Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Molecular Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1107-3756 Online ISSN: 1791-244X
Journal Cover
February-2023 Volume 51 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
February-2023 Volume 51 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML

  • Supplementary Files
    • Supplementary_Data.pdf
Article Open Access

Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway

  • Authors:
    • Xinxi Deng
    • Xiaoqiang Liu
    • Bing Hu
    • Jianyun Liu
    • Bin Fu
    • Wensheng Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Urology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Urology, Nanchang, Jiangxi 330006, P.R. China, Jiangxi Provincial Key Lab of System Biomedicine, Jiujiang University, Jiujiang, Jiangxi 332000, P.R. China, Department of Urology, Jiujiang No. 1 People's Hospital (Affiliated Jiujiang Hospital of Nanchang University), Jiujiang, Jiangxi 332000, P.R. China
    Copyright: © Deng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 14
    |
    Published online on: December 30, 2022
       https://doi.org/10.3892/ijmm.2022.5217
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) has been implicated in the etiology of various human malignant tumors; however, its exact role in bladder cancer (BC) remains to be explored. Through reverse transcription‑quantitative PCR, western blotting and immunohistochemistry detection of BC tissue, combined with The Cancer Genome Atlas (TCGA) database analysis, the present study demonstrated that MTHFD2 was upregulated in BC tissues. MTHFD2 expression in patients with BC was frequently associated with worse prognosis, tumor immune cell infiltration and programmed death‑ligand 1 (PD‑L1) expression. Subsequently, using short hairpin RNA, the expression levels of MTHFD2 were knocked down in BC cell lines, and the results revealed that the tumor cell proliferation and colony formation abilities of cells were greatly reduced, as determined by Cell Counting Kit 8 and colony formation assays, as was the expression of PD‑L1, as determined by western blotting. These findings were also confirmed in a xenograft nude mouse model. Simultaneously, it was revealed that abnormal expression of MTHFD2 was closely associated with the PI3K/AKT signaling pathway in both RNA‑sequencing and TCGA datasets. This observation was verified in vitro by detecting the protein expression levels of PI3K and AKT by western blotting. The activation of PI3K and AKT was enhanced in BC cells (T24) following stimulation with 740Y‑P, a PI3K activator, and cellular activities and PD‑L1 expression levels were restored. Finally, it was demonstrated that the MTHFD2 levels were correlated with chemosensitivity to traditional BC chemotherapeutic agents and various PI3K/AKT‑targeted drugs, as determined by analyzing the Genomics of Drug Sensitivity in Cancer database. Overall, the present findings revealed that upregulation of MTHFD2 was associated with PD‑L1 activation in BC via the PI3K/AKT signaling pathway, suggesting that it could be a promising marker of chemotherapy and immunotherapy for BC.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

View References

1 

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI

2 

Schmitz-Drager BJ, Droller M, Lokeshwar VB, Lotan Y, Hudson MA, van Rhijn BW, Marberger MJ, Fradet Y, Hemstreet GP, Malmstrom PU, et al: Molecular markers for bladder cancer screening, early diagnosis, and surveillance: The WHO/ICUD consensus. Urol Int. 94:1–24. 2015. View Article : Google Scholar

3 

Witjes JA, Bruins HM, Cathomas R, Compérat EM, Cowan NC, Gakis G, Hernández V, Espinós EL, Lorch A, Neuzillet Y, et al: European association of urology guidelines on muscle-invasive and metastatic bladder cancer: Summary of the 2020 guidelines. Eur Urol. 79:82–104. 2021. View Article : Google Scholar

4 

Lopez-Beltran A, Cimadamore A, Blanca A, Massari F, Vau N, Scarpelli M, Cheng L and Montironi R: Immune checkpoint inhibitors for the treatment of bladder cancer. Cancers (Basel). 13:1312021. View Article : Google Scholar : PubMed/NCBI

5 

Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, et al: Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet. 389:67–76. 2017. View Article : Google Scholar

6 

Stenehjem DD, Tran D, Nkrumah MA and Gupta S: PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer. Onco Targets Ther. 11:5973–5989. 2018. View Article : Google Scholar : PubMed/NCBI

7 

Mejia NR and MacKenzie RE: NAD-dependent methylenetetrahydrofolate dehydrogenase is expressed by immortal cells. J Biol Chem. 260:14616–14620. 1985. View Article : Google Scholar : PubMed/NCBI

8 

Nilsson R, Jain M, Madhusudhan N, Sheppard NG, Strittmatter L, Kampf C, Huang J, Asplund A and Mootha VK: Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 5:31282014. View Article : Google Scholar : PubMed/NCBI

9 

Cui X, Su H, Yang J, Wu X, Huo K, Jing X and Zhang S: Up-regulation of MTHFD2 is associated with clinicopathological characteristics and poor survival in ovarian cancer, possibly by regulating MOB1A signaling. J Ovarian Res. 15:232022. View Article : Google Scholar : PubMed/NCBI

10 

Ju HQ, Lu YX, Chen DL, Zuo ZX, Liu ZX, Wu QN, Mo HY, Wang ZX, Wang DS, Pu HY, et al: Modulation of redox homeostasis by inhibition of MTHFD2 in colorectal cancer: Mechanisms and therapeutic implications. J Natl Cancer Inst. 111:584–596. 2019. View Article : Google Scholar :

11 

Lin H, Huang B, Wang H, Liu X, Hong Y, Qiu S and Zheng J: MTHFD2 overexpression predicts poor prognosis in renal cell carcinoma and is associated with cell proliferation and vimentin-modulated migration and invasion. Cell Physiol Biochem. 51:991–1000. 2018. View Article : Google Scholar : PubMed/NCBI

12 

Liu F, Liu Y, He C, Tao L, He X, Song H and Zhang G: Increased MTHFD2 expression is associated with poor prognosis in breast cancer. Tumour Biol. 35:8685–8690. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Liu X, Huang Y, Jiang C, Ou H, Guo B, Liao H, Li X and Yang D: Methylenetetrahydrofolate dehydrogenase 2 overexpression is associated with tumor aggressiveness and poor prognosis in hepatocellular carcinoma. Dig Liver Dis. 48:953–960. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Huang J, Qin Y, Lin C, Huang X and Zhang F: MTHFD2 facilitates breast cancer cell proliferation via the AKT signaling pathway. Exp Ther Med. 22:7032021. View Article : Google Scholar : PubMed/NCBI

15 

Wei Y, Liu P, Li Q, Du J, Chen Y, Wang Y, Shi H, Wang Y, Zhang H, Xue W, et al: The effect of MTHFD2 on the proliferation and migration of colorectal cancer cell lines. Onco Targets Ther. 12:6361–6370. 2019. View Article : Google Scholar : PubMed/NCBI

16 

Shi Y, Xu Y, Yao J, Yan C, Su H, Zhang X, Chen E and Ying K: MTHFD2 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating AKT/GSK-3β/β-catenin signalling. J Cell Mol Med. 25:7013–7027. 2021. View Article : Google Scholar : PubMed/NCBI

17 

Liu X, Liu S, Piao C, Zhang Z, Zhang X, Jiang Y and Kong C: Non-metabolic function of MTHFD2 activates CDK2 in bladder cancer. Cancer Sci. 112:4909–4919. 2021. View Article : Google Scholar : PubMed/NCBI

18 

Zhu L, Liu X, Zhang W, Hu H, Wang Q and Xu K: MTHFD2 is a potential oncogene for its strong association with poor prognosis and high level of immune infiltrates in urothelial carcinomas of bladder. BMC Cancer. 22:5562022. View Article : Google Scholar : PubMed/NCBI

19 

Dillies MA, Rau A, Aubert J, Hennequet-Antier C, Jeanmougin M, Servant N, Keime C, Marot G, Castel D, Estelle J, et al: A comprehensive evaluation of normalization methods for Illumina high-throughput RNA sequencing data analysis. Brief Bioinform. 14:671–683. 2013. View Article : Google Scholar

20 

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B and Liu XS: TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 77:e108–e110. 2017. View Article : Google Scholar : PubMed/NCBI

21 

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Liu X, Xu X, Deng W, Huang M, Wu Y, Zhou Z, Zhu K, Wang Y, Cheng X, Zhou X, et al: CCL18 enhances migration, invasion and EMT by binding CCR8 in bladder cancer cells. Mol Med Rep. 19:1678–1686. 2019.

23 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar

24 

Kim D, Langmead B and Salzberg SL: HISAT: A fast spliced aligner with low memory requirements. Nat Methods. 12:357–360. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Anders S, Pyl PT and Huber W: HTSeq-a python framework to work with high-throughput sequencing data. Bioinformatics. 31:166–169. 2015. View Article : Google Scholar

26 

Li Y, Ma Y, Wu Z, Zeng F, Song B, Zhang Y, Li J, Lui S and Wu M: Tumor mutational burden predicting the efficacy of immune checkpoint inhibitors in colorectal cancer: A systematic review and meta-analysis. Front Immunol. 12:7514072021. View Article : Google Scholar : PubMed/NCBI

27 

Grayson M: Bladder cancer. Nature. 551:S332017. View Article : Google Scholar : PubMed/NCBI

28 

Hurst CD, Alder O, Platt FM, Droop A, Stead LF, Burns JE, Burghel GJ, Jain S, Klimczak LJ, Lindsay H, et al: Genomic subtypes of non-invasive bladder cancer with distinct metabolic profile and female gender bias in KDM6A mutation frequency. Cancer Cell. 32:701–715.e707. 2017. View Article : Google Scholar : PubMed/NCBI

29 

Kobayashi T, Owczarek TB, McKiernan JM and Abate-Shen C: Modelling bladder cancer in mice: Opportunities and challenges. Nat Rev Cancer. 15:42–54. 2015. View Article : Google Scholar :

30 

Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE III, Koeppen H, Astarita JL, Cubas R, et al: TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 554:544–548. 2018. View Article : Google Scholar : PubMed/NCBI

31 

Ducker GS, Chen L, Morscher RJ, Ghergurovich JM, Esposito M, Teng X, Kang Y and Rabinowitz JD: Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway. Cell Metab. 23:1140–1153. 2016. View Article : Google Scholar : PubMed/NCBI

32 

Singer K, Cheng WC, Kreutz M, Ho PC and Siska PJ: Immunometabolism in cancer at a glance. Dis Model Mech. 11:dmm0342722018. View Article : Google Scholar : PubMed/NCBI

33 

Sugiura A, Andrejeva G, Voss K, Heintzman DR, Xu X, Madden MZ, Ye X, Beier KL, Chowdhury NU, Wolf MM, et al: MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function. Immunity. 55:65–81.e69. 2022. View Article : Google Scholar :

34 

Shang M, Yang H, Yang R, Chen T, Fu Y, Li Y, Fang X, Zhang K, Zhang J, Li H, et al: The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation. Nat Commun. 12:19402021. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Deng X, Liu X, Hu B, Liu J, Fu B and Zhang W: Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway. Int J Mol Med 51: 14, 2023.
APA
Deng, X., Liu, X., Hu, B., Liu, J., Fu, B., & Zhang, W. (2023). Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway. International Journal of Molecular Medicine, 51, 14. https://doi.org/10.3892/ijmm.2022.5217
MLA
Deng, X., Liu, X., Hu, B., Liu, J., Fu, B., Zhang, W."Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway". International Journal of Molecular Medicine 51.2 (2023): 14.
Chicago
Deng, X., Liu, X., Hu, B., Liu, J., Fu, B., Zhang, W."Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway". International Journal of Molecular Medicine 51, no. 2 (2023): 14. https://doi.org/10.3892/ijmm.2022.5217
Copy and paste a formatted citation
x
Spandidos Publications style
Deng X, Liu X, Hu B, Liu J, Fu B and Zhang W: Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway. Int J Mol Med 51: 14, 2023.
APA
Deng, X., Liu, X., Hu, B., Liu, J., Fu, B., & Zhang, W. (2023). Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway. International Journal of Molecular Medicine, 51, 14. https://doi.org/10.3892/ijmm.2022.5217
MLA
Deng, X., Liu, X., Hu, B., Liu, J., Fu, B., Zhang, W."Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway". International Journal of Molecular Medicine 51.2 (2023): 14.
Chicago
Deng, X., Liu, X., Hu, B., Liu, J., Fu, B., Zhang, W."Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway". International Journal of Molecular Medicine 51, no. 2 (2023): 14. https://doi.org/10.3892/ijmm.2022.5217
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team