Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Molecular Medicine
  4. Volume 25, Issue 1
  5. Article
Volume 25, Issue 1
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666

Abstract

Background

Neuroblastoma (NB) is one of the most common pediatric solid tumors. Emerging evidence has indicated that ADGRL4 can act as a master regulator of tumor progression. In addition, it is well documented that the ERK/STAT3 signaling pathway can promote the proliferation, EMT, angiogenesis, and metastasis in tumors. The current study was formulated to elucidate the exact role of ADGRL4 in the malignant behaviors of NB cells and to investigate the intrinsic mechanism.

Methods

In this work, expression differences of ADGRL4 in human NB cell lines and HUVECs were assessed RT-qPCR and western blot analysis. For functional experiments, sh-ADGRL4 was transfected into SK-N-SH cells to generate ADGRL4 knockdown stable cell line. Moreover, ADGRL4 knockdown stable SK-N-SH cells were treated with LM22B-10 (an ERK activator) for rescue experiments. CCK-8, colony formation, would healing, and transwell assays determined NB cell growth, migration, and invasion. Meanwhile, proliferation-, metastasis- and EMT- associated proteins were also detected. Additionally, a tube formation assay was employed to evaluate angiogenesis. VM-cadherin, the marker of angiogenesis, was assessed using immunofluorescence staining.

Results

Data showed notably upregulated ADGRL4 in NB cells, especially in SK-N-SH cells. ADGRL4 knockdown inhibited NB cell growth, migration, invasion, EMT, and angiogenesis. ADGRL4 knockdown inactivated ERK/STAT3 signaling pathway. Activation of the ERK/STAT3 signaling pathway partially rescued the tumor suppression effects of ADGRL4 knockdown on NB cells.

Conclusion

To conclude, the downregulation of ADGRL4 may inhibit cell growth, aggressiveness, EMT, and angiogenesis in NB by inactivating the ERK/STAT3 signaling pathway.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmm/10.2174/0115665240254765231117122210
2024-01-03
2025-01-31

  • From This Site

    /content/journals/cmm/10.2174/0115665240254765231117122210
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Steliarova-FoucherE. ColombetM. RiesL.A.G. International incidence of childhood cancer, 2001–10: A population-based registry study.Lancet Oncol.201718671973110.1016/S1470‑2045(17)30186‑9 28410997
     [Google Scholar]
  2. ZafarA. WangW. LiuG. Molecular targeting therapies for neuroblastoma: Progress and challenges.Med. Res. Rev.2021412961102110.1002/med.21750 33155698
     [Google Scholar]
  3. YuanX. JinQ. ChenY. BCL11A facilitates cell proliferation and metastasis in neuroblastoma via regulating the PI3K/Akt signaling pathway.Curr. Cancer Drug Targets2022221191993010.2174/1568009622666220728123748 35909289
     [Google Scholar]
  4. WangS.S. HsiaoR. LimparM.M. Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin.Int. J. Mol. Med.2014331354210.3892/ijmm.2013.1545 24190252
     [Google Scholar]
  5. MarisJ.M. Recent advances in neuroblastoma.N. Engl. J. Med.2010362232202221110.1056/NEJMra0804577 20558371
     [Google Scholar]
  6. AustG. ZhuD. Van MeirE.G. XuL. Adhesion GPCRs in tumorigenesis.Handb. Exp. Pharmacol.201623436939610.1007/978‑3‑319‑41523‑9_17 27832497
     [Google Scholar]
  7. LuS. LiuS. WietelmannA. Developmental vascular remodeling defects and postnatal kidney failure in mice lacking Gpr116 (Adgrf5) and Eltd1 (Adgrl4).PLoS One2017128e018316610.1371/journal.pone.0183166 28806758
     [Google Scholar]
  8. NechiporukT. UrnessL.D. KeatingM.T. ETL, a novel seven-transmembrane receptor that is developmentally regulated in the heart. ETL is a member of the secretin family and belongs to the epidermal growth factor-seven-transmembrane subfamily.J. Biol. Chem.200127664150415710.1074/jbc.M004814200 11050079
     [Google Scholar]
  9. SetlaiB.P. HullR. ReisR.M. MicroRNA Interrelated Epithelial Mesenchymal Transition (EMT) in glioblastoma.Genes202213224410.3390/genes13020244 35205289
     [Google Scholar]
  10. WangX.H. WuH.Y. GaoJ. WangX.H. GaoT.H. ZhangS.F. IGF1R facilitates epithelial-mesenchymal transition and cancer stem cell properties in neuroblastoma via the STAT3/AKT axis.Cancer Manag. Res.2019115459547210.2147/CMAR.S196862 31354352
     [Google Scholar]
  11. TurriniE. MaffeiF. FimognariC. Ten years of research on fucoidan and cancer: Focus on its antiangiogenic and antimetastatic effects.Mar. Drugs202321530710.3390/md21050307 37233501
     [Google Scholar]
  12. BrignoleC. MarimpietriD. PastorinoF. Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis.J. Natl. Cancer Inst.200698161142115710.1093/jnci/djj309 16912267
     [Google Scholar]
  13. SheldonH. AlexanderJ. BridgesE. ELTD1 activation induces an endothelial-EMT transition to a myofibroblast phenotype.Int. J. Mol. Sci.202122201129310.3390/ijms222011293 34681953
     [Google Scholar]
  14. MasieroM. SimõesF.C. HanH.D. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis.Cancer Cell201324222924110.1016/j.ccr.2013.06.004 23871637
     [Google Scholar]
  15. SerbanF. ArteneS.A. GeorgescuA.M. Epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 marker, a novel angiogenesis marker.OncoTargets Ther.2015837673774 26719704
     [Google Scholar]
  16. KanA. LeY. ZhangY. ELTD1 function in hepatocellular carcinoma is carcinoma-associated fibroblast-dependent.J. Cancer20189142415242710.7150/jca.24406 30026838
     [Google Scholar]
  17. PastushenkoI. BlanpainC. EMT transition states during tumor progression and metastasis.Trends Cell Biol.201929321222610.1016/j.tcb.2018.12.001 30594349
     [Google Scholar]
  18. LuC.C. TsaiH.C. YangD.Y. The chemokine CCL4 stimulates angiopoietin-2 expression and angiogenesis via the MEK/ERK/STAT3 pathway in oral squamous cell carcinoma.Biomedicines2022107161210.3390/biomedicines10071612 35884919
     [Google Scholar]
  19. KangX. XuE. WangX. Tenascin-c knockdown suppresses vasculogenic mimicry of gastric cancer by inhibiting ERK- triggered EMT.Cell Death Dis.2021121089010.1038/s41419‑021‑04153‑1 34588421
     [Google Scholar]
  20. HanC. SunB. ZhaoX. Phosphorylation of STAT3 promotes vasculogenic mimicry by inducing epithelial-to-mesenchymal transition in colorectal cancer.Technol. Cancer Res. Treat.20171661209121910.1177/1533034617742312 29333928
     [Google Scholar]
  21. LiJ. ShenJ. WangZ. ELTD1 facilitates glioma proliferation, migration and invasion by activating JAK/STAT3/HIF-1α signaling axis.Sci. Rep.2019911390410.1038/s41598‑019‑50375‑x 31554859
     [Google Scholar]
  22. CaiY. ChenK. ChengC. Prp19 is an independent prognostic marker and promotes neuroblastoma metastasis by regulating the Hippo-YAP signaling pathway.Front. Oncol.20201057536610.3389/fonc.2020.575366 33224878
     [Google Scholar]
  23. HobbieW.L. LiY. CarlsonC. Late effects in survivors of high‐risk neuroblastoma following stem cell transplant with and without total body irradiation.Pediatr. Blood Cancer2022693e2953710.1002/pbc.29537 34971017
     [Google Scholar]
  24. SunJ. ZhangZ. ChenJ. XueM. PanX. ELTD1 promotes invasion and metastasis by activating MMP2 in colorectal cancer.Int. J. Biol. Sci.202117123048305810.7150/ijbs.62293 34421349
     [Google Scholar]
  25. Guihurt SantiagoJ. Burgos-TiradoN. LafontaineD.D. Adhesion G protein-coupled receptor, ELTD1, is a potential therapeutic target for retinoblastoma migration and invasion.BMC Cancer20212115310.1186/s12885‑020‑07768‑3 33430814
     [Google Scholar]
  26. TsaiJ.H. YangJ. Epithelial–mesenchymal plasticity in carcinoma metastasis.Genes Dev.201327202192220610.1101/gad.225334.113 24142872
     [Google Scholar]
  27. BeuranM. NegoiI. PaunS. The epithelial to mesenchymal transition in pancreatic cancer: A systematic review.Pancreatology201515321722510.1016/j.pan.2015.02.011 25794655
     [Google Scholar]
  28. TianX. ZhouD. ChenL. Polo-like kinase 4 mediates epithelial–mesenchymal transition in neuroblastoma via PI3K/Akt signaling pathway.Cell Death Dis.2018925410.1038/s41419‑017‑0088‑2 29352113
     [Google Scholar]
  29. PhillipsP.A. McCarrollJ.A. ParkS. Rat pancreatic stellate cells secrete matrix metalloproteinases: Implications for extracellular matrix turnover.Gut200352227528210.1136/gut.52.2.275 12524413
     [Google Scholar]
  30. ChenM. HuC. GuoY. Ophiopogonin B suppresses the metastasis and angiogenesis of A549 cells in vitro and in vivo by inhibiting the EphA2/Akt signaling pathway.Oncol. Rep.20184031339134710.3892/or.2018.6531 29956803
     [Google Scholar]
  31. HuangH. GeorganakiM. ConzeL.L. ELTD1 deletion reduces vascular abnormality and improves T-cell recruitment after PD-1 blockade in glioma.Neuro-oncol.202224339841110.1093/neuonc/noab181 34347079
     [Google Scholar]
  32. YuY. ZhaoY. ChoiJ. ERK inhibitor ulixertinib inhibits high-risk neuroblastoma growth in vitro and in vivo.Cancers 20221422553410.3390/cancers14225534 36428626
     [Google Scholar]
  33. ChenZ. GaoJ. SunJ. WuZ. WangB. Aminoacylase 1 (ACY-1) mediates the proliferation and migration of neuroblastoma cells in humans through the ERK/transforming growth Factor β (TGF-β) signaling pathways.Med. Sci. Monit.202127e92881310.12659/MSM.928813 33619241
     [Google Scholar]
  34. CirmiS. CelanoM. LombardoG.E. Oleacein inhibits STAT3, activates the apoptotic machinery, and exerts anti-metastatic effects in the SH-SY5Y human neuroblastoma cells.Food Funct.20201143271327910.1039/D0FO00089B 32219291
     [Google Scholar]
/content/journals/cmm/10.2174/0115665240254765231117122210
Loading
ADGRL4 Promotes Cell Growth, Aggressiveness, EMT, and Angiogenesis in Neuroblastoma via Activation of ERK/STAT3 Pathway
Current Molecular Medicine 25, 45 (2025); https://doi.org/10.2174/0115665240254765231117122210
/content/journals/cmm/10.2174/0115665240254765231117122210
/content/journals/cmm/10.2174/0115665240254765231117122210
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): ADGRL4; angiogenesis; cancer-related deaths; cell growth; ERK/STAT3 signaling pathway; neuroblastoma

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