尿液非极性代谢物中筛选结直肠癌诊断与化疗毒性标志物

摘要/Abstract

摘要： 目的：从结直肠癌（CRC）患者尿液中的内源性代谢物，寻找潜在的诊断生物标志物和卡培他滨相关不良反应(CRAE)的生物标志物。方法：采用超高效液相色谱结合四极杆飞行时间质谱（UHPLC-Q-TOF-MS）的方法，分析148例CRC患者和50例非肿瘤对照者的尿液代谢谱。对数据进行生物信息学分析并建立CRC预测模型。结果：CRC潜在诊断标志物包括3-Hexenedioic acid、Salicylic acid、(R)-Athanagrandione、PC (15∶0/20∶4)和(9E,11E)-Octadecadienoic等与脂类代谢相关的非极性代谢物。ROC曲线显示训练集的曲线下面积（area under curve, AUC）为0.980（95% CI:0.949-0.999），敏感度98.4%，特异度92.6%；测试集的AUC为1（95% CI：1-1），敏感度98.6%，特异度100%。(R)-Athanagrandione和Salicylic acid联合预测腹泻时，AUC为0.773（95% CI:0.617-0.921），敏感度为83.3%，特异度为68.2%。结论：尿液中非极性代谢标志物模型在CRC的早期诊断和CRAE的预测方面具有较高的临床价值。

关键词: font-size:medium, ">尿液；结直肠癌；脂类；非靶向代谢组学；非极性代谢物；卡培他滨；不良反应

Abstract: Objective：To identify potential diagnostic biomarkers and capecitabine-related adverse effect (CRAE) biomarkers from urinary endogenous metabolites in Chinese colorectal cancer (CRC) patients. Methods：The metabolic profiles of 148 CRC patients and 50 non-neoplastic controls were analyzed using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS).The data were bioinformatically analyzed and established a CRC predictive model. Results：A series of diagnostic markers for CRC were found, including 3-Hexenedioic acid, Salicylic acid, (R)-Athanagrandione, PC (15∶0/20∶4) and (9E, 11 E)-Octadecadienoic, which are non-polar metabolites related to lipid metabolism using.The ROC curve shows the area under the curve(AUC) of the training set is 0.980, (95%CI:0.949-0.999; Sensitivity:98.4%; Specificity:92.6%), the AUC of the test set is 1, (Sensitivity:98.6%; Specificity:100%). In addition, (R)-athanagrandione and Salicylic acid can be combined to predict diarrhea, with an AUC of 0.773(95% CI:0.617-0.921, sensitivity:83.3%, specificity:68.2%). Conclusion：The constructed models based on urine non-polar metabolites have both great clinical values in the early detection of CRC and the prediction of CRAE.

Key words: Urine, Colorectal cancer, Lipids, Untargeted metabolomics, Non-polar metabolites, Capecitabine, Adverse effects

中图分类号:

林泽帅, 晏涛, 陈佳妮a, 姚厚山b, 陈伟a, 张凤a, 李明明a, 姚佳, 陈万生a. 尿液非极性代谢物中筛选结直肠癌诊断与化疗毒性标志物[J]. 中国医药导刊, 2022, 24(2): 131-139.

LIN Zeshuai, YAN Tao, CHEN Jiania, YAO Houshanb, CHEN Weia, ZHANG Fenga, LI Mingminga, YAO Jia, CHEN Wanshenga. Screening of Toxic Markers for Diagnosis and Chemotherapy of Colorectal Cancer from Urine Non-Polar Metabolites[J]. CHINESE JOURNAL OF MEDICINAL GUIDE, 2022, 24(2): 131-139.

参考文献

[1]Mattiuzzi C, Sanchis-Gomar F, Lippi G. Concise update on colorectal cancer epidemiology[J]. Ann Transl Med,2019, 7(21):609.
     [2]Wu C, Li M, Meng H, et al. Analysis of status and countermeasures of cancer incidence and mortality in China[J]. Sci China Life Sci,2019,62(5):640-647.
     [3]Zhu J, Tan Z, Hollis-Hansen K, et al. Epidemiological trends in colorectal cancer in china:an ecological study[J]. Dig Dis Sci,2017,62(1):235-243.
     [4]Hamaguchi R, Tsuchiya T, Miyata G, et al. Efficacy of oral administration of cystine and theanine in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery:a multi-institutional, randomized, double-blinded, placebo-controlled, phase II trial (JORTC-CAM03)[J]. Support Care Cancer,2020,28(8):3649-3657.
     [5]单艳,姬卫国.术后接受以卡培他滨为基础辅助化疗的结直肠癌患者预后的影响因素和不良反应[J].河南医学研究,2020,29(1):33-36.
     [6]Beger RD, Sun J, Schnackenberg LK. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity[J]. Toxicol Appl Pharmacol,2010,243(2):154-66.
     [7]Michopoulos F, Gika H, Palachanis D, et al. Solid phase extraction methodology for UPLC-MS based metabolic profiling of urine samples[J]. Electrophoresis,2015,36(18):2170-2178.
     [8]Deng Y, Yao H, Chen W, et al. Profiling of polar urine metabolite extracts from Chinese colorectal cancer patients to screen for potential diagnostic and adverse-effect biomarkers[J]. J Cancer,2020,11(23):6925-6938.
     [9]Tipthara P, Thongboonkerd V. Differential human urinary lipid profiles using various lipid-extraction protocols:MALDI-TOF and LIFT-TOF/TOF analyses[J]. Sci Rep,2016,6:33756.
     [10]皮子凤,门丽慧,张静,等.五味子治疗大鼠糖尿病肾病作用机制的血清代谢组学研究[J].分析化学,2015,43(2):169-175.
     [11]皋文君,刘砚燕,袁长蓉.国际肿瘤化疗药物不良反应评价系统——通用不良反应术语标准4.0版[J].肿瘤,2012,32(2):142-144.
     [12]Zhang F, Zhang Y, Zhao W, et al. Metabolomics for biomarker discovery in the diagnosis, prognosis, survival and recurrence of colorectal cancer:a systematic review[J]. Oncotarget,2017,8(21):35460-35472.
     [13]Martín-Blázquez A, Díaz C, González-Flores E, et al. Untargeted LC-HRMS-based metabolomics to identify novel biomarkers of metastatic colorectal cancer[J]. Sci Rep,2019,9(1):20198.
     [14]Khamis MM, Adamko DJ, El-Aneed A. Mass spectrometric based approaches in urine metabolomics and biomarker discovery[J]. Mass Spectrom Rev,2017,36(2):115-134.
     [15]Kim ER, Kwon HN, Nam H, et al. Urine-NMR metabolomics for screening of advanced colorectal adenoma and early stage colorectal cancer[J]. Sci Rep,2019,9(1):4786.
     [16]Hu T, Zhang JL. Mass-spectrometry-based lipidomics[J]. J Sep Sci,2018,41(1):351-372.
     [17]Min HK, Kong G, Moon MH. Quantitative analysis of urinary phospholipids found in patients with breast cancer by nanoflow liquid chromatography-tandem mass spectrometry:II. Negative ion mode analysis of four phospholipid classes[J]. Anal Bioanal Chem,2010,396(3):1273-1280.
     [18]Ghosh A, Nishtala K. Biofluid lipidome:a source for potential diagnostic biomarkers[J]. Clin Transl Med,2017,6(1):22.
     [19]Nishiumi S, Kobayashi T, Ikeda A, et al. A novel serum metabolomics-based diagnostic approach for colorectal cancer[J]. PLoS One,2012,7(7):e40459.
     [20]Cheng Y, Xie G, Chen T, et al. Distinct urinary metabolic profile of human colorectal cancer[J]. J Proteome Res, 2012,11(2):1354-1363.
     [21]Coussens LM, Werb Z. Inflammation and cancer[J]. Nature,2002,420(6917):860-867.
     [22]Tan B, Qiu Y, Zou X, et al. Metabonomics identifies serum metabolite markers of colorectal cancer[J]. J Proteome Res,2013,12(6):3000-3009.
     [23]Ludwig C, Ward DG, Martin A, et al. Fast targeted multidimensional NMR metabolomics of colorectal cancer[J]. Magn Reson Chem,2009,47 （Suppl 1）:S68-573.
     [24]Wang Y, Bi C, Pang W, et al. Plasma metabolic profiling analysis of gout party on acute gout arthritis rats based on UHPLC-Q-TOF/MS combined with multivariate statistical analysis[J]. Int J Mol Sci,2019,20(22):5753.
     [25]Kadochi Y, Mori S, Fujiwara-Tani R, et al. Remodeling of energy metabolism by a ketone body and medium-chain fatty acid suppressed the proliferation of CT26 mouse colon cancer cells[J]. Oncol Lett,2017,14(1):673-680.
     [26]Fauser JK, Matthews GM, Cummins AG, et al. Induction of apoptosis by the medium-chain length fatty acid lauric acid in colon cancer cells due to induction of oxidative stress[J]. Chemotherapy,2013,59(3):214-224.
     [27]Lawrence JR, Peter R, Baxter GJ, et al. Urinary excretion of salicyluric and salicylic acids by non-vegetarians, vegetarians, and patients taking low dose aspirin[J]. J Clin Pathol,2003,56(9):651-653.
     [28]Bashir AIJ, Kankipati CS, Jones S, et al. A novel mechanism for the anticancer activity of aspirin and salicylates[J]. Int J Oncol,2019,54(4):1256-1270.
     [29]Shtivelband MI, Juneja HS, Lee S, et al. Aspirin and salicylate inhibit colon cancer medium- and VEGF-induced endothelial tube formation:correlation with suppression of cyclooxygenase-2 expression[J]. J Thromb Haemost, 2003, 1(10):2225-2233.
     [30]Paterson JR, Lawrence JR. Salicylic acid:a link between aspirin, diet and the prevention of colorectal cancer[J]. QJM,2001,94(8):445-448.
     [31]Szliszka E, Czuba ZP, Mazur B, et al. Chalcones and dihydrochalcones augment TRAIL-mediated apoptosis in prostate cancer cells[J]. Molecules,2010,15(8):5336-5353.
     [32]Kurabe N, Hayasaka T, Ogawa M, et al. Accumulated phosphatidylcholine (16:0/16:1) in human colorectal cancer; possible involvement of LPCAT4[J]. Cancer Sci,2013,104(10):1295-1302.
     [33]Uehara T, Kikuchi H, Miyazaki S, et al. Overexpression of lysophosphatidylcholine acyltransferase 1 and concomitant lipid alterations in gastric cancer[J]. Ann Surg Oncol,2016,23 Suppl 2:S206-213.
     [34]Morita Y, Sakaguchi T, Ikegami K, et al. Lysophosphatidylcholine acyltransferase 1 altered phospholipid composition and regulated hepatoma progression[J]. J Hepatol,2013,59(2):292-299.
     [35]Petkevicius K, Virtue S, Bidault G, et al. Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity[J]. Elife,2019,8:e47990.
     [36]Matsuda A, Yamada M, Matsumoto S, et al. Lysophosphatidylcholine as a predictor of postoperative complications after colorectal cancer surgery[J]. Surg Today,2018,48(10):936-943.
     [37]Liu P, Zhu W, Chen C, et al. The mechanisms of lysophosphatidylcholine in the development of diseases[J]. Life Sci,2020,247:117443.
     [38]Yeh CS, Wang JY, Cheng TL, et al. Fatty acid metabolism pathway play an important role in carcinogenesis of human colorectal cancers by Microarray-Bioinformatics analysis[J]. Cancer Lett,2006,233(2):297-308.
     [39]Palombo JD, Ganguly A, Bistrian BR, et al. The antiproliferative effects of biologically active isomers of conjugated linoleic acid on human colorectal and prostatic cancer cells[J]. Cancer Lett,2002,177(2):163-172.
     [40]Kuhz H, Kuenz A, Prüβe U, et al. Products Components:Alcohols[J]. Adv Biochem Eng Biotechnol,2019,166:339-372.
     [41]Nagykálnai T, Landherr L. Alcohol and breast cancer. A short survey[J]. Magy Onkol,2018,62(1):68-71.
     [42]He H, Liu Z, Wang W, et al. Synthesis and cytotoxic evaluation of halogenated α-exo-methylene-lactones[J]. Bioorg Med Chem,2020,28(3):115281.
     [43]Lee CS, Ryan EJ, Doherty GA. Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer:the role of inflammation[J]. World J Gastroenterol,2014,20(14):3751-3761.
     [44]Hybiak J, Broniarek I, Kiryczyński G, et al. Aspirin and its pleiotropic application[J]. Eur J Pharmacol,2020,866:172762.
     [45]Little TJ, Horowitz M, Feinle-Bisset C. Modulation by high-fat diets of gastrointestinal function and hormones associated with the regulation of energy intake:implications for the pathophysiology of obesity[J]. Am J Clin Nutr, 2007, 86(3):531-541.

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