Huang Tao, Jiao Binbin, Luo Zhenkai, Zhang Xiaolei, Wang Zengjun
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Road, Nanjing, 210029, China.
Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, 100020, China.
Discov Oncol. 2024 Dec 5;15(1):750. doi: 10.1007/s12672-024-01648-z.
Prostate cancer is a major public health challenge for men worldwide, being the second most common cancer diagnosis and the fifth leading cause of cancer-related deaths among men. The etiology of prostate cancer is multifactorial, with age, genetic predispositions, and lifestyle factors playing critical roles. The role of the peroxisome proliferator-activated receptors (PPARs) in prostate cancer remains complex and not fully elucidated.
Transcriptomic data from The Cancer Genome Atlas (TCGA) were utilized for this study. The data were analyzed using single-sample Gene Set Enrichment Analysis (ssGSEA), Gene Ontology (GO) enrichment analysis, KEGG pathway analysis, and Gene Set Enrichment Analysis (GSEA). A prognosis-prediction model was constructed using Cox regression and LASSO analysis. Functional experiments, including Western blotting, quantitative PCR (qPCR), Cell Counting Kit-8 (CCK-8) assays, and EdU incorporation assays, were performed to validate the role of BUD23 in prostate cancer.
Significant differences were observed in the immune microenvironment and HLA gene expression profiles between high and low PPAR expression groups in prostate cancer. The high PPAR group exhibited a less active immune microenvironment with higher fractions of immunosuppressive T regulatory cells (Tregs). A robust prognostic model identified key genes, including BUD23, associated with patient survival. Elevated BUD23 expression was correlated with more aggressive clinical features such as advanced pathological stages, nodal metastasis, and higher Gleason scores. Knockdown of BUD23 in PC-3 and LNCaP prostate cancer cell lines significantly inhibited cell proliferation. Western blotting and qPCR confirmed effective BUD23 knockdown, and CCK-8 and EdU assays demonstrated reduced cell proliferation. BUD23 knockdown resulted in significant reductions in PPAR-α, PPAR-β, and PPAR-γ protein levels, suggesting a regulatory axis between BUD23 and PPARs in prostate cancer.
The study highlights the distinct roles of PPARα, PPARβ/δ, and PPARγ in prostate cancer progression and their potential as therapeutic targets. Elevated BUD23 expression is associated with aggressive prostate cancer features and patient survival, making it a potential prognostic biomarker. The knockdown of BUD23 not only inhibited cell proliferation but also reduced the expression of PPAR-related proteins, indicating a potential regulatory axis between BUD23 and PPARs. These findings suggest that targeting BUD23 could modulate PPAR signaling and inhibit tumor growth in prostate cancer.
前列腺癌是全球男性面临的一项重大公共卫生挑战，是第二常见的癌症诊断类型，也是男性癌症相关死亡的第五大主要原因。前列腺癌的病因是多因素的，年龄、遗传易感性和生活方式因素起着关键作用。过氧化物酶体增殖物激活受体（PPARs）在前列腺癌中的作用仍然复杂且尚未完全阐明。
本研究利用了来自癌症基因组图谱（TCGA）的转录组数据。使用单样本基因集富集分析（ssGSEA）、基因本体（GO）富集分析、KEGG通路分析和基因集富集分析（GSEA）对数据进行分析。使用Cox回归和LASSO分析构建预后预测模型。进行了包括蛋白质免疫印迹、定量聚合酶链反应（qPCR）、细胞计数试剂盒-8（CCK-8）测定和EdU掺入测定在内的功能实验，以验证BUD23在前列腺癌中的作用。
在前列腺癌中，高PPAR表达组和低PPAR表达组之间的免疫微环境和HLA基因表达谱存在显著差异。高PPAR组表现出免疫微环境活性较低，免疫抑制性调节性T细胞（Tregs）比例较高。一个强大的预后模型确定了与患者生存相关的关键基因，包括BUD23。BUD23表达升高与更具侵袭性的临床特征相关，如晚期病理阶段、淋巴结转移和更高的Gleason评分。在PC-3和LNCaP前列腺癌细胞系中敲低BUD23可显著抑制细胞增殖。蛋白质免疫印迹和qPCR证实了BUD23的有效敲低，CCK-8和EdU测定表明细胞增殖减少。敲低BUD23导致PPAR-α、PPAR-β和PPAR-γ蛋白水平显著降低，表明前列腺癌中BUD23与PPARs之间存在调节轴。
该研究突出了PPARα、PPARβ/δ和PPARγ在前列腺癌进展中的不同作用及其作为治疗靶点的潜力。BUD23表达升高与侵袭性前列腺癌特征和患者生存相关，使其成为一种潜在的预后生物标志物。敲低BUD23不仅抑制细胞增殖，还降低了PPAR相关蛋白的表达，表明BUD23与PPARs之间存在潜在的调节轴。这些发现表明，靶向BUD2�可以调节PPAR信号并抑制前列腺癌中的肿瘤生长。
