Skip to main content

Advertisement

SpringerLink
Log in

CXCL5 promotes tumorigenesis and angiogenesis of glioblastoma via JAK-STAT/NF-κb signaling pathways

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

The tumor microenvironment contains chemokines that play a crucial role in various processes, such as tumorigenesis, inflammation, and therapy resistance, in different types of cancer. CXCL5 is a significant chemokine that has been shown to promote tumor proliferation, invasion, angiogenesis, and therapy resistance when overexpressed in various types of cancer. This research aims to investigate the impact of CXCL5 on the biological functions of glioblastoma (GBM).

Methods

The TCGA GBM and GEO databases were utilized to perform transcriptome microarray analysis and oncogenic signaling pathway analysis of CXCL5 in GBM. Validation of CXCL5 expression was performed using RT-qPCR and Western Blot. The impact of CXCL5 on cell proliferation, tumorigenesis, and angiogenesis in GBM was assessed through various methods, including cell proliferation assay, cloning assay, intracranial xenograft tumor models, and tube formation assay. Clinical prognosis was evaluated in 59 samples of gliomas with varying degrees of malignancy (grades 2, 3, and 4) and the TCGA GBM database, based on CXCL5 expression levels. The activities of the JAK-STAT and NF-κB signaling pathways were detected using Western Blot.

Results

The expression of CXCL5 was highly enriched in GBM. Moreover, the inhibition of CXCL5 showed a significant efficacy in suppressing cellular proliferation and angiogenesis, resulting in extended survival rates in xenograft mouse models in comparison to the control group. Notably, pretreatment with dapsone exhibited a reversal of the impact of CXCL5 on the formation of colonies and tubes in GBM cells. Elevated expression of CXCL5 was correlated with poor outcomes in GBM patients. Furthermore, the overexpression of CXCL5 has been associated with the activation of JAK-STAT and NF-κB signaling pathways.

Conclusions

CXCL5 plays an important role in tumorigenesis and angiogenesis, indicating the potential for novel therapies targeting CXCL5 in GBM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The datasets are available from the corresponding author on reasonable requests.

References

  1. Miller TE, Liau BB, Wallace LC et al (2017) Transcription elongation factors represent in vivo cancer dependencies in glioblastoma. Nature 547(7663):355–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chinot OL, Wick W, Mason W et al (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722

    Article  CAS  PubMed  Google Scholar 

  3. Liu H, Yang Z, Lu W et al (2020) Chemokines and chemokine receptors: a new strategy for breast cancer therapy. Cancer Med 9(11):3786–3799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Khan P, Fatima M, Khan MA et al (2022) Emerging role of chemokines in small cell lung cancer: Road signs for metastasis, heterogeneity, and immune response. Sem Cancer Biol 87:117–126

    Article  CAS  Google Scholar 

  5. Song M, He J, Pan QZ et al (2021) Cancer-Associated fibroblast-mediated Cellular Crosstalk supports Hepatocellular Carcinoma Progression. Hepatology 73(5):1717–1735

    Article  CAS  PubMed  Google Scholar 

  6. Zhang XN, Yang KD, Chen C et al (2021) Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling. Cell Res 31(10):1072–1087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sorrentino C, D’Antonio L, Ciummo SL et al (2022) CRISPR/Cas9-mediated deletion of Interleukin-30 suppresses IGF1 and CXCL5 and boosts SOCS3 reducing prostate cancer growth and mortality. J Hematol Oncol 15(1):145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xu Z, Gao H, Zhang Y, Feng W et al (2022) CCL7 and TGF-β secreted by MSCs play opposite roles in regulating CRC metastasis in a KLF5/CXCL5-dependent manner. Mol Ther 30(6):2327–2341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mao Z, Zhang J, Shi Y et al (2020) CXCL5 promotes gastric cancer metastasis by inducing epithelial-mesenchymal transition and activating neutrophils. Oncogenesis 9(7):63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang J, Hu T, Wang Q et al (2021) Repression of the AURKA-CXCL5 axis induces autophagic cell death and promotes radiosensitivity in non-small-cell lung cancer. Cancer Lett 509:89–104

    Article  CAS  PubMed  Google Scholar 

  11. Dai Z, Wu J, Chen F et al (2016) CXCL5 promotes the proliferation and migration of glioma cells in autocrine- and paracrine-dependent manners. Oncol Rep 36(6):3303–3310

    Article  CAS  PubMed  Google Scholar 

  12. Jia X, Wei S, Xiong W (2021) CXCL5/NF-κB Pathway as a Therapeutic Target in Hepatocellular Carcinoma Treatment. Journal of Oncology, 2021: 9919494

  13. Zhang W, Wang H, Sun M et al (2020) CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target. Cancer Commun 40(2–3):69–80

    Article  CAS  Google Scholar 

  14. Jang BS, Seo JY C, et al (2021) Crosstalk between head and neck cancer cells and lymphatic endothelial cells promotes tumor metastasis via CXCL5-CXCR2 signaling. FASEB J 35(1):e21181

    PubMed  Google Scholar 

  15. Zhao J, Ou B, Han D et al (2017) Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways. Mol Cancer 16(1):70

    Article  PubMed  PubMed Central  Google Scholar 

  16. Mao P, Joshi K, Li J et al (2013) Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci USA 110(21):8644–8649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mao P, Bao G, Wang YC et al (2020) PDZ-Binding kinase-dependent transcriptional regulation of CCNB2 promotes tumorigenesis and radio-resistance in Glioblastoma. Translational Oncol 13(2):287–294

    Article  Google Scholar 

  18. Kast RE, Scheuerle A, Wirtz CR et al (2011) The rationale of targeting neutrophils with dapsone during glioblastoma treatment. Anti-cancer Agents Med Chem 11(8):756–761

    Article  CAS  Google Scholar 

  19. Wang W, Hao Y, Zhang A et al (2021) miR-19a/b promote EMT and proliferation in glioma cells via SEPT7-AKT-NF-κB pathway. Mol Therapy Oncolytics 20:290–305

    Article  CAS  Google Scholar 

  20. Zhang R, Liu Q, Peng J et al (2020) CXCL5 overexpression predicts a poor prognosis in pancreatic ductal adenocarcinoma and is correlated with immune cell infiltration. J Cancer 11(9):2371–2381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhou SL, Dai Z, Zhou ZJ et al (2012) Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology 56(6):2242–2254

    Article  CAS  PubMed  Google Scholar 

  22. Simoncello F, Piperno GM, Caronni N et al (2022) CXCL5-mediated accumulation of mature neutrophils in lung cancer tissues impairs the differentiation program of anticancer CD8 T cells and limits the efficacy of checkpoint inhibitors. Oncoimmunology 11(1):2059876

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ge X, He J, Wang L et al (2022) Epigenetic alterations of CXCL5 in cr(VI)-induced carcinogenesis. Sci Total Environ 838(Pt 1):155713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhao Y, Zhang X, Zhao H et al (2018) CXCL5 secreted from adipose tissue-derived stem cells promotes cancer cell proliferation. Oncol Lett 15(2):1403–1410

    PubMed  Google Scholar 

  25. Hasan T, Caragher SP, Shireman JM et al (2019) Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma. Cell Death Dis 10(4):292

    Article  PubMed  PubMed Central  Google Scholar 

  26. Karpel-Massler G, Kast RE, Siegelin MD et al (2017) Anti-glioma activity of Dapsone and its enhancement by Synthetic Chemical modification. Neurochem Res 42(12):3382–3389

    Article  CAS  PubMed  Google Scholar 

  27. Schioppa T, Sozio F, Barbazza I et al (2020) Molecular basis for CCRL2 regulation of Leukocyte Migration. Front Cell Dev Biology 8:615031

    Article  Google Scholar 

  28. Lin Y, Cheng L, Liu Y et al (2021) Intestinal epithelium-derived BATF3 promotes colitis-associated colon cancer through facilitating CXCL5-mediated neutrophils recruitment. Mucosal Immunol 14(1):187–198

    Article  CAS  PubMed  Google Scholar 

  29. Trettel F, Di Bartolomeo S, Lauro C et al (2003) Ligand-independent CXCR2 dimerization. J Biol Chem 278(42):40980–40988

    Article  CAS  PubMed  Google Scholar 

  30. Brown AJ, Joseph PR, Sawant KV et al (2017) Chemokine CXCL7 heterodimers: structural insights, CXCR2 receptor function, and Glycosaminoglycan interactions. Int J Mol Sci 18(4):748

    Article  PubMed  PubMed Central  Google Scholar 

  31. Deng J, Jiang R, Meng E et al (2022) CXCL5: a coachman to drive cancer progression. Front Oncol 12:944494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by National Natural Science Foundation of China (Grant No. 82072781 and 81602207), Medical Foundation - Clinical Integration Program of Xi’an Jiaotong University (Grant No. YXJLRH2022040) and Shaanxi Province key research and development plan project (Grant No. 2023-YBSF-128).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, China

    Ping Mao, Tuo Wang, Chang-Wang Du, Xiao Yu & Mao-De Wang

Authors
  1. Ping Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tuo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chang-Wang Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mao-De Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study conception and design: PM and MDW. Experiments and data analysis: PM, CWD, XY. Statistical analysis: XY, CWD. Manuscript writing: PM, TW and MDW. All the authors read and approved the manuscript.

Corresponding author

Correspondence to Ping Mao.

Ethics declarations

Ethical approval

The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University (Xi’an, Shaanxi, China 710061; Approval No. 2016-021).

Consent to participate

All authors have their consent to participate.

Consent to publish

All authors have their consent to publish their work.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mao, P., Wang, T., Du, CW. et al. CXCL5 promotes tumorigenesis and angiogenesis of glioblastoma via JAK-STAT/NF-κb signaling pathways. Mol Biol Rep 50, 8015–8023 (2023). https://doi.org/10.1007/s11033-023-08671-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-023-08671-3

Keywords

Search

Navigation