Expression characteristics of NT5E in lung adenocarcinoma and its impact on tumor biological behavior_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

CUI Xiangyu ^1,2 , LI Boshi ² , HAN Wenjie ³ , LI Yongwen ² ,  LIU Hongyu ² ,  CHEN Jun ²

1. Department of Thoracic Surgery, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, 266011, Shandong, P. R. China;
2. Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, P. R. China;
3. Department of Medical Examination Center, Qingdao Women and Children’s Hospital, Affiliated to Qingdao University, Qingdao, 266042, Shandong, P. R. China;

Corresponding?author：

LIU Hongyu, Email: liuhongyu123@hotmail.com; CHEN Jun, Email: huntercj2004@qq.com

Keywords：

Lung adenocarcinoma; nucleotide metabolism; bioinformatics analysis; ecto-5'-nucleotidase; prognostic model; tumor microenvironment

DOI：

10.7507/1007-4848.202601094

Video：

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Objective To systematically investigate the functional roles of the nucleotide metabolism-related gene ecto-5'-nucleotidase (NT5E) in lung adenocarcinoma (LUAD) and to provide potential molecular targets for precision diagnosis and targeted therapy. Methods Multi-omics analyses were performed using transcriptomic data from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) to identify key prognostic genes and to construct a prognostic model. Tumor tissue specimens from patients with LUAD who underwent surgical resection at the Qingdao Central Hospital of University of Health and Rehabilitation Sciences between May and June 2023 were collected for prognostic gene validation, and tissue microarrays were constructed to evaluate protein expression. In vitro, the biological effects of NT5E on LUAD cells were validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), Western blotting, wound-healing, Transwell, EdU, cell-cycle, and apoptosis assays. Results A total of 10 paired tumor and adjacent non-tumor tissue samples were used for validation of key prognostic genes, including 4 male and 6 female patients, with a mean age of (58.00±13.06) years. In addition, tissue microarrays comprising 90 patients were analyzed, including 28 male and 62 female patients, with a mean age of (60.07±7.98) years. Bioinformatic screening identified NT5E as a representative prognostic gene that was significantly upregulated in LUAD tissues. Survival analyses demonstrated that high NT5E expression was associated with markedly poorer overall survival and served as an independent risk factor. qRT-PCR and tissue microarray-based immunohistochemistry further confirmed its elevated expression in tumor tissues. Functional experiments showed that NT5E knockdown significantly inhibited cell migration, invasion, and proliferation while promoting apoptosis, whereas NT5E overexpression exerted the opposite effects. Conclusion NT5E markedly promotes LUAD cell proliferation, migration, and invasion and suppresses apoptosis, indicating that NT5E acts as an oncogenic driver in LUAD and may serve as a promising prognostic biomarker and therapeutic target.

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14.	Jiang T, Xu X, Qiao M, et al. Comprehensive evaluation of NT5E/CD73 expression and its prognostic significance in distinct types of cancers. BMC Cancer, 2018, 18(1): 267.
15.	Hegde PS, Chen DS. Top 10 challenges in cancer immunotherapy. Immunity, 2020, 52(1): 17-35.
16.	Magagna I, Gourdin N, Kieffer Y, et al. CD73-mediated immunosuppression is linked to a specific fibroblast population that paves the way for new therapy in breast cancer. Cancers, 2021, 13(23): 5878.
17.	Yu X, Liu W, Wang Z, et al. CD73 induces gemcitabine resistance in pancreatic ductal adenocarcinoma: a promising target with non-canonical mechanisms. Cancer Lett, 2021, 519: 289-303.
18.	Lu JC, Zhang PF, Huang XY, et al. Amplification of spatially isolated adenosine pathway by tumor-macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma. J Hematol Oncol, 2021, 14(1): 200.
19.	Xue XM, Liu YY, Chen XM, et al. Pan-cancer analysis identifies NT5E as a novel prognostic biomarker on cancer-associated fibroblasts associated with unique tumor microenvironment. Front Pharmacol, 2022, 13: 1064032.
20.	Cheng L, Peng D, Liu Z, et al. Engineered bacterial outer membrane vesicles enhanced tumor immunotherapy through remodeling tumor stroma and targeted delivery of CD73 siRNA. Biomaterials, 2026, 327: 123725.
21.	Kowash RR, Akbay EA. Tumor intrinsic and extrinsic functions of CD73 and the adenosine pathway in lung cancer. Front Immunol, 2023, 14: 1130358.
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23.	Liu X, Ding Q, Zhang H, et al. The CD39-CD73-adenosine axis: master regulator of immune evasion and therapeutic target in pancreatic ductal adenocarcinoma. Biochim Biophys Acta Rev Cancer, 2025, 1880(5): 189443.
24.	Kondo M, Kumagai S, Nishikawa H. Metabolic advantages of regulatory T cells dictated by cancer cells. Int Immunol, 2024, 36(2): 75-86.
25.	Wang H, Zhou F, Qin W, et al. Metabolic regulation of myeloid-derived suppressor cells in tumor immune microenvironment: targets and therapeutic strategies. Theranostics, 2025, 15(6): 2159-2184.
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27.	Turcotte M, Spring K, Pommey S, et al. CD73 is associated with poor prognosis in high-grade serous ovarian cancer. Cancer Res, 2015, 75(21): 4494-4503.
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29.	Zhang E, Ding X, Zhang J, et al. Multi-omics analysis of polyamine metabolism implicates NT5E/CD73 in the progression of pancreatic cancer. Cancer Lett, 2025, 630: 217887.
30.	Shan L, Gong M, Zhai D, et al. Research progress of CD73-adenosine signaling regulating hepatocellular carcinoma through tumor microenvironment. J Exp Clin Cancer Res, 2025, 44(1): 161.
31.	Li H, Lv M, Qiao B, et al. Blockade of CD73/adenosine axis improves the therapeutic efficacy of docetaxel in epithelial ovarian cancer. Arch Gynecol Obstet, 2019, 299(6): 1737-1746.
32.	Sun P, Zheng X, Li X. The effects of CD73 on gastrointestinal cancer progression and treatment. J Oncol, 2022, 2022: 4330329.

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin, 2022, 72(1): 7-33.
2. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature, 2018, 553(7689): 446-454.
3. Reck M, Rabe KF. Precision diagnosis and treatment for advanced non-small-cell lung cancer. N Engl J Med, 2017, 377(9): 849-861.
4. Viviani LG, Piccirillo E, Cheffer A, et al. Be aware of aggregators in the search for potential human ecto-5'-nucleotidase inhibitors. Molecules, 2018, 23(8): 1876.
5. Ghiringhelli F, Bruchard M, Chalmin F, et al. Production of adenosine by ectonucleotidases: a key factor in tumor immunoescape. J Biomed Biotechnol, 2012, 2012: 473712.
6. Tang B, Xu W, Wang Y, et al. Identification of critical ferroptosis regulators in lung adenocarcinoma that RRM2 facilitates tumor immune infiltration by inhibiting ferroptotic death. Clin Immunol, 2021, 232: 108872.
7. Mullen NJ, Singh PK. Nucleotide metabolism: a pan-cancer metabolic dependency. Nat Rev Cancer, 2023, 23(5): 275-294.
8. Jin CY, Du L, Nuerlan AH, et al. High expression of RRM2 as an independent predictive factor of poor prognosis in patients with lung adenocarcinoma. Aging, 2020, 13(3): 3518-3535.
9. Huang WY, Liao ZB, Zhang JC, et al. USF2-mediated upregulation of TXNRD1 contributes to hepatocellular carcinoma progression by activating Akt/mTOR signaling. Cell Death Dis, 2022, 13(11): 917.
10. Jin X, Liu D, Kong D, et al. Dissecting the alternation landscape of mitochondrial metabolism-related genes in lung adenocarcinoma and their latent mechanisms. Aging, 2023, 15(12): 5482-5496.
11. Wang W, Dong M, Cui J, et al. NME4 may enhance non-small cell lung cancer progression by overcoming cell cycle arrest and promoting cellular proliferation. Mol Med Rep, 2019, 20(2): 1629-1636.
12. Zhang H, Cao Y, Tang J, et al. CD73 (NT5E) promotes the proliferation and metastasis of lung adenocarcinoma through the EGFR/AKT/mTOR pathway. Biomed Res Int, 2022, 2022: 9944847.
13. Rocha P, Salazar R, Zhang J, et al. CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma. Cancer Immunol Immunother, 2021, 70(7): 1965-1976.
14. Jiang T, Xu X, Qiao M, et al. Comprehensive evaluation of NT5E/CD73 expression and its prognostic significance in distinct types of cancers. BMC Cancer, 2018, 18(1): 267.
15. Hegde PS, Chen DS. Top 10 challenges in cancer immunotherapy. Immunity, 2020, 52(1): 17-35.
16. Magagna I, Gourdin N, Kieffer Y, et al. CD73-mediated immunosuppression is linked to a specific fibroblast population that paves the way for new therapy in breast cancer. Cancers, 2021, 13(23): 5878.
17. Yu X, Liu W, Wang Z, et al. CD73 induces gemcitabine resistance in pancreatic ductal adenocarcinoma: a promising target with non-canonical mechanisms. Cancer Lett, 2021, 519: 289-303.
18. Lu JC, Zhang PF, Huang XY, et al. Amplification of spatially isolated adenosine pathway by tumor-macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma. J Hematol Oncol, 2021, 14(1): 200.
19. Xue XM, Liu YY, Chen XM, et al. Pan-cancer analysis identifies NT5E as a novel prognostic biomarker on cancer-associated fibroblasts associated with unique tumor microenvironment. Front Pharmacol, 2022, 13: 1064032.
20. Cheng L, Peng D, Liu Z, et al. Engineered bacterial outer membrane vesicles enhanced tumor immunotherapy through remodeling tumor stroma and targeted delivery of CD73 siRNA. Biomaterials, 2026, 327: 123725.
21. Kowash RR, Akbay EA. Tumor intrinsic and extrinsic functions of CD73 and the adenosine pathway in lung cancer. Front Immunol, 2023, 14: 1130358.
22. Cen L, Ren W, Yu J, et al. Discovery of orally potent small-molecule CD73 inhibitor for cancer immunotherapy. J Med Chem, 2025, 68(11): 11039-11061.
23. Liu X, Ding Q, Zhang H, et al. The CD39-CD73-adenosine axis: master regulator of immune evasion and therapeutic target in pancreatic ductal adenocarcinoma. Biochim Biophys Acta Rev Cancer, 2025, 1880(5): 189443.
24. Kondo M, Kumagai S, Nishikawa H. Metabolic advantages of regulatory T cells dictated by cancer cells. Int Immunol, 2024, 36(2): 75-86.
25. Wang H, Zhou F, Qin W, et al. Metabolic regulation of myeloid-derived suppressor cells in tumor immune microenvironment: targets and therapeutic strategies. Theranostics, 2025, 15(6): 2159-2184.
26. Raza MZ, Cadas sou O, Dumontet C, et al. CD73 and cN-Ⅱ regulate the cellular response to chemotherapeutic and hypoxic stress in lung adenocarcinoma cells. Biochim Biophys Acta Gen Subj, 2021, 1865(5): 129842.
27. Turcotte M, Spring K, Pommey S, et al. CD73 is associated with poor prognosis in high-grade serous ovarian cancer. Cancer Res, 2015, 75(21): 4494-4503.
28. Buisseret L, Pommey S, Allard B, et al. Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase Ⅲ clinical trial. Ann Oncol, 2018, 29(4): 1056-1062.
29. Zhang E, Ding X, Zhang J, et al. Multi-omics analysis of polyamine metabolism implicates NT5E/CD73 in the progression of pancreatic cancer. Cancer Lett, 2025, 630: 217887.
30. Shan L, Gong M, Zhai D, et al. Research progress of CD73-adenosine signaling regulating hepatocellular carcinoma through tumor microenvironment. J Exp Clin Cancer Res, 2025, 44(1): 161.
31. Li H, Lv M, Qiao B, et al. Blockade of CD73/adenosine axis improves the therapeutic efficacy of docetaxel in epithelial ovarian cancer. Arch Gynecol Obstet, 2019, 299(6): 1737-1746.
32. Sun P, Zheng X, Li X. The effects of CD73 on gastrointestinal cancer progression and treatment. J Oncol, 2022, 2022: 4330329.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

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