Adenosine A3 receptor promotes epithelial-mesenchymal transition in glioma and its effect on prognosis

CHENG Gong; TONG Xiang; XU Meng; CAI Qiang

doi:10.11659/jjssx.05E024072

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Adenosine A3 receptor promotes epithelial-mesenchymal transition in glioma and its effect on prognosis

Basic Research | 更新时间：2025-05-26

- Adenosine A3 receptor promotes epithelial-mesenchymal transition in glioma and its effect on prognosis
- JOURNAL OF REGIONAL ANATOMY AND OPERATIVE SURGERY Vol. 34, Issue 5, Pages: 373-378(2025)
- 作者机构：
  
  1.洪湖市人民医院重症医学科，湖北洪湖 433200
  2.武汉大学人民医院神经外科，湖北武汉 430060
  3.洪湖市人民医院神经外科，湖北洪湖 433200
- 作者简介：
- 基金信息：
- DOI：10.11659/jjssx.05E024072
  CLC： R739.4
- Received：15 May 2024，
  
  Published：25 May 2025
- 稿件说明：
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程功,童祥,徐梦等.腺苷A3受体促进胶质瘤上皮间质转化及其对预后的影响[J].局解手术学杂志,2025,34(05):373-378.

CHENG Gong,TONG Xiang,XU Meng,et al.Adenosine A3 receptor promotes epithelial-mesenchymal transition in glioma and its effect on prognosis[J].JOURNAL OF REGIONAL ANATOMY AND OPERATIVE SURGERY,2025,34(05):373-378.
程功,童祥,徐梦等.腺苷A3受体促进胶质瘤上皮间质转化及其对预后的影响[J].局解手术学杂志,2025,34(05):373-378. DOI： 10.11659/jjssx.05E024072.

CHENG Gong,TONG Xiang,XU Meng,et al.Adenosine A3 receptor promotes epithelial-mesenchymal transition in glioma and its effect on prognosis[J].JOURNAL OF REGIONAL ANATOMY AND OPERATIVE SURGERY,2025,34(05):373-378. DOI： 10.11659/jjssx.05E024072.

摘要

目的

探究腺苷A3受体（ADORA3）在人脑胶质瘤中的表达及其对预后和上皮间质转化的影响。

方法

从TCGA、CGGA、Rembrandt、Gravendeel和Gill数据库中获取ADORA3的mRNA表达数据与对应的临床信息，分析ADORA3的表达对胶质瘤患者预后及上皮间质转化进程的影响。收集武汉大学人民医院神经外科2023年7月至2024年4月手术切除的胶质瘤样本35例及重型颅脑损伤减压术中切取的非肿瘤脑组织7例，采用免疫组化染色检测ADORA3的表达。于多形性胶质母细胞瘤（GBM）细胞U87和U251中分别转染NcRNA、SiRNA，作为对照组和敲低组，Transwell和免疫印迹法分析ADORA3对细胞侵袭能力和上皮间质转化相关蛋白的影响。

结果

生物信息分析及免疫组化染色结果显示，ADORA3在人脑胶质瘤组织中的表达水平明显高于非肿瘤脑组织（

0.05），且ADORA3表达与胶质瘤WHO分级有关（

0.05）。在TCGA、CGGA、Rembrandt和Gravendeel数据库中进行

Kaplan

Meier

生存曲线分析，结果显示，ADORA3高表达的患者总生存率明显低于低表达患者（

0.001）；

Cox

回归分析显示，ADORA3高表达是胶质瘤患者预后不良的独立危险因素（

0.05）；ADORA3在GBM患者的间充质型中的表达水平明显高于古典型和前神经型；此外，ADOR3与上皮间质转化进程相关的标志物Vimentin、SNAI1、SNAI2、TWIST1、TWIST2、MMP2、CD44和FN1明显相关。体外敲低ADORA3后细胞侵袭能力降低，MMP2、Vimentin和SNAI1蛋白表达下调，E-cadherin表达增加，差异均有统计学意义

（

0.05）。

结论

ADORA3在胶质瘤中高表达，可促进患者上皮间质转化进程，且是预后不良的独立危险因素。

Abstract

Objective

To investigate the expression of adenosine A3 receptor （ADORA3） in human glioma and its effects on prognosis and epithelial-mesenchymal transition.

Methods

The mRNA expression data and corresponding clinical information of ADORA3 were obtained from TCGA，CGGA，Rembrandt，Gravendeel and Gill databases，and the effects of ADORA3 expression on the prognosis of glioma patients and the process of epithelial-mesenchymal transition were analyzed. The surgically resected glioma samples of 35 cases，along with non-tumor brain tissues of 7 cases obtained from decompression surgery for severe craniocerebral injury were collected in the Department of Neurosurgery at Renmin Hospital of Wuhan University from July 2023 to April 2024，and the ADORA3 expression was detected by immunohistochemical staining. Glioblastoma multiforme （GBM） cells of U87 and U251 were transfected with NcRNA and SiRNA，respectively，as the control group and the knockdown group，and the effects of ADORA3 on cell invasion ability and epithelial-mesenchymal transition related proteins were analyzed by Transwell and Western blot.

Results

Bioinformatics analysis and immunohistochemical staining showed that the expression level of ADORA3 in human glioma tissues was significantly higher than that in non-tumor brain tissues

（P

0.05），and the expression of ADORA3 was associated with glioma WHO grading （

0.05）.

Kaplan-Meier

survival curve analysis in TCGA，CGGA，Rembrandt and Gravendeel databases showed that the overall survival rate of patients with high ADORA3 expression was significantly lower than that of patients with low ADORA3 expression （

0.001）； and

Cox

regression analysis showed that high expressi

on of ADORA3 was an independent risk factor for poor prognosis in patients with glioma （

0.05）； the expression level of ADORA3 in the mesenchymal type of GBM patients was significantly higher than that of the classical type and the proneural type； furthermore，ADORA3 showed significant correlations with epithelial-mesenchymal transition related markers of Vimentin，SNAI1，SNAI2，TWIST1，TWIST2，MMP2，CD44，and FN1. The knockdown of ADORA3 in vitro reduced the cell invasive ability，decreased the expression levels of MMP2，Vimentin，and SNAI1 proteins，and increased the expression of E-cadherin，with statistically significant differences （

0.05）.

Conclusion

ADORA3 is highly expressed in glioma，which can promote the process of epithelial-mesenchymal transition in patients，and serve as an independent risk factor for poor prognosis.

关键词

Keywords

references

Xu A ， Wang X ， Luo J ， et al . Overexpressed P75CUX1 promotes EMT in glioma infiltration by activating β-catenin ［J］. Cell Death Dis ， 2021 ， 12 （ 2 ）： 157 - 168 . doi： 10.1038/s41419-021-03424-1 http://dx.doi.org/10.1038/s41419-021-03424-1 .

Babu D ， Mudiraj A ， Yada N . Rabeprazole has efficacy per se and reduces resistance to temozolomide in glioma via EMT inhibition ［J］. Cell Oncol ， 2021 ， 44 （ 4 ）： 889 - 905 . doi： 10.1007/s13402-021-00609-w http://dx.doi.org/10.1007/s13402-021-00609-w .

Yang Y ， Wang J ， Shi F ， et al . BDKRB2 is a novel EMT-related biomarker and predicts poor survival in glioma ［J］. Aging ， 2021 ， 13 （ 5 ）： 7499 - 7516 . doi： 10.18632/aging.202614 http://dx.doi.org/10.18632/aging.202614 .

Xu J ， Zhang J ， Zhang Z ， et al . Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction ［J］. Cell Death Dis ， 2021 ， 12 （ 4 ）： 373 - 389 . doi： 10.1038/s41419-021-03664-1 http://dx.doi.org/10.1038/s41419-021-03664-1 .

Teske N ， Karschnia P ， Weller J ， et al . Extent， pattern， and prognostic value of MGMT promotor methylation：does it differ between glioblastoma and IDH-wildtype/TERT-mutated astrocytoma？［J］. J Neurooncol ， 2022 ， 156 （ 2 ）： 317 - 327 . doi： 10.1007/s11060-021-03912-6 http://dx.doi.org/10.1007/s11060-021-03912-6 .

Tang X ， Xu P ， Chen A ， et al . Prognostic and predictive value of an immunoscore signature in glioblastoma multiform ［J］. Front Genet ， 2020 ， 11 （ 9 ）： 514 - 531 . doi： 10.3389/fgene.2020.514363 http://dx.doi.org/10.3389/fgene.2020.514363 .

Smith HL ， Wadhwani N ， Horbinski C . Major features of the 2021 WHO classification of CNS tumors ［J］. Neurotherapeutics ， 2022 ， 9 （ 6 ）： 1691 - 1704 . doi： 10.1007/s13311-022-01249-0 http://dx.doi.org/10.1007/s13311-022-01249-0 .

Yang K ， Wu Z ， Zhang H ， et al . Glioma targeted therapy： insight into future of molecular approaches ［J］. Mol Cancer ， 2022 ， 21 （ 1 ）： 39 - 57 . doi： 10.1186/s12943-022-01513-z http://dx.doi.org/10.1186/s12943-022-01513-z .

Ayoub BM ， Attia YM ， Ahmed MS . Structural re-positioning，in silico molecular modelling，oxidative degradation，and biological screening of linagliptin as adenosine 3 receptor （ADORA3） modulators targeting hepatocellular carcinoma ［J］. J Enzyme Inhib Med Chem ， 2018 ， 33 （ 1 ）： 858 - 866 . doi： 10.1080/14756366.2018.1462801 http://dx.doi.org/10.1080/14756366.2018.1462801 .

Bowman RL ， Wang Q ， Carro A ， et al . GlioVis data portal for visualization and analysis of brain tumor expression datasets ［J］. Neuro Oncol ， 2017 ， 19 （ 1 ）： 139 - 141 . doi： 10.1093/neuonc/now247 http://dx.doi.org/10.1093/neuonc/now247 .

He HR ， Li YJ ， He GH ， et al . The polymorphism in ADORA3 decreases transcriptional activity and influences the chronic heart failure risk in the Chinese ［J］. Biomed Res Int ， 2018 ， 18 （ 11 ）： 369 - 385 . doi： 10.1155/2018/4969385 http://dx.doi.org/10.1155/2018/4969385 .

Torres Á ， Eriches JI ， Sanchez F ， et al . Extracellular adenosine promotes cell migration/invasion of glioblastoma stem-like cells through A 3 adenosine receptor activation under hypoxia ［J］. Cancer Lett ， 2019 ， 446 （ 2 ）： 112 - 122 . doi： 10.1016/j.canlet.2019.01.004 http://dx.doi.org/10.1016/j.canlet.2019.01.004 .

Barkan K ， Lagarias P ， Stampelout M ， et al . Pharmacological characterisation of novel adenosine A 3 receptor antagonists ［J］. Sci Rep ， 2020 ， 10 （ 1 ）： 20781 - 20791 . doi： 10.1038/s41598-020-74521-y http://dx.doi.org/10.1038/s41598-020-74521-y .

Brabletz S ， Schuhwerk CH ， Brabletz T ， et al . Dynamic EMT： a multi-tool for tumor progression ［J］. EMBO J ， 2021 ， 40 （ 18 ）： e108647 - e108657 . doi： 10.15252/embj.2021108647 http://dx.doi.org/10.15252/embj.2021108647 .

Li L ， Xia S ， Zhao Z ， et al . EMP3 as a prognostic biomarker correlates with EMT in GBM ［J］. BMC Cancer ， 2024 ， 24 （ 1 ）： 89 - 103 . doi： 10.1186/s12885-023-11796-0 http://dx.doi.org/10.1186/s12885-023-11796-0 .

Kim JY ， Hong N ， Park S ， et al . Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion ［J］. Cell Death Dis ， 2023 ， 14 （ 12 ）： 822 - 834 . doi： 10.1038/s41419- 023-06356-0 http://dx.doi.org/10.1038/s41419-023-06356-0 .

Liu J ， Zhu X ， Gao L ， et al . Expression and prognostic role of glia maturation factor-γ in gliomas ［J］. Front Mol Neurosci ， 2022 ， 15 （ 3 ）： 906762 - 906772 . doi： 10.3389/fnmol.2022.906762 http://dx.doi.org/10.3389/fnmol.2022.906762 .

Fu Z ， Chen Z ， Ye J ， et al . Identifying PLAUR as a pivotal gene of tumor microenvironment and regulating mesenchymal phenotype of glioblastoma ［J］. Cancers （Basel）， 2024 ， 16 （ 4 ）： 840 - 857 . doi： 10.3390/cancers16040840 http://dx.doi.org/10.3390/cancers16040840 .

Lu H ， Cao LL ， Ballout F ， et al . Reflux conditions induce E-cadherin cleavage and EMT via APE1 redox function in oesophageal adenocarcinoma ［J］. Gut ， 2023 ， 73 （ 1 ）： 47 - 62 . doi： 10.1136/gutjnl-2023-329455 http://dx.doi.org/10.1136/gutjnl-2023-329455 .

Muniz-Bongeers LR ， Mclain CB ， Saxena M ， et al . MMP2 and TLRs modulate immune responses in the tumor microenvironment ［J］. JCI Insight ， 2021 ， 6 （ 12 ）： e144913 - e144927 . doi： 10.1172/jci.insight. 144913 http://dx.doi.org/10.1172/jci.insight.144913 .

Bao Z ， Zeng W ， Zhang D ， et al . SNAI1 induces EMT and lung metastasis of tumours secreting CXCL2 to promote the invasion of M2-type immunosuppressed macrophages in colorectal cancer ［J］. Int J Biol Sci ， 2022 ， 18 （ 7 ）： 2867 - 2881 . doi： 10.7150/ijbs.66854 http://dx.doi.org/10.7150/ijbs.66854 .

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