Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer.
Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer.
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血浆外泌体蛋白和代谢的改变与去势抵抗性前列腺癌的进展相关
DOI：
10.1186/s12967-022-03860-3
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发表时间：
2023-01-21
影响因子：
7.4
通讯作者：
Wu, Dinglan
中科院分区：
文献类型：
--
作者：
Liu, Pengyu;Wang, Wenxuan;Wang, Fei;Fan, Jiaqi;Guo, Jinan;Wu, Tao;Lu, Dongliang;Zhou, Qingchun;Liu, Zhuohao;Wang, Yuliang;Shang, Zhiqun;Chan, Franky Leung;Yang, Wei;Li, Xin;Zhao, Shan-Chao;Zheng, Qingyou;Wu, Dinglan
目前的前列腺癌（PCa）诊断工具如血清PSA检测和前列腺活检不能区分休眠肿瘤和侵袭性恶性肿瘤，也不能作为去势抵抗性前列腺癌（CRPC）的预后标志物，CRPC是PCa患者的致命阶段。外泌体已被广泛研究作为各种疾病的有前途的生物标志物。我们的目的是表征外泌体的蛋白质组学和代谢组学特征，并评估其对PCa，特别是CRPC诊断的潜在价值。我们还研究了一些特定的外泌体生物标志物在CRPC进展中的作用。对从无肿瘤对照（TFC）、PCa和CRPC患者收集的血浆来源的外泌体进行整合的蛋白质组学和代谢组学分析。通过靶向4D平行反应监测（PRM）质谱法在三个群组中进一步验证特异性外泌体蛋白的表达。在临床PCa组织样品和细胞系模型中研究了外泌体蛋白LRG 1的组织分布和功能作用。鉴定了三种潜在的外泌体蛋白标记物。PCa组载脂蛋白E水平是TFC组的1.7倍（受试者操作特征值0.74）。同样，CRPC组中外来体来源的富含亮氨酸的α 2-糖蛋白1（LRG 1）和α-胰蛋白酶间抑制剂重链H3（ITIH 3）的水平分别是PCa组的1.7倍和2.04倍（ROC值分别为0.84和0.85），这表明LRG 1和ITIH 3可以作为CRPC的预测标志物。对于外来体的代谢组学评价，鉴定了一系列差异表达的代谢物，并且组合的代谢物组显示用于区分PCa与TFC的ROC值为0.94，用于区分CRPC与PCa的ROC值为0.97。组织芯片免疫组化显示LRG 1蛋白在晚期前列腺癌中表达显著上调，功能检测显示LRG 1的异位表达可显著增强前列腺癌细胞的恶性表型。更重要的是，PCa细胞来源的LRG 1过表达的外泌体显著促进血管生成。蛋白质组学和代谢组学数据的整合产生了血浆外泌体的蛋白质组学和代谢特征，这可能有助于区分PCa和TFC患者的CRPC，表明外泌体蛋白和代谢物作为CRPC标志物的潜力。该研究还证实了外泌体蛋白LRG 1在PCa恶性进展中的重要作用。在线版本包含补充材料，可通过10.1186/s12967-022-03860-3获得。
Current diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC. Integrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins were further validated by targeted 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models. Three potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolomic evaluation of exosomes, a series of differentially expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa. Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis. Integration of proteomics and metabolomics data generated proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression. The online version contains supplementary material available at 10.1186/s12967-022-03860-3.
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影响因子：
3.7
作者：
Putluri N;Shojaie A;Vasu VT;Nalluri S;Vareed SK;Putluri V;Vivekanandan-Giri A;Byun J;Pennathur S;Sana TR;Fischer SM;Palapattu GS;Creighton CJ;Michailidis G;Sreekumar A
通讯作者：
Sreekumar A
影响因子：
4.4
作者：
Chong, Poh Kuan;Lee, Huiyin;Zhou, Jianbiao;Liu, Shaw-Cheng;Loh, Marie Chiew Shia;Wang, Ting Ting;Chan, Siew Pang;Smoot, Duane T.;Ashktorab, Hassan;So, Jimmy Bok Yan;Lim, Khong Hee;Yeoh, Khay Guan;Lim, Yoon Pin
通讯作者：
Lim, Yoon Pin
影响因子：
16
作者：
Clos-Garcia M;Loizaga-Iriarte A;Zuñiga-Garcia P;Sánchez-Mosquera P;Rosa Cortazar A;González E;Torrano V;Alonso C;Pérez-Cormenzana M;Ugalde-Olano A;Lacasa-Viscasillas I;Castro A;Royo F;Unda M;Carracedo A;Falcón-Pérez JM
通讯作者：
Falcón-Pérez JM
影响因子：
11.2
作者：
Bhagirath D;Yang TL;Bucay N;Sekhon K;Majid S;Shahryari V;Dahiya R;Tanaka Y;Saini S
通讯作者：
Saini S
影响因子：
64.8
作者：
Melo SA;Luecke LB;Kahlert C;Fernandez AF;Gammon ST;Kaye J;LeBleu VS;Mittendorf EA;Weitz J;Rahbari N;Reissfelder C;Pilarsky C;Fraga MF;Piwnica-Worms D;Kalluri R
通讯作者：
Kalluri R