基于NMR的绒癌化疗耐药机制的代谢组学研究

丁来丰; 张聪聪; 胡庆宇; Olivier E. PARDO; Michael J. SECKL; 王玉兰; 吴俊芳

doi:10.11938/cjmr20192719

波谱学杂志 >

2019 , Vol. 36 >Issue 4: 534 - 543

DOI: https://doi.org/10.11938/cjmr20192719

研究论文

基于NMR的绒癌化疗耐药机制的代谢组学研究

丁来丰 ,
张聪聪 ,
胡庆宇 ,
Olivier E. PARDO ,
Michael J. SECKL ,
王玉兰 ,
吴俊芳

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1. 波谱与原子分子物理国家重点实验室, 武汉磁共振中心(中国科学院武汉物理与数学研究所), 湖北武汉 430071;
2. 中国科学院大学, 北京 100049;
3. 复旦大学生命科学学院, 上海 200433;
4. Division of Cancer, Department of Surgery and Cancer, Imperial College London, London W120NN;
5. Singapore Phenome Center, Lee Kong Chian School of Medicine, School of Biological Sciences, Nanyang Technological University, Singapore 639798;
6. 基因诊断中心, 华中科技大学同济医学院附属同济医院, 湖北武汉 430030

收稿日期: 2019-03-08

网络出版日期: 2019-05-30

基金资助

湖北省自然科学基金资助项目（2017CFB536）；国家自然科学基金资助项目（31971358）.

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Mechanisms Underlying Chemoresistance of Choriocarcinoma Investigated with NMR-Based Metabonomics

DING Lai-feng ,
ZHANG Cong-cong ,
HU Qing-yu ,
Olivier E. PARDO ,
Michael J. SECKL ,
WANG Yu-lan ,
WU Jun-fang

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1. State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan(Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences), Wuhan 430071, China;
2. University of Chinese Academy of Sciences, Beijing 100049, China;
3. School of Life Sciences, Fudan University, Shanghai 200433, China;
4. Division of Cancer, Department of Surgery and Cancer, Imperial College London, London W120NN, UK;
5. Singapore Phenome Center, Lee Kong Chian School of Medicine, School of Biological Sciences, Nanyang Technological University, Singapore 639798, Singapore;
6. Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

Received date: 2019-03-08

Online published: 2019-05-30

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摘要

绒癌是一种发生于育龄妇女的恶性滋养细胞肿瘤.经甲氨蝶呤、5-氟尿嘧啶等单药或多药联合化疗后，其治愈率通常高达90%.然而耐药仍是绒癌治疗失败的主要原因.目前绒癌耐药的机制尚不明确，前人多从蛋白和转录水平阐述，鲜有涉及代谢物层次的研究.本文采用基于核磁共振（NMR）的代谢组学方法，研究了甲氨蝶呤耐药株JEG3R与敏感株JEG3绒癌细胞及其培养基在代谢物水平上的差异.结果发现JEG3R耐药极可能与糖代谢异常相关，主要表现为耐药株细胞中山梨糖醇的累积，提示醛糖还原酶可能在耐药过程中起重要作用；其次，耐药株细胞中乳酸积累、丙氨酸流入三羧酸循环途径增强；此外，耐药株细胞相比敏感株细胞中氨基酸、核苷酸及磷酸胆碱等必需营养物质的显著性改变，且其变化与绒癌增殖速率正相关.本研究为绒癌的耐药机制研究补充了代谢层次的数据，为后续从分子生物学水平上揭示耐药机制提供了新思路.

关键词： 绒癌; 化疗耐药; 山梨糖醇; 代谢组学

本文引用格式

丁来丰 , 张聪聪 , 胡庆宇 , Olivier E. PARDO , Michael J. SECKL , 王玉兰 , 吴俊芳 . 基于NMR的绒癌化疗耐药机制的代谢组学研究[J]. 波谱学杂志, 2019 , 36(4) : 534 -543 . DOI: 10.11938/cjmr20192719

Abstract

Choriocarcinoma (CC) is a malignant trophoblastic tumor that occurs in women of childbearing age. Its cure rate could be over 90% following single drug or multidrug chemotherapy with methotrexate, 5-fluorouracil and etc. Chemoresistance is the main cause of treatment failure in CC, and the mechanisms have yet to be elucidated. Most of the previous works on the chemoresistance of CC focused on the transcript and protein levels, and much less attention was put on the metabolic level. In this study, the metabolomic phenotypes of two lines of CC cell, methotrexate-resistant cell (JEG3R) and methotrexate-sensitive cell (JEG3), as well as the medium extracts, were investigated using an NMR-based metabonomics method. The results showed that the chemoresistance of CC was likely related to disturbed glucose metabolism. Glucitol accumulation was observed only in the JEG3R cell line, suggesting the involvement of aldose reductase in the development of chemoresistance. In addition, methotrexate chemoresistance was also associated with lactate accumulation and stimulated alanine synthesis to fuel the Krebs cycle. The levels of amino acids, nucleotides and phosphocholine in the resistant line showed significant differences from the non-resistant line, and positive correlations with the proliferation rate of CC. This study provided insights into the chemoresistance of CC from the metabolism aspect.

Key words： choriocarcinoma; chemoresistance; glucitol; metabonomics

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