Exploring the Functional Role of Programmed Death-Ligand 1 (PD-L1) in the Castration-Resistant Prostate Cancer Using Transcriptomic Sequencing Analysis.

[BACKGROUND] Prostate cancer is one of the principal malignancies threatening human health, and the development of castration resistance often constitutes a major cause of treatment failure in its management.

[METHODS] To elucidate the potential association between programmed death-ligand 1 (PD-L1) and castration resistance in prostate cancer, we analyzed the expression levels of PD-L1 in both primary prostate cancer tissues and castration-resistant prostate cancer (CRPC) specimens as well as in corresponding cell lines by using western blots and immunohistochemistry. Then, we explored the specific mechanisms through transcriptomic sequencing technology.

[RESULTS] Our findings revealed that, compared to adjacent non-cancerous tissue, PD-L1 expression was unexpectedly lower in primary prostate cancer but notably elevated in CRPC tissues and cells. In CRPC cell lines where PD-L1 was knocked down, a significant suppression of proliferation, invasion, and migration capabilities was observed. By employing next-generation sequencing technology, we investigated the impact of PD-L1 knockdown on intracellular signaling pathways in castration-resistant cells. The results demonstrated that PD-L1 knockdown led to alterations in gene expression within several signaling pathways, including those involved in cell surface interactions, regulation of natural killer cell activity, and sodium channel regulatory activity. We further elucidated through experimentation that PD-L1 contributes to tumor progression in CRPC by modulating the expression of SCUBE1. More intriguingly, PD-L1 knockdown also appeared to induce changes at the level of alternative splicing in multiple genes.

[CONCLUSIONS] PD-L1 is upregulated in CRPC and can modulate the expression of multiple tumor-associated genes in CRPC cells. Finally, we found that PD-L1 contributes to tumor progression in CRPC by modulating the expression of SCUBE1. This study provides a theoretical basis for understanding the intracellular signaling mediated by PD-L1 and offers valuable insights into the mechanisms underlying castration resistance in prostate cancer.