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Nanotrap-enabled quantification of KRAS-induced peptide hydroxylation in blood for cancer early detection

Nano Research 2019年第6期12卷 1445-1452页

作者： zaian deng Zhen Zhao Bo Ning Jeffery Basilio Karen Mann Jie Fu Yajun Gu Yuanqing Ye Xifeng Wu Jia Fan Paul Chiao Tony Hu College of Health Science and Environmental Engineering Shenzhen Technology UniversityShenzhen 518118 China School of Biological and Health Systems Engineering Virginia G. Piper Biodesign Center for Personalized DiagnosticsThe Biodesign InstituteArizona State UniversityTempeArizona 85287USA Department of Nanomedicine Houston Methodist Research InstituteHoustonTexas 77030USA Pathology and Laboratory Medicine Weill Cornell Medical CollegeNew York New York 10065USA Center for Molecular Design and Biomimetics The Biodesign InstituteArizona State UniversityTempeArizona 85287USA Department of Laboratory Medicine Clinical CenterNational Institutes of HealthBethesdaMaryland 20892USA Department of Molecular Oncology H. Lee Moffitt Cancer CenterTampaFlorida 33612USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTexas 77030USA School of Medical Laboratory Tianjin Medical UniversityTianjin 300203China Department of Epidemiology The University of Texas MD Anderson Cancer CenterHoustonTexas 77030USA

Circulating peptide is a potential source of biomarkers for cancer detection.However,the existence of large molecular weight proteins in plasma have a disastrous effect on circulating peptides isolating and detecting.Herein,nanotrap fractionation following by mass spectrometry have been applied to quantify the levels of bradykinin (BK) and hydroxylated bradykinin (Hyp-BK) as a relative measure of KRAS-regulated prolyl-4-hydroxylase alpha-1 (P4HA1) which may serve as early diagnosis marker for pancreatic ductal adenocarcinoma (PDAC).We found that P4HA1 can be upregulated by KRASG12v,which is a PDAC driver mutation,using HPNE/KRAS and HPNE cells.And we revealed that P4HA1 is overexpressed in PDAC tumors,compared to normal and inflamed pancreatic tissues.RNA interference revealed that P4HA1 activity was primarily responsible for Hyp-BK production.Mass spectrometry analysis revealed that plasma Hyp-BK/BK ratio was higher in PDAC than pancreatitis patients and healthy controls,while the area under the receiver operating characteristic (ROC) curve (AUC) is 0.8209 (95%Cl,0.7269-0.9149).The Hyp-BK/BK association with PDAC was reproduced in another cohort,where this ratio was found to increase with advancing tumor stage.These novel findings paved the way for wider applications of Nanotrap coupled mass spectrometry as a powerful tool for revealing biosignatures from plasma.

关键词： nanotrap hydroxylation level bradykinin pancreatic ductal adenocarcinoma

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血液中羟基化缓激肽作为肿瘤厌氧指标的研究

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Science Bulletin 2020年第18期65卷 1570-1579,M0004页

作者：刘洋谷雅君 Serina Ng 邓载安 Christopher J.Lyon Eugene J.Koay 宁波 Matthew H.Katz Paul J.Chiao 范佳韩海勇 Daniel Von Hoff 胡晔 Department of Biochemistry and Molecular Biology Tulane University School of MedicineNew Orleans.LA 70112USA Department of Nanomedicine Houston Methodist Research InstituteHoustonTX 77030USA Molecular Medicine Division Translational Genomics Research InstitutePhoenixAZ 85004USA Department of Radiation Oncology Division of Radiation OncologyThe University of Texas M.D.Anderson Cancer CenterHoustonTX 77030USA Department of Surgical Oncology Division of SurgeryThe University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Molecular and Cellular Oncology Division of Basic SciencesThe University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

组织缺氧在消化系统、呼吸系统、肾脏疾病和癌症等多种疾病的发生发展中起到关键作用.然而,由于缺乏快速、准确和非侵入性的检测方法,评估组织缺氧情况和预测患者的预后结果仍然具有非常大的挑战性.本文假设血液中Hyp-BK/BK比率可以作... 详细信息

组织缺氧在消化系统、呼吸系统、肾脏疾病和癌症等多种疾病的发生发展中起到关键作用.然而,由于缺乏快速、准确和非侵入性的检测方法,评估组织缺氧情况和预测患者的预后结果仍然具有非常大的挑战性.本文假设血液中Hyp-BK/BK比率可以作为缺氧检测的标志物,以胰腺癌作为研究模型,通过监测Hyp-BK/BK比率可以预测组织缺氧水平以及抗肿瘤治疗的预后情况.研究表明,缺氧条件下肿瘤组织中高表达的P4HA1和治疗前患者血液样本中Hyp-BK/BK比率升高有关,并且两者都与患者预后不良相关.这些结果有力地表明血液中Hyp-BK/BK比率可以作为非侵入性的组织缺氧标志物,对胰腺癌的预后和治疗效果进行预测.

关键词： HIF-1α Hypoxia Circulating indicator Hydroxyprolyl bradykinin P4HA1

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