Al Shareef Zainab, Hachim Mahmood Y, Bouzid Amal, Talaat Iman M, Al-Rawi Natheer, Hamoudi Rifat, Hachim Ibrahim Y
Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
Front Mol Biosci. 2024 May 24;11:1351888. doi: 10.3389/fmolb.2024.1351888. eCollection 2024.
Prostate cancer (PCa) is considered one of the most common cancers worldwide. Despite advances in patient diagnosis, management, and risk stratification, 10%-20% of patients progress to castration-resistant disease. Our previous report highlighted a protective role of Dickkopf-3 (DKK3) in PCa stroma. This role was proposed to be mediated through opposing extracellular matrix protein 1 (ECM-1) and TGF-β signalling activity. However, a detailed analysis of the prognostic value of DKK3, ECM-1 and members of the TGF-β signalling pathway in PCa was not thoroughly investigated. In this study, we explored the prognostic value of DKK3, ECM-1 and TGFB1 using a bioinformatical approach through analysis of large publicly available datasets from The Cancer Genome Atlas Program (TGCA) and Pan-Cancer Atlas databases. Our results showed a significant gradual loss of expression with PCa progression ( < 0.0001) associated with increased DNA methylation in its promoter region ( < 1.63E-12). In contrast, patients with metastatic lesions showed significantly higher levels of expression compared to primary tumours ( < 0.00001). Our results also showed a marginal association between more advanced tumour stage presented as positive lymph node involvement and low mRNA expression ( = 0.082). However, while showed no association with tumour stage ( = 0.773), high expression showed a significant association with more advanced stage presented as advanced T3 stage compared to patients with low mRNA expression ( < 0.001). Interestingly, while showed no significant association with patient outcome, patients with high mRNA expression showed a significant association with favourable outcomes presented as prolonged disease-specific ( = 0.0266), progression-free survival ( = 0.047) and disease-free ( = 0.05). In contrast, high mRNA expression showed a significant association with poor patient outcomes presented as shortened progression-free ( = 0.00032) and disease-free survival ( = 0.0433). Moreover, and have acted as immune-associated genes in the PCa tumour microenvironment. In conclusion, our findings showed a distinct prognostic value for this three-gene signature in PCa. While both DKK3 and TGFB1 showed a potential role as a clinical marker for PCa stratification, ECM1 showed no significant association with the majority of clinicopathological parameters, which reduce its clinical significance as a reliable prognostic marker.
前列腺癌（PCa）被认为是全球最常见的癌症之一。尽管在患者诊断、管理和风险分层方面取得了进展，但仍有10%-20%的患者进展为去势抵抗性疾病。我们之前的报告强调了Dickkopf-3（DKK3）在PCa基质中的保护作用。该作用被认为是通过对抗细胞外基质蛋白1（ECM-1）和转化生长因子-β（TGF-β）信号活性来介导的。然而，对DKK3、ECM-1和TGF-β信号通路成员在PCa中的预后价值的详细分析尚未得到充分研究。在本研究中，我们通过分析来自癌症基因组图谱计划（TGCA）和泛癌图谱数据库的大量公开可用数据集，采用生物信息学方法探讨了DKK3、ECM-1和TGFB1的预后价值。我们的结果显示，随着PCa进展，表达显著逐渐丧失（<0.0001），这与其启动子区域DNA甲基化增加有关（<1.63E-12）。相比之下，有转移病灶的患者与原发性肿瘤相比，表达水平显著更高（<0.00001）。我们的结果还显示，以阳性淋巴结受累为表现的更晚期肿瘤阶段与低mRNA表达之间存在边缘关联（=0.082）。然而，虽然与肿瘤分期无关联（=0.773），但与低mRNA表达的患者相比，高表达与以T3晚期为表现的更晚期阶段存在显著关联（<0.001）。有趣的是，虽然与患者预后无显著关联，但高mRNA表达的患者与以延长疾病特异性生存期（=0.0266）、无进展生存期（=0.047）和无病生存期（=0.05）为表现的良好预后存在显著关联。相比之下，高mRNA表达与以缩短无进展生存期（=0.00032）和无病生存期（=0.0433）为表现的不良患者预后存在显著关联。此外，和在PCa肿瘤微环境中作为免疫相关基因发挥作用。总之，我们的研究结果显示了这三个基因特征在PCa中具有独特的预后价值。虽然DKK3和TGFB1都显示出作为PCa分层临床标志物的潜在作用，但ECM1与大多数临床病理参数无显著关联，这降低了其作为可靠预后标志物的临床意义。
