WTAP通过调节BMI1 mRNA的m6A修饰促进胶质瘤细胞增殖和有氧糖酵解

刁新峰; 李新茂; 候亮; 魏志玄

doi:10.19401/j.cnki.1007-3639.2023.07.003

您当前的位置：

首页 >

文章列表页 >

WTAP通过调节BMI1 mRNA的m6A修饰促进胶质瘤细胞增殖和有氧糖酵解

论著 | 更新时间：2025-12-31

- WTAP通过调节BMI1 mRNA的m6A修饰促进胶质瘤细胞增殖和有氧糖酵解
- WTAP promotes proliferation and aerobic glycolysis via regulating m6A modification of BMI1 mRNA
- 中国癌症杂志 2023年33卷第7期页码：655-663
- 作者机构：
  
  1. 南阳医学高等专科学校第一附属医院神经外科，河南南阳 473000
  2. 武安市第一人民医院神经外科，河北邯郸 056300
- 作者简介：
  
  [ "刁新峰（ORCID: 0009-0004-6457-0852），本科，副主任医师。" ]
  魏志玄（ORCID: 0008-0003-5287-1395），硕士，主治医师
- 基金信息：
  
  河北省医学科学研究重点课题计划项目(20171165)
- DOI：10.19401/j.cnki.1007-3639.2023.07.003
  中图分类号： R739.41
- 收稿：2022-09-24，
  
  修回：2023-03-23，
  
  纸质出版：2023-07-30
- 稿件说明：
移动端阅览
刁新峰, 李新茂, 候亮, 等. WTAP通过调节BMI1 mRNA的m6A修饰促进胶质瘤细胞增殖和有氧糖酵解[J]. 中国癌症杂志, 2023,33(7):655-663.

Xinfeng Diao, Xinmao Li, Liang HOU, et al. WTAP promotes proliferation and aerobic glycolysis via regulating m6A modification of BMI1 mRNA[J]. China Oncology, 2023, 33(7): 655-663.
刁新峰, 李新茂, 候亮, 等. WTAP通过调节BMI1 mRNA的m6A修饰促进胶质瘤细胞增殖和有氧糖酵解[J]. 中国癌症杂志, 2023,33(7):655-663. DOI： 10.19401/j.cnki.1007-3639.2023.07.003.

Xinfeng Diao, Xinmao Li, Liang HOU, et al. WTAP promotes proliferation and aerobic glycolysis via regulating m6A modification of BMI1 mRNA[J]. China Oncology, 2023, 33(7): 655-663. DOI： 10.19401/j.cnki.1007-3639.2023.07.003.

摘要

背景与目的：

甲基转移酶Wilms瘤1-相关蛋白（Wilms’ tumor 1-associating protein，WTAP）被证实在肿瘤中发挥重要作用，本研究旨在从N6-甲基腺苷（N6-methyladenosine，m6A）修饰的角度探讨WTAP在胶质瘤发生、发展过程中的作用及其机制。

方法：

通过芯片筛选胶质瘤中差异表达的m6A调节因子，采用实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction，RTFQ-PCR）和蛋白质印迹法（Western blot）评估WTAP/B细胞特异性莫洛尼氏鼠白血病病毒整合位点1（B cell-specific Moloney murine leukemia virus integration site 1，BMI1）在胶质瘤组织和细胞系中的表达。借助四甲基偶氮唑盐（methyl thiazoyl terazolium，MTT）探究WTAP/BMI1对胶质瘤细胞增殖的作用。采用细胞外酸化率（extracellular acidification rate，ECAR）试剂盒、葡萄糖消耗及乳酸生成检测试剂盒评估胶质瘤细胞有氧糖酵解情况。

结果：

相对于正常组织，WTAP、BMI1在胶质瘤组织中表达上调。此外，相对于HEB细胞中的WTAP（1.01±0.13）和BMI1（1.02±0.11）表达，U251细胞中的WTAP（2.38±0.17）、BMI1（2.25±0.14）表达增强（

均

0.05）。敲减WTAP在体外能抑制细胞增殖和糖酵解能力，而过表达WTAP则显示相反效果。过表达WTAP对胶质瘤细胞增殖、糖酵解的作用能被敲减BMI1部分挽救（

均

0.05）。在机制上，WTAP促进BMI1的m6A甲基化修饰，使BMI1 mRNA的稳定性增强（

均

0.05）。

结论：

WTAP能以m6A甲基化依赖方式促进BMI1表达，从而促进胶质瘤细胞增殖和有氧糖酵解，靶向WTAP的分子治疗手段可能为改善胶质瘤治疗效果提供新方向。

Abstract

Background and purpose:

Methyltransferase Wilms’ tumor 1-associating protein (WTAP) has been proven to play an important role in the development of tumors. This study aimed to explore the influence of WTAP on the occurrence and development of glioma from the perspective of N6-methyladenosine (m6A) modification.

Methods:

The differentially expressed m6A regulators in glioma were screened from GEO database. The expression of WTAP/B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) in glioma tissue and cell lines was evaluated by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) and Western blot. Methyl thiazoyl terazolium (MTT) was used to explore the effects of WTAP/BMI1 on glioma cell proliferation. Extracellular acidification rate (ECAR) kits and glucose consumption and lactate production detection kits were utilized to detect aerobic glycolysis of glioma cells.

Results:

Compared with normal tissues

WTQP and BMI1 expressions were upregulated in glioma tissues. Otherwise

compared with WTAP (1.01±0.13) and BMI1 (1.02±0.11) exp

ressions in HEB cells

WTAP (2.38±0.17) and BMI1 (2.25±0.14) expressions in U251 cells were increased (

0.05). Downregulation of WTAP inhibited cell proliferation and glycolytic potential

in vitro

while overexpression of WTAP showed opposite effects. The effects of WTAP overexpression on glioma cell proliferation and glycolysis were partially rescued by BMI1 inhibition (

0.05). WTAP promoted m6A methylation modification of BMI1 and enhanced the stability of BMI1 mRNA (

0.05).

Conclusion:

WTAP upregulates the level of BMI1 in a m6A methylation modification dependent manner

subsequently promotes glioma cell proliferation and aerobic glycolysis. Molecular therapy targeting WTAP may provide a new method for the treatment of glioma.

关键词

Keywords

references

CHEN X R , ZHANG Y G , WANG Q . miR-9-5p mediates ABCC1 to elevate the sensitivity of glioma cells to temozolomide [J ] . Front Oncol , 2021 , 11 : 661653 . DOI: 10.3389/fonc.2021.661653 http://doi.org/10.3389/fonc.2021.661653 https://www.frontiersin.org/articles/10.3389/fonc.2021.661653/full https://www.frontiersin.org/articles/10.3389/fonc.2021.661653/full

黄灵 , 邹有瑞 , 李琢琦 , 等 . CHKA基因沉默对胶质瘤细胞生物学行为的影响及其机制 [J ] . 中国癌症杂志 , 2021 , 31 ( 11 ): 1041 - 1049 .

HUANG L , ZOU Y R , LI Z Q , et al . Effect of CHKA gene silencing on biological behavior of glioma cell and its mechanism [J ] . China Oncol , 2021 , 31 ( 11 ): 1041 - 1049 .

刘玉清 , 柴睿超 , 李阳芳 , 等 . 肿瘤坏死因子α诱导蛋白6基因在脑胶质瘤中的表达及其临床意义 [J ] . 中华神经外科杂志 , 2021 , 37 ( 5 ) 509 - 515

LIU Y Q , CHAI R C , LI Y F , et al . The expression and clinical significance of TNFAIP6 in gliomas [J ] . Chin J Neurosurg , 2021 , 37 ( 5 ) 509 - 515

ZENG J , ZHANG H Y , TAN Y G , et al . Genetic alterations and functional networks of m6A RNA methylation regulators in pancreatic cancer based on data mining [J ] . J Transl Med , 2021 , 19 ( 1 ): 323 . DOI: 10.1186/s12967-021-03001-2 http://doi.org/10.1186/s12967-021-03001-2

孙善文 , 雍红梅 , 周学义 . m6A与mRNA代谢及其与恶性肿瘤关系的研究进展 [J ] . 现代肿瘤医学 , 2020 , 28 ( 10 ) 1781 - 1786

SUN S W , YONG H M , ZHOU X Y . Effects of N6-methyladenosine on metabolism of mRNA and the relationship with malignant tumors [J ] . J Mod Oncol , 2020 , 28 ( 10 ) 1781 - 1786

MA Z , LI Q , LIU P , et al . METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP [J ] . Cell Biol Int , 2020 , 44 ( 12 ): 2524 - 2531 . DOI: 10.1002/cbin.v44.12 http://doi.org/10.1002/cbin.v44.12 https://onlinelibrary.wiley.com/toc/10958355/44/12 https://onlinelibrary.wiley.com/toc/10958355/44/12

XI Z , XUE Y X , ZHENG J , et al . WTAP expression predicts poor prognosis in malignant glioma patients [J ] . J Mol Neurosci , 2016 , 60 ( 2 ): 131 - 136 . DOI: 10.1007/s12031-016-0788-6 http://doi.org/10.1007/s12031-016-0788-6

FENG L , LIN T , CHE H J , et al . Long noncoding RNA DANCR knockdown inhibits proliferation, migration and invasion of glioma by regulating miR-135a-5p/BMI1 [J ] . Cancer Cell Int , 2020 , 20 : 53 . DOI: 10.1186/s12935-020-1123-4 http://doi.org/10.1186/s12935-020-1123-4

BAXTER P A , LIN Q , MAO H , et al . Silencing BMI1 eliminates tumor formation of pediatric glioma CD133+ cells not by affecting known targets but by down-regulating a novel set of core genes [J ] . Acta Neuropathol Commun , 2014 , 2 : 160 . DOI: 10.1186/s40478-014-0160-4 http://doi.org/10.1186/s40478-014-0160-4 https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-014-0160-4 https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-014-0160-4

MA H Y , SHEN L Y , YANG H , et al . m6A methyltransferase Wilms’ tumor 1-associated protein facilitates cell proliferation and cisplatin resistance in NK/T cell lymphoma by regulating dual-specificity phosphatases 6 expression via m6A RNA methylation [J ] . IUBMB Life , 2021 , 73 ( 1 ): 108 - 117 . DOI: 10.1002/iub.v73.1 http://doi.org/10.1002/iub.v73.1 https://onlinelibrary.wiley.com/toc/15216551/73/1 https://onlinelibrary.wiley.com/toc/15216551/73/1

ZHU B Q , GONG Y Y , SHEN L , et al . Total Panax notoginseng saponin inhibits vascular smooth muscle cell proliferation and migration and intimal hyperplasia by regulating WTAP/p16 signals via m6A modulation [J ] . Biomedecine Pharmacother , 2020 , 124 : 109935 .

SORCI M , IANNIELLO Z , CRUCIANI S , et al . METTL3 regulates WTAP protein homeostasis [J ] . Cell Death Dis , 2018 , 9 ( 8 ): 796 . DOI: 10.1038/s41419-018-0843-z http://doi.org/10.1038/s41419-018-0843-z

WANG J Y , ZHANG J H , MA Y , et al . WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m6A modification of ATF4 mRNA [J ] . Aging (Albany NY) , 2021 , 13 ( 8 ): 11135 - 11149 .

YU H , ZHAO K , ZENG H , et al . N6-methyladenosine (m6A) methyltransferase WTAP accelerates the Warburg effect of gastric cancer through regulating HK2 stability [J ] . Biomed Pharmacother , 2021 , 133 : 111075 . DOI: 10.1016/j.biopha.2020.111075 http://doi.org/10.1016/j.biopha.2020.111075 https://linkinghub.elsevier.com/retrieve/pii/S0753332220312683 https://linkinghub.elsevier.com/retrieve/pii/S0753332220312683

OU B C , LIU Y , YANG X W , et al . C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1 [J ] . Cell Death Dis , 2021 , 12 ( 8 ): 737 . DOI: 10.1038/s41419-021-04028-5 http://doi.org/10.1038/s41419-021-04028-5

ZHANG X , WEI C Y , LI J , et al . MicroRNA-194 represses glioma cell epithelial-to-mesenchymal transition by targeting Bmi1 [J ] . Oncol Rep , 2017 , 37 ( 3 ): 1593 - 1600 . DOI: 10.3892/or.2017.5376 http://doi.org/10.3892/or.2017.5376 https://www.spandidos-publications.com/10.3892/or.2017.5376 https://www.spandidos-publications.com/10.3892/or.2017.5376

LU J J , LIU X B , ZHENG J , et al . Lin28A promotes IRF6-regulated aerobic glycolysis in glioma cells by stabilizing SNHG14 [J ] . Cell Death Dis , 2020 , 11 ( 6 ): 447 . DOI: 10.1038/s41419-020-2650-6 http://doi.org/10.1038/s41419-020-2650-6

ZHU X , JIN C , PAN Q , et al . Determining the quantitative relationship between glycolysis and GAPDH in cancer cells exhibiting the Warburg effect [J ] . J Biol Chem , 2021 , 296 : 100369 . DOI: 10.1016/j.jbc.2021.100369 http://doi.org/10.1016/j.jbc.2021.100369 https://linkinghub.elsevier.com/retrieve/pii/S0021925821001411 https://linkinghub.elsevier.com/retrieve/pii/S0021925821001411

LIU X , ZHU Q J , GUO Y , et al . LncRNA LINC00689 promotes the growth, metastasis and glycolysis of glioma cells by targeting miR-338-3p/PKM2 axis [J ] . Biomedecine Pharmacother , 2019 , 117 : 109069 .

LIU X S , ZHOU L M , YUAN L L , et al . NPM1 is a prognostic biomarker involved in immune infiltration of lung adenocarcinoma and associated with m6A modification and glycolysis [J ] . Front Immunol , 2021 , 12 : 724741 . DOI: 10.3389/fimmu.2021.724741 http://doi.org/10.3389/fimmu.2021.724741 https://www.frontiersin.org/articles/10.3389/fimmu.2021.724741/full https://www.frontiersin.org/articles/10.3389/fimmu.2021.724741/full

浏览量

2140

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

胶质瘤中MGMT甲基化状态及其临床意义的回顾性研究

胶质母细胞瘤复发相关基因的筛选、表达和临床预后分析

CHKA基因沉默对胶质瘤细胞生物学行为的影响及其机制

微流控芯技术检测循环肿瘤细胞在脑胶质瘤预后预测中的价值

胆碱激酶α在不同级别胶质瘤中的表达差异及临床意义