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Translational Therapeutics

ABCC4 suppresses glioblastoma progression and recurrence by restraining cGMP-PKG signalling

British Journal of Cancer volume 130, pages 1324–1336 (2024)Cite this article

Subjects

Abstract

Background

Cyclic nucleotides are critical mediators of cellular signalling in glioblastoma. However, the clinical relevance and mechanisms of regulating cyclic nucleotides in glioblastoma progression and recurrence have yet to be thoroughly explored.

Methods

In silico, mRNA, and protein level analyses identified the primary regulator of cyclic nucleotides in recurrent human glioblastoma. Lentiviral and pharmacological manipulations examined the functional impact of cyclic nucleotide signalling in human glioma cell lines and primary glioblastoma cells. An orthotopic xenograft mice model coupled with aspirin hydrogels verified the in vivo outcome of targeting cyclic nucleotide signalling.

Results

Elevated intracellular levels of cGMP, instead of cAMP, due to a lower substrate efflux from ATP-binding cassette sub-family C member 4 (ABCC4) is engaged in the recurrence of glioblastoma. ABCC4 gene expression is negatively associated with recurrence and overall survival outcomes in glioblastoma specimens. ABCC4 loss-of-function activates cGMP-PKG signalling, promoting malignancy in glioblastoma cells and xenografts. Hydrogels loaded with aspirin, inhibiting glioblastoma progression partly by upregulating ABCC4 expressions, augment the efficacy of standard-of-care therapies in orthotopic glioblastoma xenografts.

Conclusion

ABCC4, repressing the cGMP-PKG signalling pathway, is a tumour suppressor in glioblastoma progression and recurrence. Aspirin hydrogels impede glioblastoma progression through ABCC4 restoration and constitute a viable translational approach.

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Fig. 1: Low expression of ABCC4 is related to tumour recurrence and poor clinical prognosis of glioma.
Fig. 2: ABCC4 inhibits the proliferation, clonogenic potential, and neurosphere formation of glioma cells.
Fig. 3: ABCC4 suppresses the migration and invasion of glioma cells.
Fig. 4: The cGMP-PKG signalling pathway contributes to ABCC4-mediated biological functions of glioma cells.
Fig. 5: ABCC4 regulates glioma tumorigenicity and invasiveness in vivo.
Fig. 6: ABCC4 inducer, aspirin, provides therapeutic benefits for glioma.

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Data availability

Additional data will be made available upon request.

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Funding

Grant support was provided by the National Science and Technology Council of the Republic of China (Grant Nos. NSTC 110-2628-B-039-006, 112-2628-B-039-004-MY3) and the China Medical University and Hospital (Grant Nos. DMR-112-133, DMR-112-079, CMU112-MF-34, DMR-113-122), the China Medical University Hsinchu Hospital (CMUHCH-DMR-111-007, CMUHCH-DMR-113-010).

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Author notes

  1. These authors contributed equally: Jung-Ying Chiang, Sung-Tai Wei.

Authors and Affiliations

  1. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan

    Jung-Ying Chiang, Huan-Jui Chang, Hwai-Lee Wang, Kai-Yu Wei & Chia-Hung Hsieh

  2. Department of Neurosurgery, China Medical University Hsinchu Hospital, Hsinchu, Taiwan

    Jung-Ying Chiang

  3. Division of Neurosurgery, Asia University Hospital, Taichung, Taiwan

    Sung-Tai Wei

  4. Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan

    Sung-Tai Wei

  5. School of Medicine, Chung Shan Medical University, Taichung, Taiwan

    Huan-Jui Chang

  6. Department of Neurosurgery, China Medical University and Hospital, Taichung, Taiwan

    Der-Cherng Chen

  7. Graduate Institute of Clinical Medical Sciences, China Medical University, Taichung, Taiwan

    Fu-Ju Lei

  8. Mingdao High School, Taichung, Taiwan

    Kai-Yu Wei

  9. Department of Medical Imaging, China Medical University and Hospital, Taichung, Taiwan

    Yen‐Chih Huang

  10. Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei, Taiwan

    Chi-Chung Wang

  11. Department of Medical Research, China Medical University Hospital, Taichung, Taiwan

    Chia-Hung Hsieh

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Contributions

JYC and STW designed the study, performed the experiments, analysed the data and wrote the paper. HJC, HLW, FJL, KYW and YCH performed the cell or animal studies and analysed the data. DCC and CCW provided essential material and analysed the data. CHH conceptualised the project, designed the study, analysed the data, and wrote the paper. All authors had final approval of the submitted versions.

Corresponding author

Correspondence to Chia-Hung Hsieh.

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The authors declare no competing interests.

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All animal studies were conducted in accordance with the Institutional Guidelines of China Medical University (Taichung, Taiwan) with the permission of the local Ethical Committee for Animal Experimentation (CMUIACUC- 2016-209). The use of clinical samples was approved by the Institutional Review Board (CMUH108-REC2-062) of China Medical University Hospital (Taichung, Taiwan).

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Chiang, JY., Wei, ST., Chang, HJ. et al. ABCC4 suppresses glioblastoma progression and recurrence by restraining cGMP-PKG signalling. Br J Cancer 130, 1324–1336 (2024). https://doi.org/10.1038/s41416-024-02581-2

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