Circulating levels of hydroxylated bradykinin function as an indicator of tissue HIF-1a expression  

血液中羟基化缓激肽作为肿瘤厌氧指标的研究

作　　者：Yang Liu Yajun Gu Serina Ng Zaian Deng Christopher J.Lyon Eugene J.Koay Bo Ning Matthew H.Katz Paul J.Chiao Jia Fan Haiyong Han Daniel Von Hoff Tony Y.Hu 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 Medicine,New Orleans.LA 70112,USA;Department of Nanomedicine,Houston Methodist Research Institute,Houston,TX 77030,USA;Molecular Medicine Division,Translational Genomics Research Institute,Phoenix,AZ 85004,USA;Department of Radiation Oncology,Division of Radiation Oncology,The University of Texas M.D.Anderson Cancer Center,Houston,TX 77030,USA;Department of Surgical Oncology,Division of Surgery,The University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA;Department of Molecular and Cellular Oncology,Division of Basic Sciences,The University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA)

机构地区：[1]Department of Biochemistry and Molecular Biology,Tulane University School of Medicine,New Orleans.LA 70112,USA [2]Department of Nanomedicine,Houston Methodist Research Institute,Houston,TX 77030,USA [3]Molecular Medicine Division,Translational Genomics Research Institute,Phoenix,AZ 85004,USA [4]Department of Radiation Oncology,Division of Radiation Oncology,The University of Texas M.D.Anderson Cancer Center,Houston,TX 77030,USA [5]Department of Surgical Oncology,Division of Surgery,The University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA [6]Department of Molecular and Cellular Oncology,Division of Basic Sciences,The University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA

出　　处：《Science Bulletin》2020年第18期1570-1579,M0004,共11页科学通报（英文版）

基　　金：the Arizona Biomedical Research Commission(ABRC)young investigator award;the Fred Hutchinson Cancer Research Center(0000917241);Tulane University Startup fund。

摘　　要：The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.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 

分 类 号：R735.9[医药卫生—肿瘤]