Protein disulfide-isomerase A4 confers glioblastoma angiogenesis promotion capacity and resistance to anti-angiogenic therapy

  • J Exp Clin Cancer Res. 2023 Mar 30;42(1):77. doi: 10.1186/s13046-023-02640-1.
Zewei Tu  1  2  3  4 ,  Chong Wang  1  2  3  4 ,  Qing Hu  1  2  3  4 ,  Chuming Tao  1  2  3  4 ,  Zhansheng Fang  1  2  3  4 ,  Li Lin  1  2  3  4 ,  Kunjian Lei  1  2  3  4 ,  Min Luo  1  2  3  4 ,  Yilei Sheng  5 ,  Xiaoyan Long  6 ,  Jingying Li  7 ,  Lei Wu  8  9  10  11 ,  Kai Huang  12  13  14  15 ,  Xingen Zhu  16  17  18  19
Affiliations
  • 1. Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Jiangxi, 330006, Nanchang, P. R. China.
  • 2. Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular Diseases, Jiangxi, 330006, Nanchang, P. R. China.
  • 3. Institute of Neuroscience, Nanchang University, Jiangxi, 330006, Nanchang, P. R. China.
  • 4. JXHC Key Laboratory of Neurological Medicine, Jiangxi, 330006, Nanchang, P. R. China.
  • 5. The Huan Kui Medical College of Nanchang University, Jiangxi, 330006, Nanchang, P. R. China.
  • 6. East China Institute of Digital Medical Engineering, Shangrao, China.
  • 7. Department of Comprehensive Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, P. R. China.
  • 8. Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 9. Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular Diseases, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 10. Institute of Neuroscience, Nanchang University, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 11. JXHC Key Laboratory of Neurological Medicine, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 12. Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 13. Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular Diseases, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 14. Institute of Neuroscience, Nanchang University, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 15. JXHC Key Laboratory of Neurological Medicine, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 16. Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 17. Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular Diseases, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 18. Institute of Neuroscience, Nanchang University, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
  • 19. JXHC Key Laboratory of Neurological Medicine, Jiangxi, 330006, Nanchang, P. R. China. [email protected].
PMID: 36997943 DOI: 10.1186/s13046-023-02640-1
Abstract

Introduction: Increasing evidence has revealed the key activity of protein disulfide isomerase A4 (PDIA4) in the endoplasmic reticulum stress (ERS) response. However, the role of PDIA4 in regulating glioblastoma (GBM)-specific pro-angiogenesis is still unknown.

Methods: The expression and prognostic role of PDIA4 were analyzed using a bioinformatics approach and were validated in 32 clinical samples and follow-up data. RNA-sequencing was used to search for PDIA4-associated biological processes in GBM cells, and proteomic mass spectrum (MS) analysis was used to screen for potential PDIA4 substrates. Western blotting, real-time quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assays (ELISA) were used to measure the levels of the involved factors. Cell migration and tube formation assays determined the pro-angiogenesis activity of PDIA4 in vitro. An intracranial U87 xenograft GBM animal model was constructed to evaluate the pro-angiogenesis role of PDIA4 in vivo.

Results: Aberrant overexpression of PDIA4 was associated with a poor prognosis in patients with GBM, although PDIA4 could also functionally regulate intrinsic GBM secretion of vascular endothelial growth factor-A (VEGF-A) through its active domains of Cys-X-X-Cys (CXXC) oxidoreductase. Functionally, PDIA4 exhibits pro-angiogenesis activity both in vitro and in vivo, and can be upregulated by ERS through transcriptional regulation of X-box binding protein 1 (XBP1). The XBP1/PDIA4/VEGFA axis partially supports the mechanism underlying GBM cell survival under ER stress. Further, GBM cells with higher expression of PDIA4 showed resistance to antiangiogenic therapy in vivo.

Conclusions: Our findings revealed the pro-angiogenesis role of PDIA4 in GBM progression and its potential impact on GBM survival under a harsh microenvironment. Targeting PDIA4 might help to improve the efficacy of antiangiogenic therapy in patients with GBM.

Keywords
Angiogenesis; Endoplasmic reticulum stress (ERS); Glioblastoma (GBM); Protein disulfide-isomerase A4 (PDIA4); X-box binding protein 1 (XBP1).
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