更新于：2024-09-19

ASCC3

更新于：2024-09-19

基本信息

别名

activating signal cointegrator 1 complex subunit 3、ASC-1 complex subunit p200、ASC1p200

+ [8]

简介

ATPase involved both in DNA repair and rescue of stalled ribosomes (PubMed:22055184, PubMed:28757607, PubMed:32099016, PubMed:32579943, PubMed:36302773). 3'-5' DNA helicase involved in repair of alkylated DNA: promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3, enabling ALKBH3 to process alkylated N3-methylcytosine (3mC) within double-stranded regions (PubMed:22055184). Also involved in activation of the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation (PubMed:28757607, PubMed:32099016, PubMed:32579943, PubMed:36302773). Drives the splitting of stalled ribosomes that are ubiquitinated in a ZNF598-dependent manner, as part of the ribosome quality control trigger (RQT) complex (PubMed:28757607, PubMed:32099016, PubMed:32579943, PubMed:36302773). Part of the ASC-1 complex that enhances NF-kappa-B, SRF and AP1 transactivation (PubMed:12077347).

关联

100 项与 ASCC3 相关的临床结果

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100 项与 ASCC3 相关的转化医学

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0 项与 ASCC3 相关的专利（医药）

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项与 ASCC3 相关的文献（医药）

2024-08-01·Arab Journal of Gastroenterology

Mutational and transcriptional profile predicts the prognosis of stage IV gastric cancer – Prognostic factors for metastatic gastric cancer

Article

作者: Xie, Zhengyong ; Ke, Yongli ; Li, Zehang ; Zhao, Wenzhen ; Zhang, Xuhui ; He, Yongzhong

BACKGROUND AND STUDY AIMSThe clinicopathological risk factors in the prognosis of stage IV gastric cancer have been comprehensively studied. However, the influencing factors of stage IV gastric cancer prognosis at genomic and transcriptional levels have not been well defined.PATIENTS AND METHODSThe mutational and transcriptional data, along with demographic, clinicopathological and prognostic information of 44 stage IV gastric cancer patients were downloaded from the TCGA database. Univariate and multivariate analyses were performed to identify the significant risk factors and a Nomogram model was established to predict the patient prognosis.RESULTSTTN, TP53, FLG, LRP1B, SYNE1 and ARID1A were among the top mutated genes without hot-spot mutations. The mutational status of AHNAK2, ASCC3, DNAH3, DOP1A, MYLK, SIPA1L1, SORBS2, SYNE1 and ANF462 significantly stratified the patient prognosis. The transcription of several genes, such as AQP10, HOXC8/9/10, COL10A1/COL11A1, WNT7B, KRT17 and KLK6 was significantly up-regulated or down-regulated. Enrichment analysis on mutations and transcription revealed cell skeleton and membrane function, extracellular matrix function, HPV infection, and several cancer-related pathways as the main aberrancies. Univariate analyses revealed a series of significant factors stratifying patient prognosis, mainly including cancer location, several mutated genes and many up- or down-regulated genes. However, subsequent multivariate analysis revealed SYNE1 mutation, DNAH3 mutation, COMMD3 transcription level, and cancer location as the independent risk factors. A Nomogram model has been established with these significant risk factors to predict the patient prognosis. Further validation is needed to ensure the effectiveness of the model in real clinical practice.CONCLUSIONSCancer location, along with the mutational status of SYNE1 and DNAH3 and the transcriptional level of COMMD3 were independent risk factors of stage IV gastric cancer. A Nomogram model was established with these factors for prognosis prediction.

2024-07-01·Journal for ImmunoTherapy of Cancer

Correction: ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3

Article

2024-06-01·Veterinary Microbiology

Identification critical host factors for Japanese encephalitis virus replication via CRISPR screening of human sgRNA library

Article

作者: Ma, Kai-Xiong ; Qi, Wen-Bao ; Huang, Li-Hong ; Liao, Ming ; Yin, You-Qin ; Liu, Le-le ; Huang, Jin-Yu ; Ren, Xing-Xing ; Xing, Jin-Chao

Japanese encephalitis virus (JEV) is a pathogen with a substantial impact on both livestock and human health. However, the critical host factors in the virus life cycle remain poorly understood. Using a library comprising 123411 small guide RNAs (sgRNAs) targeting 19050 human genes, we conducted a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-based screen to identify essential genes for JEV replication. By employing knockout or knockdown techniques on genes, we identified eleven human genes crucial for JEV replication, such as prolactin releasing hormone receptor (PRLHR), activating signal cointegrator 1 complex subunit 3 (ASCC3), acyl-CoA synthetase long chain family member 3 (ACSL3), and others. Notably, we found that PRLHR knockdown blocked the autophagic flux, thereby inhibiting JEV infection. Taken together, these findings provide effective data for studying important host factors of JEV replication and scientific data for selecting antiviral drug targets.

项与 ASCC3 相关的新闻（医药）

2023-12-31

·生物制品圈

最新靶点！复旦大学附属中山医院发文：促进非小细胞肺癌的免疫抑制和进展新机制

导读：激活信号协整剂 3 （ASCC3）已被确定为损害宿主免疫防御的致癌因子。然而，致癌的潜在机制及其对抗肿瘤免疫反应的影响仍不清楚。近日，复旦大学附属中山医院丁建勇、蒋家好联合在期刊《Journal for Immuno Therapy of Cancer》发表题为“ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3”的研究论文，研究表明ASCC3可通过CAND1稳定STAT3通路，重塑肿瘤微环境，诱导抗PD-1治疗耐药，促进NSCLC进展。它是一种可靠的预后指标，可以作为NSCLC联合治疗的靶点。https://jitc-bmj-com.libproxy1.nus.edu.sg/content/11/12/e007766研究背景 01 肺癌是全球癌症相关死亡的主要原因，非小细胞肺癌（NSCLC）占大多数病例。许多无症状患者在晚期被诊断为非小细胞肺癌，限制了手术联合放化疗等常规治疗的有效性。在NSCLC中发现了体细胞突变、拷贝数变异和染色体重排，包括EGFR/KRAS突变和ALK或ROS1重排，并开发了靶向这些基因改变的小分子抑制剂。这些药物可抑制肿瘤细胞增殖并调节免疫反应，从而改善 NSCLC 患者的预后。免疫疗法，尤其是免疫检查点抑制剂，在治疗晚期非小细胞肺癌方面显示出良好的疗效。尽管取得了这些进展，但挑战依然存在，包括对各种治疗方案的耐药性发展，这阻碍了NSCLC的综合管理。远处转移是导致晚期NSCLC患者治愈率和生存率低的主要因素。因此，进一步了解NSCLC发展背后的机制并确定提高治疗效果的有效策略至关重要。先前的研究表明，激活信号协整合器3（ASCC3）是一种具有解旋酶活性的蛋白质，与DNA损伤修复和免疫调节有关，它可能参与多种实体瘤的发展。然而，尚未研究 ASCC3 在肺癌中的作用。单细胞RNA测序分析揭示了非小细胞肺癌组织、原发肿瘤和转移中的差异表达基因，其中一些与NSCLC转移有关，通过直接影响肿瘤细胞的恶性特征或参与肿瘤进展相关的信号通路。我们发现ASCC3在NSCLC中也上调，重要的是，在远处转移中观察到更高的表达水平。作为解旋酶家族的一员，ASCC3 被认为参与 DNA 损伤修复和癌症进展。此外，ASCC3 已被证明可以调节免疫相关基因的表达，影响免疫细胞浸润和甲状腺癌复发。通过基因本体论（GO）和京都基因和基因组百科全书（KEGG）对我们的 RNA 测序数据的分析，我们发现 ASCC3 参与信号转导和转录激活因子（STAT）信号传导以及 I 型干扰素（IFN）相关通路。进一步的机制研究表明，ASCC3调控STAT3信号通路。STAT3 是恶性肿瘤行为和抗肿瘤免疫反应的关键调节因子，是许多致癌信号通路的聚集点。探索影响 STAT3 表达和激活的因素将增强我们对支撑肿瘤进展的复杂机制的理解，并促进新的治疗策略。研究进展 02 我们测试了ASCC3在一些NSCLC细胞系中的表达，并证实在某些细胞系中表达高于正常细胞系人支气管上皮细胞（HBE）（图2A）。用 ASCC3-shRNA 慢病毒转染 ASCC3 表达水平最高的 H1299 和 H460 细胞。在验证转染效率（图2B，C）后，使用为后续实验选择的shRNA（称为shASCC3与shNC）生成了两个稳定转染的细胞系。菌落形成和CCK8检测表明，ASCC3敲除抑制NSCLC细胞的增殖（图2D-G）。伤口愈合和Transwell试验对ASCC3敲低细胞的迁移显示出显著的抑制作用（图2H-M）。同样，Matrigel Transwell测定显示，ASCC3敲低损害了H1299和H460细胞的侵袭（图2N，O）。此外，皮下植入H1299-shNC/shASCC3细胞的裸鼠的体内测定（图2P）显示，与shNC肿瘤相比，shASCC3皮下肿瘤中ASCC3的表达显著下调（图 2Q），并且ASCC3敲低抑制了NSCLC的生长（图 2R）。总体而言，这些结果表明，ASCC3促进了NSCLC的进展，并且ASCC3敲低可以抑制这一过程。ASCC3的高表达促进了NSCLC在体外和体内的进展研究结论 03 图8总结了本研究的主要发现。NSCLC 中的 ASCC3 过表达有助于免疫抑制 TME，并赋予免疫治疗耐药性。从机制上讲，ASCC3 通过抑制 Ub 介导的 STAT3 降解来招募 CAND1 以稳定 STAT3 信号传导，从而损害肿瘤细胞中的 I 型 IFN 反应并促进对抗肿瘤免疫细胞的耐药性。此外，敲低ASCC3联合抗PD-1治疗可显著提高ASCC3高表达NSCLC患者免疫治疗的敏感性和疗效。本研究主要发现的示意图综上所述，本研究揭示了ASCC3在重塑TME和促进NSCLC进展中的关键作用，我们提供了一种可以靶向改善抗PD-1治疗疗效和NSCLC患者预后的新分子。参考资料：https://jitc-bmj-com.libproxy1.nus.edu.sg/content/11/12/e007766识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

免疫疗法

2023-12-29

·奇点网

靶点多多益善~

*仅供医学专业人士阅读参考非小细胞肺癌（NSCLC）可以说是癌症精准治疗的“示范田”，针对各个靶点的创新药层出不穷，但可用的靶点肯定是越多越好，来者不拒嘛。如果能找到与现有手段治疗，例如和免疫治疗有机联动的靶点，就更是有可能破解临床难题了。近日，复旦大学附属中山医院丁建勇、蒋家好团队就在Journal for ImmunoTherapy of Cancer期刊发表最新论文，首次揭示了NSCLC中的表观遗传干预靶点——ASCC3，它可通过抑制STAT3的泛素化降解来促进免疫抑制、减弱抗肿瘤免疫应答强度，因此干预ASCC3有望与免疫治疗携手破敌[1]。论文核心内容总结ASCC3既往被认为具有DNA解螺旋酶活性，可参与DNA损伤及修复，由此影响癌症的发生发展[2]，有分析把它和骨髓瘤患者的不良预后联系到了一起[3]，但在NSCLC中它可能扮演了更为不光彩的角色：复旦团队初步分析癌症基因组图谱计划（TCGA）和GEO数据库资料时，发现ASCC3在NSCLC中表达显著升高，且在远处转移灶中表达多于原发灶。就冲这一条，ASCC3就很可能参与了要命的肺癌远处转移，它的表达水平也确实与NSCLC患者总生存期（OS）呈负相关；而在细胞实验中，转染ASCC3后的NSCLC细胞确实具有更强的侵袭性，而敲除ASCC3则可有效抑制NSCLC细胞的增殖和侵袭。ASCC3在NSCLC中高表达，且表达水平与患者不良预后相关接下来就是标准的RNA测序+基因集富集分析组合拳了：与ASCC3表达关系最密切的基因，主要涉及I型干扰素信号等调控免疫应答的信号通路，敲除ASCC3可使ISG15、CXCL10等多个基因表达上调，同时敲除ASCC3还与JAK/STAT通路激活状态负相关；流式细胞术分析也证实，ASCC3高表达会明显减少CD8+T细胞、NK细胞等抗癌主力向肿瘤的浸润。看来，ASCC3很可能是通过调控I型干扰素信号影响抗肿瘤免疫，而I型干扰素信号又受JAK/STAT通路的影响，免疫共沉淀（Co-IP）分析也证实，STAT3正是最可能与ASCC3发生相互作用的蛋白质之一，但敲除ASCC3只影响STAT3蛋白，并不影响其mRNA水平。那么ASCC3对STAT3的影响，应该就是在表观遗传层面了，进一步实验显示，ASCC3其实是STAT3与类泛素化分离蛋白1（CAND1）的“中间人”：ASCC3能够把CAND1募集到STAT3附近，使二者发生相互作用，CAND1就能帮助抑制STAT3被泛素化降解，上调STAT3的蛋白质水平，增多的STAT3即会抑制I型干扰素信号，下调抗肿瘤免疫应答。最后一步实验相信各位读者也能猜个八九不离十，那就是测试敲除ASCC3是否能增敏免疫治疗，小鼠实验的结果也确实不出所料。研究者们还分析了17例接受免疫治疗的NSCLC患者，发现ASCC3表达水平与患者治疗应答、肿瘤免疫细胞浸润情况均显著相关，提示了以ASCC3作为干预靶点，突破NSCLC免疫抑制机制的初步可行性。ASCC3表达水平与NSCLC患者对免疫治疗的应答及肿瘤免疫细胞浸润相关参考文献：[1]Yong-Qiang A, Jian G, Chun J, et al. ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3[J]. Journal for ImmunoTherapy of Cancer, 2023, 11(12): e007766.[2]Jia J, Absmeier E, Holton N, et al. The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations[J]. Nature Communications, 2020, 11: 5535.[3]Liao C, Talluri S, Mu S, et al. Flap Structure-Specific Endonuclease 1 Coordinates with a Helicase (ASCC3) to Drive Genomic Instability, Proliferation and Poor Clinical Outcome in Myeloma[J]. Blood, 2022, 140(Supplement 1): 9963.本文作者丨谭硕

免疫疗法