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卵巢癌细胞系A2780向其三种顺铂耐药变体发展过程中N-糖组和转录组变化的动态分析。

Dynamic analysis of N-glycomic and transcriptomic changes in the development of ovarian cancer cell line A2780 to its three cisplatin-resistant variants.

作者信息

Lin Guiling, Zhao Ran, Wang Yisheng, Han Jing, Gu Yong, Pan Yiqing, Ren Changhao, Ren Shifang, Xu Congjian

机构信息

Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China.

NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

出版信息

Ann Transl Med. 2020 Mar;8(6):289. doi: 10.21037/atm.2020.03.12.

DOI:10.21037/atm.2020.03.12
PMID:32355733
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7186709/
Abstract

BACKGROUND

Platinum resistance development is a dynamic process that occurs during continuous chemotherapy and contributes to high mortality in ovarian cancer. Abnormal glycosylation has been reported in platinum resistance. Many studies on platinum resistance have been performed, but few of them have investigated platinum resistance-associated glycans based on N-glycomics. Moreover, glycomic alterations during platinum resistance development in ovarian cancer are rarely reported. Therefore, the objective of this study was to determine platinum resistance-related N-glycans in ovarian cancer cells during continuous exposure to cisplatin. These glycans might be involved in the mechanism of platinum resistance and serve as biomarkers to monitor its development.

METHODS

This study mimicked the development of platinum resistance in ovarian cancer by continuously exposing A2780 cells to cisplatin. Cisplatin-resistant variants were confirmed by higher half maximal inhibitory concentration (IC) values and increased P-glycoprotein (ABCB1, P-gp) expression compared to A2780 cells. Analysis of dynamic N-glycomic changes during the development of platinum resistance in cisplatin-resistant variants was performed with MALDI-time-of-flight (TOF)-MS combined with ethyl esterification derivatization, which were used to discriminate between α2,3- and α2,6-linkage N-acetylneuraminic acid. N-glycan alterations were further validated on a glycotransferase level via transcriptome sequencing and real-time PCR (RT-PCR).

RESULTS

Compared to the A2780 cells, MS analysis indicated that α2,3-linked sialic structures and N-glycan gal-ratios were significantly higher, while fucosylated glycans were lower in three cisplatin-resistant variants. Transcriptome sequencing and RT-PCR showed that gene expression of and increased, while gene expression of , , , and decreased in three cisplatin-resistant variants.

CONCLUSIONS

Analysis of N-glycans and glycogene expression showed that α2,3-linked sialic structures might serve as biomarkers to monitor the development of platinum resistance and to guide individualized treatment of ovarian cancer patients.

摘要

背景

铂耐药的产生是一个在持续化疗过程中发生的动态过程，它导致卵巢癌的高死亡率。已有报道称铂耐药中存在异常糖基化。关于铂耐药已经进行了许多研究，但基于N-糖组学研究铂耐药相关聚糖的却很少。此外，卵巢癌铂耐药发展过程中的糖组改变鲜有报道。因此，本研究的目的是确定在持续暴露于顺铂的过程中卵巢癌细胞中与铂耐药相关的N-聚糖。这些聚糖可能参与铂耐药机制，并作为监测其发展的生物标志物。

方法

本研究通过将A2780细胞持续暴露于顺铂来模拟卵巢癌铂耐药的发展。与A2780细胞相比，通过更高的半数最大抑制浓度（IC）值和增加的P-糖蛋白（ABCB1，P-gp）表达来确认顺铂耐药变体。使用基质辅助激光解吸电离飞行时间（TOF）-质谱结合乙酯化衍生化对顺铂耐药变体中铂耐药发展过程中的动态N-糖组变化进行分析，该方法用于区分α2,3-和α2,6-连接的N-乙酰神经氨酸。通过转录组测序和实时PCR（RT-PCR）在糖基转移酶水平上进一步验证N-聚糖改变。

结果

与A2780细胞相比，质谱分析表明，在三个顺铂耐药变体中，α2,3-连接的唾液酸结构和N-聚糖半乳糖比率显著更高，而岩藻糖基化聚糖更低。转录组测序和RT-PCR显示，在三个顺铂耐药变体中， 和 的基因表达增加，而 、 、 和 的基因表达降低。

结论

N-聚糖和糖基因表达分析表明，α2,3-连接的唾液酸结构可能作为监测铂耐药发展和指导卵巢癌患者个体化治疗的生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/174f6d23cbe1/atm-08-06-289-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/c7354135df7b/atm-08-06-289-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/2007a633a30c/atm-08-06-289-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/3b5ff319591e/atm-08-06-289-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/9dcef751f3ba/atm-08-06-289-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/4c97d066266c/atm-08-06-289-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/a270d00fbd24/atm-08-06-289-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/174f6d23cbe1/atm-08-06-289-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/c7354135df7b/atm-08-06-289-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/2007a633a30c/atm-08-06-289-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/3b5ff319591e/atm-08-06-289-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/9dcef751f3ba/atm-08-06-289-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/4c97d066266c/atm-08-06-289-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/a270d00fbd24/atm-08-06-289-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad42/7186709/174f6d23cbe1/atm-08-06-289-f7.jpg

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