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Updated: Jun 10, 2025
Immunofluorescence Imaging of DNA Damage and Repair Foci in Human Colon Cancer Cells
Published on: June 9, 2020
AR expression-independent XRCC3 mediates DNA damage-induced p53/Bax signaling pathway activation against prostate
Hailong Xie1,2, Mingjiang Dan3, Yi Cen4
1Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
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.
Insights
This study identifies XRCC3 as a novel target for prostate cancer (PCa) treatment, independent of androgen receptor (AR) status. Silencing XRCC3 inhibits cancer growth and promotes apoptosis by activating DNA damage pathways.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Androgen deprivation therapy (ADT) resistance in prostate cancer (PCa) is linked to altered androgen receptor (AR) status.
- Identifying AR-independent targets is crucial for overcoming ADT resistance.
Purpose of the Study:
- To identify novel AR expression-independent therapeutic targets for PCa.
- To establish a prognostic model for PCa based on AR-independent genes.
Main Methods:
- Bioinformatic screening of TCGA transcriptomic data for AR-independent PCa genes.
- Prognostic model development using LASSO Cox regression and validation via co-expression and survival analyses.
- In vitro validation of target gene function and molecular mechanisms.
Main Results:
- XRCC3 was identified as a key AR-independent prognostic factor for PCa, predicting disease-free survival (DFS).
- Higher XRCC3 expression correlated with advanced tumor stage (T3-T4) and poorer DFS.
- Silencing XRCC3 inhibited PCa cell proliferation, migration, and invasion, while promoting apoptosis and activating the p53/Bax signaling pathway.
Conclusions:
- XRCC3 silencing demonstrates anti-PCa effects through AR-independent activation of DNA damage-induced p53/Bax signaling.
- XRCC3 represents a promising therapeutic target for AR-independent PCa treatment.
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