Aggresomes predict poor outcomes and implicate proteostasis in the pathogenesis of pediatric choroid plexus tumors.
Aggresomes predict poor outcomes and implicate proteostasis in the pathogenesis of pediatric choroid plexus tumors.
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在儿童脉络丛肿瘤的发病机制中，侵袭体预测不良结局并暗示蛋白质稳态。
DOI：
10.1007/s11060-020-03694-3
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发表时间：
2021-03
影响因子：
3.9
通讯作者：
El-Naggar S
中科院分区：
文献类型：
--
作者：
Amer N;Taha H;Hesham D;Al-Shehaby N;Mosaab A;Soudy M;Osama A;Mahmoud N;Elayadi M;Youssef A;Elbeltagy M;Zaghloul MS;Magdeldin S;Sayed AA;El-Naggar S
蛋白质的错误折叠和聚集导致蛋白毒性应激，是许多疾病发病的基础。为了克服蛋白质毒性，细胞将错误折叠和聚集的蛋白质分隔在不同的包涵体中。侵略体是一个核旁包涵体，它的功能是错误折叠的蛋白质的储存室。脉络丛肿瘤(CPT)是一种罕见的肿瘤，包括三种病理亚型。其发病机制尚不清楚。本研究旨在阐明侵袭体在儿童CPT中的预后作用和生物学效应。我们通过免疫组织化学检测了42例患者来源的肿瘤组织中侵袭体的存在，并确定了它们对患者预后的影响。然后，我们利用全基因组DNA甲基化和蛋白质组学分析研究了与侵袭体相关的蛋白质组学特征，以确定它们在儿童CPT发病机制中的作用。在64.2%的样本中检测到聚集体，分布于不同的病理和分子亚群。不同比例的侵袭体的出现与患者的预后相关。与病理和分子分层相比， ≥ 25%的分界值对总体和无事件生存率的影响最显著(p值 <； 0.001)。这些结果支持侵袭体作为一种新的儿童CPT预后分子标志物的作用，其作用类似于将样本分成两个不同亚组的分子分类，以及在预测患者预后方面的病理分层。此外，CPT的蛋白质组学特征显示蛋白质动态平衡改变，表现为与蛋白质质量控制相关的过程中的丰富。网上版载有补充材料，可在10.1007/s11060020-03694-3查阅。
Protein misfolding and aggregation result in proteotoxic stress and underlie the pathogenesis of many diseases. To overcome proteotoxicity, cells compartmentalize misfolded and aggregated proteins in different inclusion bodies. The aggresome is a paranuclear inclusion body that functions as a storage compartment for misfolded proteins. Choroid plexus tumors (CPTs) are rare neoplasms comprised of three pathological subgroups. The underlying mechanisms of their pathogenesis remain unclear. This study aims to elucidate the prognostic role and the biological effects of aggresomes in pediatric CPTs. We examined the presence of aggresomes in 42 patient-derived tumor tissues by immunohistochemistry and we identified their impact on patients’ outcomes. We then investigated the proteogenomics signature associated with aggresomes using whole-genome DNA methylation and proteomic analysis to define their role in the pathogenesis of pediatric CPTs. Aggresomes were detected in 64.2% of samples and were distributed among different pathological and molecular subgroups. The presence of aggresomes with different percentages was correlated with patients’ outcomes. The ≥ 25% cutoff had the most significant impact on overall and event-free survival (p-value < 0.001) compared to the pathological and the molecular stratifications. These results support the role of aggresome as a novel prognostic molecular marker for pediatric CPTs that was comparable to the molecular classification in segregating samples into two distinct subgroups, and to the pathological stratification in the prediction of patients’ outcomes. Moreover, the proteogenomic signature of CPTs displayed altered protein homeostasis, manifested by enrichment in processes related to protein quality control. The online version contains supplementary material available at 10.1007/s11060-020-03694-3.
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影响因子：
1.7
作者：
Ma X;Drannik A;Jiang F;Peterson R;Turnbull J
通讯作者：
Turnbull J
影响因子：
64.8
作者：
Capper D;Jones DTW;Sill M;Hovestadt V;Schrimpf D;Sturm D;Koelsche C;Sahm F;Chavez L;Reuss DE;Kratz A;Wefers AK;Huang K;Pajtler KW;Schweizer L;Stichel D;Olar A;Engel NW;Lindenberg K;Harter PN;Braczynski AK;Plate KH;Dohmen H;Garvalov BK;Coras R;Hölsken A;Hewer E;Bewerunge-Hudler M;Schick M;Fischer R;Beschorner R;Schittenhelm J;Staszewski O;Wani K;Varlet P;Pages M;Temming P;Lohmann D;Selt F;Witt H;Milde T;Witt O;Aronica E;Giangaspero F;Rushing E;Scheurlen W;Geisenberger C;Rodriguez FJ;Becker A;Preusser M;Haberler C;Bjerkvig R;Cryan J;Farrell M;Deckert M;Hench J;Frank S;Serrano J;Kannan K;Tsirigos A;Brück W;Hofer S;Brehmer S;Seiz-Rosenhagen M;Hänggi D;Hans V;Rozsnoki S;Hansford JR;Kohlhof P;Kristensen BW;Lechner M;Lopes B;Mawrin C;Ketter R;Kulozik A;Khatib Z;Heppner F;Koch A;Jouvet A;Keohane C;Mühleisen H;Mueller W;Pohl U;Prinz M;Benner A;Zapatka M;Gottardo NG;Driever PH;Kramm CM;Müller HL;Rutkowski S;von Hoff K;Frühwald MC;Gnekow A;Fleischhack G;Tippelt S;Calaminus G;Monoranu CM;Perry A;Jones C;Jacques TS;Radlwimmer B;Gessi M;Pietsch T;Schramm J;Schackert G;Westphal M;Reifenberger G;Wesseling P;Weller M;Collins VP;Blümcke I;Bendszus M;Debus J;Huang A;Jabado N;Northcott PA;Paulus W;Gajjar A;Robinson GW;Taylor MD;Jaunmuktane Z;Ryzhova M;Platten M;Unterberg A;Wick W;Karajannis MA;Mittelbronn M;Acker T;Hartmann C;Aldape K;Schüller U;Buslei R;Lichter P;Kool M;Herold-Mende C;Ellison DW;Hasselblatt M;Snuderl M;Brandner S;Korshunov A;von Deimling A;Pfister SM
通讯作者：
Pfister SM
DOI：
10.1083/jcb.143.7.1883
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnston JA;Ward CL;Kopito RR
通讯作者：
Kopito RR
影响因子：
5.2
作者：
Moriya S;Komatsu S;Yamasaki K;Kawai Y;Kokuba H;Hirota A;Che XF;Inazu M;Gotoh A;Hiramoto M;Miyazawa K
通讯作者：
Miyazawa K
影响因子：
7.2
作者：
Chen, Bryan;Retzlaff, Marco;Frydman, Judith
通讯作者：
Frydman, Judith