Downregulation of the cytochrome P450 4B1 protein confers a poor prognostic factor in patients with urothelial carcinomas of upper urinary tracts and urinary bladder.

Abstract

The objective of this study was to examine the expression level of cytochrome P450 4B1 (CYP4B1) protein and its clinical significance in specimens from patients with urothelial carcinomas (UC) including upper tract urothelial carcinoma (UTUC, n=340) and urinary bladder urothelial carcinoma (UBUC, n=295). Data mining on public domains identified five potential candidate transcripts which were downregulated in advanced UBUCs, indicating that it might implicate in UC progression. Immunohistochemistry was performed to analyze the CYP4B1 protein levels on 635 tissues from UC patients retrospectively. Immunoexpression of CYP4B1 was further estimated using the H-score method. Correlations between CYP4B1 H-score and important clinicopathological factors, as well as the significance of CYP4B1 expression level for disease-specific and metastasis-free survivals were evaluated. In UTUCs and UBUCs, 118 (34.7%) and 92 (31.2%) patients, respectively, were identified to be of CYP4B1 downregulation. The CYP4B1 expression level was found to be associated with several clinicopathological factors and patient survivals. Downregulation of CYP4B1 protein was correlated to advanced primary tumor (p<0.001), nodal metastasis (p<0.001), high histological grade (p=0.001), vascular invasion (p<0.001), perineural invasion (p=0.017) and mitotic rate (p=0.036) in UTUCs and/or UBUCs. Low CYP4B1 protein level independently predicted inferior disease-specific (p=0.009; p<0.001) and metastasis-free (p=0.035; p<0.001) survivals in UTUC and UBUC patients. Our findings showed that downregulation of CYP4B1 protein level is an independent unfavorable prognosticator. Loss of the CYP4B1 gene expression may play an important role in UC progression.