Contribution of the Testosterone Androgen Receptor-PARD3B Signaling Axis to Tumorigenesis and Malignance of Glioblastoma Multiforme through Stimulating Cell Proliferation and Colony Formation

Jr-Di Yang; Jui-Tai Chen; Shing-Hwa Liu; Ruei-Ming Chen

doi:10.3390/jcm11164818

Contribution of the Testosterone Androgen Receptor-PARD3B Signaling Axis to Tumorigenesis and Malignance of Glioblastoma Multiforme through Stimulating Cell Proliferation and Colony Formation

J Clin Med. 2022 Aug 17;11(16):4818. doi: 10.3390/jcm11164818.

Authors

Jr-Di Yang^{1

2}, Jui-Tai Chen^{3

4}, Shing-Hwa Liu^{2

5}, Ruei-Ming Chen^{2

6

7

8

9}

Affiliations

¹ Division of Urology, Department of Surgery, National Yang-Ming Chiao Tung University Hospital, Yilan County 260006, Taiwan.
² Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.
³ Department of Anesthesiology, Shuang Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan.
⁴ Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
⁵ Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
⁶ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
⁷ International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
⁸ Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan.
⁹ TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.

Abstract

Background: Glioblastoma multiforme (GBM) is the most common and malignant brain tumor with very poor prognoses. After surgical resection of the primary tumor, rapid proliferation of residual glioblastoma cells is a critical cause explaining tumor malignance and recurrence. In this study, we evaluated de novo roles of the testosterone androgen receptor (AR)-PARD3B signaling axis in the tumorigenesis and malignance of human GBM and the possible related mechanisms.

Methods: AR and PARD3B gene expressions and their correlations were mined from The Cancer Genome Atlas (TCGA) database and analyzed using the UALCAN system. Analyses using a real-time PCR, cell proliferation, and colony formation and a loss-of-function strategy by suppressing AR activity with its specific inhibitor, enzalutamide, were then carried out to determine roles of the testosterone AR-PARD3B signaling axis in tumor malignance.

Results: Expressions of AR, PARD3B mRNA, and proteins in human GBM tissues were upregulated compared to normal human brain tissues. In contrast, levels of AR and PARD3B mRNA in most TCGA pan-cancer types were downregulated compared to their respective normal tissues. Interestingly, a highly positive correlation between AR and PARD3B gene expressions in human GBM was identified. The results of a bioinformatics search further showed that there were five AR-specific DNA-binding elements predicted in the 5' promoter of the PARD3B gene. Regarding the mechanisms, exposure of human glioblastoma cells to testosterone induced AR and PARD3B gene expressions and successively stimulated cell proliferation and colony formation. Suppressing AR activity concurrently resulted in significant attenuations of testosterone-induced PARD3B gene expression, cell proliferation, and colony formation in human glioblastoma cells.

Conclusions: This study showed the contribution of the testosterone AR-PARD3B signaling axis to the tumorigenesis and malignance of human GBM through stimulating cell proliferation and colony formation. Therefore, the AR-PARD3B signaling axis could be targeted for potential therapy for human GBM.

Keywords: PARD3B; cell proliferation; colony formation; glioblastoma multiforme; testosterone androgen receptor signaling.

Abstract

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