基于UPLC-MS/MS方法分析哈萨克族食管鳞癌患者的血清脂质组学特征

doi:10.3969/j.issn.1004-616x.2024.01.004

摘要/Abstract

摘要： 目的：基于血清脂质组学研究新疆哈萨克族食管鳞状细胞癌（ESCC）患者的脂质代谢特征。方法：选取2018年1月—2020年12月新疆医科大学第一附属医院胸外科就诊的30例哈萨克族ESCC患者（ESCC组），另外选择同期在新疆医科大学健康管理中心体检的哈萨克族健康体检者30例（对照组）。采用超高效液相色谱质谱联用技术（UPLC-MS/MS）对两组人群血清进行靶向定量脂质组学分析。根据同类脂质内标峰面积和实际浓度关系进行脂质定量。利用脂质数据进行多变量统计分析。结果：60例血清样本中共筛选出13种脂类，其中浓度最高的是三酰甘油、磷脂酰胆碱和磷脂酰乙醇胺，溶血磷脂酰胆碱是两组人群血清中差异最大的脂类。相较对照组血清样本，哈萨克族ESCC患者血清中三酰甘油、溶血磷脂酰胆碱的浓度上调，磷脂酰乙醇胺下调。溶血磷脂酰胆碱、磷脂酰乙醇胺和磷脂酰胆碱的链长度和不饱和度在哈萨克族ESCC患者血清中显著下调。根据正交偏最小二乘法-判别分析（OPLS-DA），以阈值（P<0.05和差异倍数>2或<0.5）筛选差异脂质代谢物，共筛选出77种差异脂类，其中与对照组比较，ESCC组上调的有34种，下调的有43种。包括甘油三酯、甘油二酯、溶血磷脂酰胆碱、磷脂酰乙醇胺及游离脂肪酸。结论：哈萨克族ESCC患者血清中不同脂质浓度及变化趋势存在差异。其中甘油三酯、溶血磷脂酰胆碱的浓度上调，磷脂酰乙醇胺、溶血磷脂酰胆碱、磷脂酰乙醇胺和磷脂酰胆碱链长度及不饱和度下调。分析这些脂质分布的变化和筛选新靶标有助于阐明新疆哈萨克族ESCC的发生发展机制。

关键词: 食管鳞状细胞癌, 哈萨克族, 脂质组学, 脂质代谢物, 差异表达

Abstract: OBJECTIVE: To explore characteristics of lipid metabolism in Xinjiang Kazakh patients with esophageal squamous cell carcinoma(ESCC) based on serum lipidomics. METHODS: From January 2018 to December 2020, 30 Kazakh ESCC patients in the thoracic surgery department of the First Affiliated Hospital of Xinjiang Medical University(ESCC group) and 30 Kazakh healthy people who underwent physical examination in the Health Management Center of Xinjiang Medical University(control group) were selected.Ultra-high performance liquid chromatography-mass spectrometry(UPLC-MS/MS) was used to analyze the targeted quantitative lipidomics of serum in the two groups. Absolute lipid quantification was performed according to relationships between the peak areas and the actual concentrations of internal standard(IS) of similar lipids. Multivariate statistical analyses were performed using the lipid data. RESULTS: A total of 13lipids were screened out in 60 serum samples, among which triacylglycerol(TAG), phosphatidyl choline(PC)and phosphatidyl ethanolamine(PE) were the most abundant. Lysophosphatidylcholine(LPC) was the most different lipid in serum between the two groups. Compared with the control group, the levels of TAG and LPC in the serum of Kazakh ESCC patients were up-regulated, while PE was down-regulated. According to the orthogonal partial least squares-discriminant analysis(OPLS-DA), the threshold(P<0.05 and fold change>2 or <0.5), a total of 77 differential lipid metabolites were screened, among which 34 were up-regulated and 43 were down-regulated in ESCC group compared with control group. Including triglycerides, diglycerides, lysophosphatidyl choline, phosphatidyl ethanolamine and free fatty acids. CONCLUSION: The contents and trends of different lipids in the patients were different. The contents of triglyceride, phosphatidyl choline and ceramide in serum of patients were up-regulated, while the contents of lysatidyl choline and diglyceride were overall down-regulated. The contents of triglyceride and lysophosphatidyl choline in the serum of the Kazakh patients were up-regulated, while phosphatidyl ethanolamine was down-regulated, and the chain length and unsaturation of lysophosphatidyl choline, phosphatidyl ethanolamine and phosphatidyl choline were down-regulated in the serum of patients. Therefore, the analysis of changes in the distribution of these lipids and the screening of new targets are helpful to clarify mecahnisms for occurrence and development of ESCC patients of Xinjiang Kazak nationality.

Key words: esophageal squamous cell carcinoma, Kazakhs, lipidomics, lipid metabolites, differential expression

中图分类号:

R730.2

刘瑞雪, 李德生, 张力为. 基于UPLC-MS/MS方法分析哈萨克族食管鳞癌患者的血清脂质组学特征[J]. 癌变·畸变·突变, 2024, 36(1): 21-28,34.

LIU Ruixue, LI Desheng, ZHANG Liwei. Characteristics of serum lipidomics among Kazakhs with esophageal squamous cell carcinomas based on the UPLC-MS/MS method[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2024, 36(1): 21-28,34.

参考文献

[1] SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249.
[2] 刘宗超,李哲轩,张阳,等. 2020全球癌症统计报告解读[J].肿瘤综合治疗电子杂志, 2021, 7(2):1-14.
[3] YANG S, LIN S, LI N, et al. Burden, trends, and risk factors of esophageal cancer in China from 1990 to 2017:an up-to-date overview and comparison with those in Japan and South Korea[J]. J Hematol Oncol, 2020, 13(1):146.
[4] NAPIER K J, SCHEERER M, MISRA S. Esophageal cancer:a Review of epidemiology, pathogenesis, staging workup and treatment modalities[J]. World J Gastrointest Oncol, 2014, 6(5):112-120.
[5] FATEHI HASSANABAD A, CHEHADE R, BREADNER D, et al. Esophageal carcinoma:towards targeted therapies[J]. Cell Oncol, 2020, 43(2):195-209.
[6] CHENG C M, GENG F, CHENG X, et al. Lipid metabolism reprogramming and its potential targets in cancer[J]. Cancer Commun, 2018, 38(1):27.
[7] LI W, WANG X B, ZHANG X B, et al. Revealing potential lipid biomarkers in clear cell renal cell carcinoma using targeted quantitative lipidomics[J]. Lipids Health Dis, 2021, 20(1):160.
[8] ZHANG Q, XU H R, LIU R, et al. A novel strategy for targeted lipidomics based on LC-tandem-MS parameters prediction,quantification, and multiple statistical data mining:evaluation of lysophosphatidylcholines as potential cancer biomarkers[J].Anal Chem, 2019, 91(5):3389-3396.
[9] SNAEBJORNSSON M T, JANAKI-RAMAN S, SCHULZE A.Greasing the wheels of the cancer machine:the role of lipid metabolism in cancer[J]. Cell Metab, 2020, 31(1):62-76.
[10] PERROTTI F, ROSA C, CICALINI I, et al. Advances in lipidomics for cancer biomarkers discovery[J]. Int J Mol Sci,2016, 17(12):1992.
[11] ZHANG H P, WANG L, HOU Z C, et al. Metabolomic profiling reveals potential biomarkers in esophageal cancer progression using liquid chromatography-mass spectrometry platform[J].Biochem Biophys Res Commun, 2017, 491(1):119-125.
[12] PARK J, CHOI J, KIM D D, et al. Bioactive lipids and their derivatives in biomedical applications[J]. Biomol Ther, 2021, 29(5):465-482.
[13] MANZO T, PRENTICE B M, ANDERSON K G, et al.Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+T cells[J]. J Exp Med, 2020, 217(8):e20191920.
[14] WANG C C, TONG Y, WEN Y K, et al. Hepatocellular carcinoma-associated protein TD26 interacts and enhances sterol regulatory element-binding protein 1 activity to promote tumor cell proliferation and growth[J]. Hepatology, 2018, 68(5):1833-1850.
[15] LI J J, CONDELLO S, THOMES-PEPIN J, et al. Lipid desaturation is a metabolic marker and therapeutic target of ovarian cancer stem cells[J]. Cell Stem Cell, 2017, 20(3):303-314.e5.
[16] SZLASA W, ZENDRAN I, ZALESIŃSKA A, et al. Lipid composition of the cancer cell membrane[J]. J Bioenerg Biomembr, 2020, 52(5):321-342.
[17] XU J, CHEN Y H, ZHANG R P, et al. Global and targeted metabolomics of esophageal squamous cell carcinoma discovers potential diagnostic and therapeutic biomarkers[J]. Mol Cell Proteomics, 2013, 12(5):1306-1318.
[18] KÜHN T, FLOEGEL A, SOOKTHAI D, et al. Higher plasma levels of lysophosphatidylcholine 18:0 are related to a lower risk of common cancers in a prospective metabolomics study[J].BMC Med, 2016, 14:13.
[19] XIONG J H. Fatty acid oxidation in cell fate determination[J].Trends Biochem Sci, 2018, 43(11):854-857.
[20] YANG T, HUI R T, NOUWS J, et al. Untargeted metabolomics analysis of esophageal squamous cell cancer progression[J]. J Transl Med, 2022, 20(1):127.
[21] HOEJHOLT K L, MUŽIĆT, JENSEN S D, et al. Calcium electroporation and electrochemotherapy for cancer treatment:importance of cell membrane composition investigated by lipidomics, calorimetry and in vitro efficacy[J]. Sci Rep, 2019, 9(1):4758.
[22] HONSHO M, ABE Y, FUJIKI Y. Plasmalogen biosynthesis is spatiotemporally regulated by sensing plasmalogens in the inner leaflet of plasma membranes[J]. Sci Rep, 2017, 7:43936.
[23] ZHENG K H, CHEN Z T, FENG H Z, et al. Sphingomyelin synthase 2 promotes an aggressive breast cancer phenotype by disrupting the homoeostasis of ceramide and sphingomyelin[J].Cell Death Dis, 2019, 10(3):157.
[24] CORCELLE-TERMEAU E, VINDELØV S D, HÄMÄLISTÖS,et al. Excess sphingomyelin disturbs ATG9A trafficking and autophagosome closure[J]. Autophagy, 2016, 12(5):833-849.
[25] HORVATH S E, DAUM G. Lipids of mitochondria[J]. Prog Lipid Res, 2013, 52(4):590-614.
[26] MORO K, NAGAHASHI M, GABRIEL E, et al. Clinical application of ceramide in cancer treatment[J]. Breast Cancer,2019, 26(4):407-415.
[27] ZHOU X T, HUANG F R, MA G, et al. Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis[J]. Signal Transduct Target Ther, 2022, 7(1):370.