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

IF 3.1 2区医学 Q2 ONCOLOGY

Cancer Medicine Pub Date : 2025-09-09 DOI:10.1002/cam4.71225

Lin Zhong, Pengxin Zhang, Jialin Ji, Jun Mao, Lianhong Li

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Abstract

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.

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利用转录组测序分析探索程序性死亡配体1 （PD-L1）在去势抵抗性前列腺癌中的功能作用

前列腺癌是威胁人类健康的主要恶性肿瘤之一，去势抵抗的发展往往是其治疗失败的主要原因。方法为了阐明程序性死亡配体1 （programmed death-ligand 1, PD-L1）与前列腺癌去势抵抗之间的潜在关联，我们采用western blot和免疫组织化学方法分析了PD-L1在原发性前列腺癌组织和去势抵抗前列腺癌（CRPC）标本以及相应细胞系中的表达水平。然后，我们通过转录组测序技术探讨了具体的机制。我们的研究结果显示，与邻近的非癌组织相比，PD-L1在原发性前列腺癌中的表达出乎意料地低，但在CRPC组织和细胞中的表达明显升高。在PD-L1被敲除的CRPC细胞系中，观察到其增殖、侵袭和迁移能力受到显著抑制。通过下一代测序技术，我们研究了PD-L1敲低对去势抵抗细胞胞内信号通路的影响。结果表明，PD-L1敲低可导致几种信号通路中基因表达的改变，包括参与细胞表面相互作用、自然杀伤细胞活性调节和钠通道调节活性的信号通路。我们通过实验进一步阐明了PD-L1通过调节SCUBE1的表达促进CRPC的肿瘤进展。更有趣的是，PD-L1敲低似乎也会诱导多个基因中选择性剪接水平的变化。结论PD-L1在CRPC中表达上调，可调节CRPC细胞中多种肿瘤相关基因的表达。最后，我们发现PD-L1通过调节SCUBE1的表达来促进CRPC的肿瘤进展。本研究为理解PD-L1介导的细胞内信号传导提供了理论基础，并为前列腺癌去势抵抗的机制提供了有价值的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.