth cells in all fibrotic diseases. This was confirmed in sex-mismatched kidney transplants by the discovery that ECM-producing cells originated from recipient, not donor, bone marrow-derived progenitor cells (BMPCs). Moreover, these BMPCs-derived ECM-producing cells exhibited a proinflammatory phenotype. Thus, bone marrow-derived proinflammatory and profibrotic fibroblasts/myofibroblasts with stem cell properties serve as a major source of ECM-producing cells and may play a driving role in tissue fibrosis across a wide range of human fibrotic diseases. Targeting these ECM-producing cells may provide a novel therapy for diseases with fibrosis.

纤维化的特点是由于组织修复反应失调导致细胞外基质(ECM)异常沉积,给纤维化相关疾病造成了巨大的全球性负担。虽然表达α-平滑肌肌动蛋白(α-SMA/ACTA2)的肌成纤维细胞被认为是纤维化过程中的关键角色,但 ECM 生成细胞的来源仍存在争议。为了解决这个问题,我们整合并分析了大规模单细胞转录组数据集,这些数据集来自患有不同纤维化疾病的患者,涉及心脏、肺、肝脏或肾脏。意想不到的是,并非所有表达 ACTA2 的细胞都是通过表达胶原基因鉴定的 ECM 生成细胞;相反,在所有纤维化疾病中,大多数 ECM 生成细胞都是来源于循环骨髓前体的肌成纤维细胞和成纤维细胞,少量来源于局部周细胞和血管平滑细胞。在性别不匹配的肾脏移植中发现,产生 ECM 的细胞来源于受体而非供体的骨髓来源祖细胞(BMPCs),从而证实了这一点。此外,这些源自 BMPCs 的 ECM 生成细胞表现出一种促炎表型。因此,具有干细胞特性的骨髓源性促炎症和坏死性成纤维细胞/肌成纤维细胞是ECM生成细胞的主要来源,可能在多种人类纤维化疾病的组织纤维化中起着推动作用。以这些产生 ECM 的细胞为靶标,可为纤维化疾病提供一种新型疗法。
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引用次数: 0
ESM1 facilitates the EGFR/HER3-triggered epithelial-to-mesenchymal transition and progression of gastric cancer via modulating interplay between Akt and angiopoietin-2 signaling ESM1通过调节Akt和血管生成素-2信号之间的相互作用,促进表皮生长因子受体(EGFR)/表皮生长因子受体(HER3)触发的上皮细胞向间质转化和胃癌的进展
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-09 DOI: 10.7150/ijbs.100276
Yi-Chieh Yang, Ko-Hao Ho, Ke-Fan Pan, Kuo-Tai Hua, Min-Che Tung, Chia-Chi Ku, Ji-Qing Chen, Michael Hsiao, Chi-Long Chen, Wei-Jiunn Lee, Ming-Hsien Chien
Gastric cancer (GC) poses global challenges due to its difficult early diagnosis and drug resistance, necessitating the identification of early detection markers and understanding of oncogenic pathways for effective GC therapy. Endothelial cell-specific molecule 1 (ESM1), a secreted glycoprotein, is elevated in various cancers, but its role in GC remains controversial. In our study, ESM1 was elevated in GC tissues, and its concentration was correlated with progression and poorer patient prognosis in independent cohorts. Functionally, ESM1 expression promoted proliferation, anoikis resistance, and motility of GC cells, as well as tumor growth in PDOs and in GC xenograft models. Mechanistically, ESM1 expression triggered the epithelial-to-mesenchymal transition (EMT) of GC cells by enhancing epidermal growth factor receptor (EGFR)/human EGFR 3 (HER3) association and activating the EGFR/HER3-Akt pathway. Additionally, angiopoietin-2 (ANGPT2) was found to be highly correlated with ESM1 and interplayed with Akt to induce the EMT and cancer progression. Use of a signal peptide deletion mutant (ESM1-19del) showed that the secreted form of ESM1 is crucial for its protumorigenic effects by activating the EGFR/HER3-Akt/ANGPT2 pathway to promote the EMT. Patients with high levels of both ESM1 and ANGPT2 had the poorest prognoses. Furthermore, therapeutic peptides successfully inhibited ESM1's induction of the aforementioned signals and motility of GC cells. ESM1's oncogenic role in GC involves activating the EGFR/HER3-Akt/ANGPT2 pathway, presenting a potential therapeutic target for GC.
胃癌(GC)因其难以早期诊断和耐药性而构成全球性挑战,因此有必要确定早期检测标志物并了解致癌途径,以便对胃癌进行有效治疗。内皮细胞特异性分子 1(ESM1)是一种分泌性糖蛋白,在多种癌症中都会升高,但它在 GC 中的作用仍存在争议。在我们的研究中,ESM1在GC组织中升高,在独立队列中,其浓度与疾病进展和较差的患者预后相关。在功能上,ESM1的表达促进了GC细胞的增殖、耐嗜酸性和运动性,并促进了PDOs和GC异种移植模型中的肿瘤生长。从机理上讲,ESM1的表达通过增强表皮生长因子受体(表皮生长因子受体)/人表皮生长因子受体3(HER3)的结合和激活表皮生长因子受体/HER3-Akt通路,触发了GC细胞的上皮细胞向间质转化(EMT)。此外,研究还发现血管生成素-2(ANGPT2)与 ESM1 高度相关,并与 Akt 相互作用,诱导 EMT 和癌症进展。信号肽缺失突变体(ESM1-19del)的使用表明,ESM1的分泌形式对于其通过激活表皮生长因子受体/HER3-Akt/ANGPT2通路促进表皮生长因子受体转化(EMT)的原癌基因效应至关重要。ESM1和ANGPT2水平都很高的患者预后最差。此外,治疗肽成功地抑制了ESM1对上述信号的诱导和GC细胞的运动。ESM1在GC中的致癌作用包括激活表皮生长因子受体/HER3-Akt/ANGPT2通路,为GC提供了一个潜在的治疗靶点。
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引用次数: 0
Bridging Chronic Inflammation and Digestive Cancer: The Critical Role of Innate Lymphoid Cells in Tumor Microenvironments 慢性炎症与消化道癌症之间的桥梁:先天性淋巴细胞在肿瘤微环境中的关键作用
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-09 DOI: 10.7150/ijbs.96338
Guanliang Shen, Qi Wang, Zhengrui Li, Jiaheng Xie, Xinda Han, Zehao Wei, Pengpeng Zhang, Songyun Zhao, Xiumei Wang, Xufeng Huang, Min Xu
The incidence and mortality of digestive system-related cancers have always been high and attributed to the heterogeneity and complexity of the immune microenvironment of the digestive system. Furthermore, several studies have shown that chronic inflammation in the digestive system is responsible for cancer incidence; therefore, controlling inflammation is a potential strategy to stop the development of cancer. Innate Lymphoid Cells (ILC) represent a heterogeneous group of lymphocytes that exist in contrast to T cells. They function by interacting with cytokines and immune cells in an antigen-independent manner. In the digestive system cancer, from the inflammatory phase to the development, migration, and metastasis of tumors, ILC have been found to interact with the immune microenvironment and either control or promote these processes. The conventional treatments for digestive tumors have limited efficacy, therefore, ILC-associated immunotherapies are promising strategies. This study reviews the characterization of different ILC subpopulations, how they interact with and influence the immune microenvironment as well as chronic inflammation, and their promotional or inhibitory role in four common digestive system tumors, including pancreatic, colorectal, gastric, and hepatocellular cancers. In particular, the review emphasizes the role of ILC in associating chronic inflammation with cancer and the potential for enhanced immunotherapy with cytokine therapy and adoptive immune cell therapy.
消化系统相关癌症的发病率和死亡率一直居高不下,这归因于消化系统免疫微环境的异质性和复杂性。此外,多项研究表明,消化系统中的慢性炎症是癌症发病的罪魁祸首;因此,控制炎症是阻止癌症发展的潜在策略。先天性淋巴细胞(ILC)是与 T 细胞不同的异质性淋巴细胞群。它们以不依赖抗原的方式与细胞因子和免疫细胞相互作用。在消化系统癌症中,从炎症阶段到肿瘤的发展、迁移和转移,人们发现 ILC 与免疫微环境相互作用,并控制或促进这些过程。传统的消化系统肿瘤治疗方法疗效有限,因此,与ILC相关的免疫疗法是一种很有前景的策略。本研究综述了不同ILC亚群的特征,它们如何与免疫微环境以及慢性炎症相互作用并产生影响,以及它们在四种常见消化系统肿瘤(包括胰腺癌、结直肠癌、胃癌和肝细胞癌)中的促进或抑制作用。综述特别强调了ILC在慢性炎症与癌症相关联方面的作用,以及通过细胞因子疗法和收养性免疫细胞疗法增强免疫疗法的潜力。
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引用次数: 0
Mechanisms of hepatic and renal injury in lipid metabolism disorders in metabolic syndrome 代谢综合征脂质代谢紊乱导致肝肾损伤的机制
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-09 DOI: 10.7150/ijbs.100394
Jin Rong, Zixuan Zhang, Xiaoyu Peng, Ping Li, Tingting Zhao, Yifei Zhong
Metabolic syndrome (MetS) is a group of metabolic abnormalities that identifies people at risk for diabetes and cardiovascular disease. MetS is characterized by lipid disorders, and non-alcoholic fatty liver disease (NAFLD) and diabetic kidney disease (DKD) are thought to be the common hepatic and renal manifestations of MetS following abnormal lipid metabolism. This paper reviews the molecular mechanisms of lipid deposition in NAFLD and DKD, highlighting the commonalities and differences in lipid metabolic pathways in NAFLD and DKD. Hepatic and renal steatosis is the result of lipid acquisition exceeding lipid processing, i.e., fatty acid uptake and lipid regeneration exceed fatty acid oxidation and export. This process is directly regulated by the interactions of nuclear receptors, transporter proteins and transcription factors, whereas pathways such as oxidative stress, autophagy, cellular pyroptosis and gut flora are also key regulatory hubs for lipid metabolic homeostasis but act slightly differently in the liver and kidney. Such insights based on liver-kidney similarities and differences offer potential options for improved treatment.
代谢综合征(MetS)是一组代谢异常,可识别出糖尿病和心血管疾病的高危人群。代谢综合征以血脂紊乱为特征,非酒精性脂肪肝(NAFLD)和糖尿病肾病(DKD)被认为是代谢综合征在血脂代谢异常后常见的肝脏和肾脏表现。本文回顾了非酒精性脂肪性肝病和糖尿病肾病脂质沉积的分子机制,强调了非酒精性脂肪性肝病和糖尿病肾病脂质代谢途径的共性和差异。肝脏和肾脏脂肪变性是脂质获取超过脂质加工的结果,即脂肪酸摄取和脂质再生超过脂肪酸氧化和输出。这一过程由核受体、转运蛋白和转录因子的相互作用直接调控,而氧化应激、自噬、细胞热解和肠道菌群等途径也是脂质代谢平衡的关键调控枢纽,但在肝脏和肾脏中的作用略有不同。这些基于肝肾异同的见解为改善治疗提供了潜在的选择。
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引用次数: 0
METTL3-mediated m6A modification of OTUD1 aggravates press overload induced myocardial hypertrophy by deubiquitinating PGAM5 METTL3 介导的 OTUD1 m6A 修饰通过去泛素化 PGAM5 加重了压力过载诱导的心肌肥厚
IF 9.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-09 DOI: 10.7150/ijbs.95707
Kai Huang, Xiaotian Sun, Xiangyang Xu, Jie Lu, Boyao Zhang, Qin Li, Chuyi Wang, Sufan Ding, Xiaolei Huang, Xiaohong Liu, Zhiyun Xu, Lin Han
Background: Pathological cardiac hypertrophy, a condition that contributes to heart failure, is characterized by its intricate pathogenesis. The meticulous regulation of protein function, localization, and degradation is a crucial role played by deubiquitinating enzymes in cardiac pathophysiology. This study clarifies the participation and molecular mechanism of OTUD1 (OTU Deubiquitinase 1) in pathological cardiac hypertrophy./nMethods: We generated a cardiac-specific Otud1 knockout mouse line (Otud1-CKO) and adeno-associated virus serotype 9-Otud1 mice to determine the role of Otud1 in cardiac hypertrophy. Its impact on cardiomyocytes enlargement was investigated using the adenovirus. RNA immunoprecipitation was used to validate the specific m6a methyltransferase interacted with OTUD1 transcript. RNA sequencing in conjunction with immunoprecipitation-mass spectrometry analysis was employed to identify the direct targets of OTUD1. A series of depletion mutant plasmids were constructed to detect the interaction domain of OTUD1 and its targets./nResults: Ang II-stimulated neonatal rat cardiac myocytes and mice hearts subjected to transverse aortic constriction (TAC) showed increased protein levels of Otud1. Cardiac hypertrophy and dysfunction were less frequent in Otud1-CKO mice during TAC treatment, while Otud1 overexpression worsened cardiac hypertrophy and remodeling. METTL3 mediated m6A modification of OTUD1 transcript promoted mRNA stability and elevated protein expression. In terms of pathogenesis, Otud1 plays a crucial role in cardiac hypertrophy by targeting Pgam5, leading to the robust activation of the Ask1-p38/JNK signal pathway to accelerate cardiac hypertrophy. Significantly, the pro-hypertrophy effects of Otud1 overexpression were largely eliminated when Ask1 knockdown./nConclusion: Our findings confirm that targeting the OTUD1-PGAM5 axis holds significant potential as a therapeutic approach for heart failure associated with pathological hypertrophy./n/n
背景:病理性心肌肥厚是导致心力衰竭的病因之一,其发病机制错综复杂。去泛素化酶对蛋白质功能、定位和降解的精细调控是其在心脏病理生理学中发挥的关键作用。本研究阐明了OTUD1(OTU去泛素化酶1)在病理性心肌肥厚中的参与和分子机制:为了确定Otud1在心肌肥大中的作用,我们培育了心脏特异性Otud1基因敲除小鼠品系(Otud1-CKO)和腺相关病毒血清型9-Otud1小鼠。使用腺病毒研究了它对心肌细胞增大的影响。使用 RNA 免疫沉淀验证了与 OTUD1 转录本相互作用的特异性 m6a 甲基转移酶。利用 RNA 测序和免疫沉淀-质谱分析来确定 OTUD1 的直接靶标。构建了一系列缺失突变质粒,以检测 OTUD1 与其靶标的相互作用结构域:Ang II刺激的新生大鼠心肌细胞和横纹主动脉收缩(TAC)后的小鼠心脏显示出Otud1蛋白水平的升高。在TAC治疗过程中,Otud1-CKO小鼠的心肌肥厚和功能障碍发生率较低,而Otud1过表达会加重心肌肥厚和重塑。METTL3 介导的 OTUD1 转录本 m6A 修饰促进了 mRNA 的稳定性并提高了蛋白质的表达。在发病机制方面,Otud1 通过靶向 Pgam5 在心肌肥厚中起着关键作用,导致 Ask1-p38/JNK 信号通路的强力激活,从而加速心肌肥厚。值得注意的是,当Ask1被敲除时,Otud1过表达的促肥厚效应在很大程度上被消除:我们的研究结果证实,靶向 OTUD1-PGAM5 轴作为一种治疗与病理性肥厚相关的心力衰竭的方法具有巨大潜力。
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