2. Academic Validation
  3. AR expression-independent XRCC3 mediates DNA damage-induced p53/Bax signaling pathway activation against prostate cancer

AR expression-independent XRCC3 mediates DNA damage-induced p53/Bax signaling pathway activation against prostate cancer

  • J Cancer Res Clin Oncol. 2024 Oct 16;150(10):463. doi: 10.1007/s00432-024-05989-8.
Hailong Xie # 1 2,  Mingjiang Dan # 3,  Yi Cen # 4,  Jing Ning 2,  Chong Sun 2,  Guangbin Zhu 5,  Shourui Feng 6,  Haiyan Wang 7,  Jinxian Pu 8 9
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
  • 2 Department of Urology, The Second Affiliated Hospital of Bengbu Medical College, Benbu, 233080, China.
  • 3 Department of Urology, Huiya Hospital of the First Affiliated Hospital of Sun Yat Sen University, Huizhou, 516081, China.
  • 4 Guangzhou Medical University, Guangzhou, 511436, China.
  • 5 Department of Medical Imaging, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China.
  • 6 School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
  • 7 Shenzhen Bao'an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, 518100, China. why6838260@163.com.
  • 8 Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China. pjx62@sina.com.
  • 9 Department of Urology, The Fourth Affiliated Hospital of Soochow University, Suzhou, 215000, China. pjx62@sina.com.
  • # Contributed equally.
PMID: 39414634 DOI: 10.1007/s00432-024-05989-8
Abstract

Background: Androgen deprivation therapy (ADT) resistance is closely associated with altered AR status. Aberrant AR expression is critical for the induction of ADT resistance, necessitating the identification of an anti-PCa target independent of AR expression.

Methods: Transcriptomic data and clinical information of PRAD were obtained from TCGA database. Genes with PCa-related and AR expression-independent were screened by bioinformatics, and characterized by PPI and GO functional enrichment analyses. Candidate genes were locked by co-expression correlation and disease-free survival (DFS) analyses. A prognostic gene set was established using LASSO COX regression algorithm. COX proportional risk regression was performed to identify a key prognostic gene. Expression of the target protein in PCa tissues was verified by The Human Protein Atlas database. In vitro validation of cellular function and molecular mechanism by knockdown and overexpression of the target gene.

Results: Two AR expression-independent genes (SLC43A1 and XRCC3) were available for the optimal prognostic model. This gene set effectively predicted PRAD patients' DFS at 1-, 3- and 5-year, where XRCC3 and tumor (T) stage were independent risk factors. XRCC3 was higher expressed in PRAD patients with T3-T4 stages and accompanied by poorer DFS. IHC staining also validated its higher expression in high-risk PCa tissues. In vitro experiments demonstrated that silencing XRCC3 significantly inhibited 22Rv1 and DU145 cell proliferation, migration and invasion, while promoted Apoptosis. Further, silencing XRCC3 promoted DNA damage-induced p53/Bax signaling pathway activation, which was absent with overexpression.

Conclusion: Silencing XRCC3 exerts anti-PCa effects by promoting DNA damage-induced p53/Bax signaling pathway activation in an AR expression-independent manner.

Keywords

AR; DNA damage; P53/Bax signaling pathway; Prostate cancer; XRCC3.

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