AUTHOR=Al Shareef Zainab , Hachim Mahmood Y. , Bouzid Amal , Talaat Iman M. , Al-Rawi Natheer , Hamoudi Rifat , Hachim Ibrahim Y. 

TITLE=The prognostic value of Dickkopf-3 (Dkk3), TGFB1 and ECM-1 in prostate cancer

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=11

YEAR=2024

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2024.1351888

DOI=10.3389/fmolb.2024.1351888

ISSN=2296-889X

ABSTRACT=<p>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 <italic>DKK3</italic> expression with PCa progression (<italic>p</italic> &lt; 0.0001) associated with increased DNA methylation in its promoter region (<italic>p</italic> &lt; 1.63E-12). In contrast, patients with metastatic lesions showed significantly higher levels of <italic>TGFB1</italic> expression compared to primary tumours (<italic>p</italic> &lt; 0.00001). Our results also showed a marginal association between more advanced tumour stage presented as positive lymph node involvement and low <italic>DKK3</italic> mRNA expression (<italic>p</italic> = 0.082). However, while <italic>ECM1</italic> showed no association with tumour stage (<italic>p</italic> = 0.773), high <italic>TGFB1</italic> expression showed a significant association with more advanced stage presented as advanced T3 stage compared to patients with low <italic>TGFB1</italic> mRNA expression (<italic>p</italic> &lt; 0.001). Interestingly, while <italic>ECM1</italic> showed no significant association with patient outcome, patients with high <italic>DKK3</italic> mRNA expression showed a significant association with favourable outcomes presented as prolonged disease-specific (<italic>p</italic> = 0.0266), progression-free survival (<italic>p</italic> = 0.047) and disease-free (<italic>p</italic> = 0.05). In contrast, high <italic>TGFB1</italic> mRNA expression showed a significant association with poor patient outcomes presented as shortened progression-free (<italic>p</italic> = 0.00032) and disease-free survival (<italic>p</italic> = 0.0433). Moreover, <italic>DKK3, TGFB1</italic> and <italic>ECM1</italic> 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.</p>