Skip to content
2000
image of FOLR1 Regulates the Malignant Progression of Glioblastoma through the SRC/ERK1/2 Axis

Abstract

Background

GBM is an aggressive brain tumor with limited treatment options. Prior research has indicated FOLR1 as a pivotal gene involved in cancer pathogenesis.

Aim

This study aimed to explore the involvement of folate receptor alpha (FOLR1) in glioblastoma (GBM) and evaluate its potential as a therapeutic target.

Objective

This study investigated the expression pattern of FOLR1 in GBM, its impact on patient prognosis, and its role in GBM cell growth and the SRC/ERK1/2 signaling axis.

Methods

Initially, we conducted an expression analysis of FOLR1 based on public databases and examined its expression pattern in GBM and its impact on patient prognosis. Subsequently, cell experiments were carried out to evaluate the regulation of GBM cells by differential FOLR1 expression. We then downloaded 100 FOLR1 co-expressed genes from the Linkedomics data repository and performed an enrichment analysis. Finally, the role of FOLR1 and SRC/ERK1/2 axis in GBM was analyzed again by cell experiments.

Results

FOLR1 was found to be substantially expressed in GBM patients and was linked to a poor prognosis. Cell experiments showed that overexpression of FOLR1 promoted GBM cell growth, while low expression of FOLR1 inhibited cell growth. Additionally, genes related to FOLR1 were enriched in the lysosome, toxoplasmosis, and other pathways. This study further indicated that FOLR1 facilitates the activation of the SRC/ERK1/2 signaling pathway in GBM cells, and the attenuation of these pathways can effectively impede the malignancy-promoting effects triggered by FOLR1 in GBM cells.

Conclusions

We revealed that FOLR1 orchestrates the malignant advancement of GBM by stimulating the SRC/ERK1/2 signaling axis, underscoring its pivotal role in the pathogenesis of GBM.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cchts/10.2174/0113862073335351241226070841
2025-01-20
2025-09-14

  • From This Site

    /content/journals/cchts/10.2174/0113862073335351241226070841
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Partridge B.R. Overcoming therapeutic resistance in glioblastoma using novel electroporation-based therapies Virginia Tech 2022 http://hdl.handle.net/10919/112279
    [Google Scholar]
  2. Crespo I. Vital A.L. Gonzalez-Tablas M. Patino M.C. Otero A. Lopes M.C. de Oliveira C. Domingues P. Orfao A. Tabernero M.D. Molecular and genomic alterations in glioblastoma multiforme. Am. J. Pathol. 2015 185 7 1820 1833 10.1016/j.ajpath.2015.02.023 25976245
    [Google Scholar]
  3. Aldape K. Zadeh G. Mansouri S. Reifenberger G. von Deimling A. Glioblastoma: Pathology, molecular mechanisms and markers. Acta Neuropathol. 2015 129 6 829 848 10.1007/s00401‑015‑1432‑1 25943888
    [Google Scholar]
  4. Kim H.J. Park J.W. Lee J.H. Genetic architectures and cell-of-origin in glioblastoma. Front. Oncol. 2021 10 615400 10.3389/fonc.2020.615400 33552990
    [Google Scholar]
  5. Ostrom Q.T. Fahmideh M.A. Cote D.J. Muskens I.S. Schraw J.M. Scheurer M.E. Bondy M.L. Risk factors for childhood and adult primary brain tumors. Neuro-oncol. 2019 21 11 1357 1375 10.1093/neuonc/noz123 31301133
    [Google Scholar]
  6. Butowski N.A. Epidemiology and diagnosis of brain tumors. Continuum (Minneap. Minn.) 2015 21 2 301 313 10.1212/01.CON.0000464171.50638.fa 25837897
    [Google Scholar]
  7. Kenessey I. Patócs A. Dobozi M. Nagy P. Polgár C. The epidemiology of primary brain malignancies. Magy. Onkol. 2023 67 4 279 287 38109507
    [Google Scholar]
  8. Pagano C. Navarra G. Coppola L. Savarese B. Avilia G. Giarra A. Pagano G. Marano A. Trifuoggi M. Bifulco M. Laezza C. Impacts of environmental pollution on brain tumorigenesis. Int. J. Mol. Sci. 2023 24 5 5045 10.3390/ijms24055045 36902485
    [Google Scholar]
  9. Petrecca K. Guiot M.C. Panet-Raymond V. Souhami L. Failure pattern following complete resection plus radiotherapy and temozolomide is at the resection margin in patients with glioblastoma. J. Neurooncol. 2013 111 1 19 23 10.1007/s11060‑012‑0983‑4 23054563
    [Google Scholar]
  10. Hardigan A.A. Jackson J.D. Patel A.P. Surgical management and advances in the treatment of glioma. Semin. Neurol. 2023 43 6 810 824 10.1055/s‑0043‑1776766 37963582
    [Google Scholar]
  11. Yuen C.M. Tsai H.P. Tseng T.T. Tseng Y.L. Lieu A.S. Kwan A.L. Chang A.Y.W. Hyperbaric oxygen therapy adjuvant chemotherapy and radiotherapy through inhibiting stemness in glioblastoma. Curr. Issues Mol. Biol. 2023 45 10 8309 8320 10.3390/cimb45100524 37886967
    [Google Scholar]
  12. Nawaz F.Z. Kipreos E.T. Emerging roles for folate receptor FOLR1 in signaling and cancer. Trends Endocrinol. Metab. 2022 33 3 159 174 10.1016/j.tem.2021.12.003 35094917
    [Google Scholar]
  13. Wu J. Han Y. Lyu R. Zhang F. Jiang N. Tao H. You Q. Zhang R. Yuan M. Nawaz W. Chen D. Wu Z. FOLR1-induced folate deficiency reduces viral replication via modulating APOBEC3 family expression. Virol. Sin. 2023 38 3 409 418 10.1016/j.virs.2023.04.001 37028598
    [Google Scholar]
  14. Patrick S. Lathoria K. Suri V. Sen E. Reduced YAP1 and FOLR1 in gliomas predict better response to chemotherapeutics. Cell. Signal. 2023 109 110738 10.1016/j.cellsig.2023.110738 37269960
    [Google Scholar]
  15. Gonen N. Assaraf Y.G. Antifolates in cancer therapy: Structure, activity and mechanisms of drug resistance. Drug Resist. Updat. 2012 15 4 183 210 10.1016/j.drup.2012.07.002 22921318
    [Google Scholar]
  16. Löser R. Pietzsch J. Cysteine cathepsins: Their role in tumor progression and recent trends in the development of imaging probes. Front Chem. 2015 3 37 10.3389/fchem.2015.00037 26157794
    [Google Scholar]
  17. Garcia-Bennett A. Nees M. Fadeel B. In search of the Holy Grail: Folate-targeted nanoparticles for cancer therapy. Biochem. Pharmacol. 2011 81 8 976 984 10.1016/j.bcp.2011.01.023 21300030
    [Google Scholar]
  18. Atallah G.A. Abd Aziz N.H. Teik C.K. Shafiee M.N. Kampan N.C. New predictive biomarkers for ovarian cancer. Diagnostics (Basel) 2021 11 3 465 10.3390/diagnostics11030465 33800113
    [Google Scholar]
  19. Kato T. Jin C.S. Ujiie H. Lee D. Fujino K. Wada H. Hu H. Weersink R.A. Chen J. Kaji M. Kaga K. Matsui Y. Wilson B.C. Zheng G. Yasufuku K. Nanoparticle targeted folate receptor 1-enhanced photodynamic therapy for lung cancer. Lung Cancer 2017 113 59 68 10.1016/j.lungcan.2017.09.002 29110850
    [Google Scholar]
  20. Gonzalez T. Muminovic M. Nano O. Vulfovich M. Folate receptor Alpha—a novel approach to cancer therapy. Int. J. Mol. Sci. 2024 25 2 1046 10.3390/ijms25021046 38256120
    [Google Scholar]
  21. Varaganti P. Buddolla V. Lakshmi B.A. Kim Y.J. Recent advances in using folate receptor 1 (FOLR1) for cancer diagnosis and treatment, with an emphasis on cancers that affect women. Life Sci. 2023 326 121802 10.1016/j.lfs.2023.121802 37244363
    [Google Scholar]
  22. Mekler A.A. Schwartz D.R. Savelieva O.E. Genetic discrimination of grade 3 and grade 4 gliomas by artificial neural network. Cell. Mol. Neurobiol. 2024 44 1 13 10.1007/s10571‑023‑01448‑z 38150033
    [Google Scholar]
  23. Kucheryavykh Y.V. Davila J. Ortiz-Rivera J. Inyushin M. Almodovar L. Mayol M. Morales-Cruz M. Cruz-Montañez A. Barcelo-Bovea V. Griebenow K. Kucheryavykh L.Y. Targeted delivery of nanoparticulate cytochrome C into glioma cells through the proton-coupled folate transporter. Biomolecules 2019 9 4 154 10.3390/biom9040154 31003476
    [Google Scholar]
  24. Sun S. Shi R. Xu L. Sun F. Identification of heterogeneity and prognostic key genes associated with uveal melanoma using single-cell RNA-sequencing technology. Melanoma Res. 2022 32 1 18 26 10.1097/CMR.0000000000000783 34879031
    [Google Scholar]
  25. Liu C.J. Hu F.F. Xie G.Y. Miao Y.R. Li X.W. Zeng Y. Guo A.Y. GSCA: An integrated platform for gene set cancer analysis at genomic, pharmacogenomic and immunogenomic levels. Brief. Bioinform. 2023 24 1 bbac558 10.1093/bib/bbac558 36549921
    [Google Scholar]
  26. Subramanian I. Verma S. Kumar S. Jere A. Anamika K. Multi-omics data integration, interpretation, and its application. Bioinform. Biol. Insights 2020 14 10.1177/1177932219899051 32076369
    [Google Scholar]
  27. Puthdee N. Sriswasdi S. Pisitkun T. Ratanasirintrawoot S. Israsena N. Tangkijvanich P. The LIN28B/TGF-β/TGFBI feedback loop promotes cell migration and tumour initiation potential in cholangiocarcinoma. Cancer Gene Ther. 2022 29 5 445 455 10.1038/s41417‑021‑00387‑5 34548635
    [Google Scholar]
  28. Alaseem A. Alhazzani K. Dondapati P. Alobid S. Bishayee A. Rathinavelu A. Matrix Metalloproteinases: A challenging paradigm of cancer management. Seminars in cancer biology. Elsevier 2019 10.1016/j.semcancer.2017.11.008 29155240
    [Google Scholar]
  29. Chen A.Y. Chen Y.C. A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem. 2013 138 4 2099 2107 10.1016/j.foodchem.2012.11.139 23497863
    [Google Scholar]
  30. Yu X. Jin J. Zheng Y. Zhu H. Xu H. Ma J. Lan Q. Zhuang Z. Chen C.C. Li M. GBP5 drives malignancy of glioblastoma via the Src/ERK1/2/MMP3 pathway. Cell Death Dis. 2021 12 2 203 10.1038/s41419‑021‑03492‑3 33608513
    [Google Scholar]
  31. Cruickshanks N. Zhang Y. Yuan F. Pahuski M. Gibert M. Abounader R. Role and therapeutic targeting of the HGF/MET pathway in glioblastoma. Cancers (Basel) 2017 9 7 87 10.3390/cancers9070087 28696366
    [Google Scholar]
  32. Orentas R.J. Yang J.J. Wen X. Wei J.S. Mackall C.L. Khan J. Identification of cell surface proteins as potential immunotherapy targets in 12 pediatric cancers. Front. Oncol. 2012 2 194 10.3389/fonc.2012.00194 23251904
    [Google Scholar]
  33. Guo J. Schlich M. Cryan J.F. O’Driscoll C.M. Targeted drug delivery via folate receptors for the treatment of brain cancer: Can the promise deliver? J. Pharm. Sci. 2017 106 12 3413 3420 10.1016/j.xphs.2017.08.009 28842300
    [Google Scholar]
  34. Orozco-Morales M. Sánchez-García F.J. Guevara-Salazar P. Arrieta O. Hernández-Pedro N.Y. Sánchez-García A. Perez-Madrigal R. Rangel-López E. Pineda B. Sotelo J. Adjuvant immunotherapy of C6 glioma in rats with pertussis toxin. J. Cancer Res. Clin. Oncol. 2012 138 1 23 33 10.1007/s00432‑011‑1069‑y 21947268
    [Google Scholar]
  35. Liu Y. Wang X. Zhu W. Sui Z. Wei X. Zhang Y. Qi J. Xing Y. Wang W. TRPML1-induced autophagy inhibition triggers mitochondrial mediated apoptosis. Cancer Lett. 2022 541 215752 10.1016/j.canlet.2022.215752 35644286
    [Google Scholar]
  36. Dance M. Montagner A. Salles J.P. Yart A. Raynal P. The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell. Signal. 2008 20 3 453 459 10.1016/j.cellsig.2007.10.002 17993263
    [Google Scholar]
  37. Pasantes-Morales H. Lezama R.A. Ramos-Mandujano G. Tuz K.L. Mechanisms of cell volume regulation in hypo-osmolality. Am. J. Med. 2006 119 7 Suppl. 1 S4 S11 10.1016/j.amjmed.2006.05.002 16843084
    [Google Scholar]
  38. Claesson-Welsh L. Welsh M. VEGFA and tumour angiogenesis. J. Intern. Med. 2013 273 2 114 127 10.1111/joim.12019 23216836
    [Google Scholar]
  39. Yousefi H. Vatanmakanian M. Mahdiannasser M. Mashouri L. Alahari N.V. Monjezi M.R. Ilbeigi S. Alahari S.K. Understanding the role of integrins in breast cancer invasion, metastasis, angiogenesis, and drug resistance. Oncogene 2021 40 6 1043 1063 10.1038/s41388‑020‑01588‑2 33420366
    [Google Scholar]
  40. Lucas R.M. Luo L. Stow J.L. ERK1/2 in immune signalling. Biochem. Soc. Trans. 2022 50 5 1341 1352 10.1042/BST20220271 36281999
    [Google Scholar]
  41. Asl E.R. Amini M. Najafi S. Mansoori B. Mokhtarzadeh A. Mohammadi A. Lotfinejad P. Bagheri M. Shirjang S. Lotfi Z. Rasmi Y. Baradaran B. Interplay between MAPK/ERK signaling pathway and MicroRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression. Life Sci. 2021 278 119499 10.1016/j.lfs.2021.119499 33865878
    [Google Scholar]
  42. Lee S. Park S. Ryu J.S. Kang J. Kim I. Son S. Lee B.S. Kim C.H. Kim Y.S. c-Src inhibitor PP2 inhibits head and neck cancer progression through regulation of the epithelial–mesenchymal transition. Exp. Biol. Med. (Maywood) 2023 248 6 492 500 10.1177/15353702221139183 36527337
    [Google Scholar]
  43. Tao M. Shi Y. Tang L. Wang Y. Fang L. Jiang W. Lin T. Qiu A. Zhuang S. Liu N. Blockade of ERK1/2 by U0126 alleviates uric acid-induced EMT and tubular cell injury in rats with hyperuricemic nephropathy. Am. J. Physiol. Renal Physiol. 2019 316 4 F660 F673 10.1152/ajprenal.00480.2018 30648910
    [Google Scholar]
  44. Chuliá-Peris L. Carreres-Rey C. Gabasa M. Alcaraz J. Carretero J. Pereda J. Matrix metalloproteinases and their inhibitors in pulmonary fibrosis: EMMPRIN/CD147 comes into play. Int. J. Mol. Sci. 2022 23 13 6894 10.3390/ijms23136894 35805895
    [Google Scholar]
  45. Cabral-Pacheco G.A. Garza-Veloz I. Castruita-De la Rosa C. Ramirez-Acuña J.M. Perez-Romero B.A. Guerrero-Rodriguez J.F. Martinez-Avila N. Martinez-Fierro M.L. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int. J. Mol. Sci. 2020 21 24 9739 10.3390/ijms21249739 33419373
    [Google Scholar]
/content/journals/cchts/10.2174/0113862073335351241226070841
Loading
FOLR1 Regulates the Malignant Progression of Glioblastoma through the SRC/ERK1/2 Axis
Bentham Science Publishers ; https://doi.org/10.2174/0113862073335351241226070841
/content/journals/cchts/10.2174/0113862073335351241226070841
/content/journals/cchts/10.2174/0113862073335351241226070841
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: FOLR1 ; ERK1/2 ; prognosis ; glioblastoma ; SRC ; Cell growth

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test