DHCR24 is an Independent Predictor of Progression in Patients with Non-Muscle-Invasive Urothelial Carcinoma, and Its Functional Role is Involved in the Aggressive Properties of Urothelial Carcinoma Cells
The DHCR24 gene that encodes 3b-hydroxysterol Δ24-reductase, an oxidoreductase involved in cholesterol biosynthesis, has been identified as a progression-related gene based on the quantitative real-time PCR (qPCR) gene signature. Here, the functional role of DHCR24 and its clinical relevance in non-muscle-invasive urothelial carcinoma (NMIUC) were investigated.
Primary NMIUC tissue specimens (n = 162) were analyzed by qPCR. Immunohistochemical staining was also performed on 63 subsets of NMIUC tissues. The present study was also undertaken in order to verify the effect of DHCR24 on human urothelial carcinoma cells.
The mRNA expression levels of DHCR24 were significantly higher for patients in with higher grades of tumors than for those with lower grades of tumors (P = 0.003). Kaplan–Meier estimates revealed significant differences in the time to progression between low- and high-mRNA expression groups (log-rank test, P < 0.001). Multivariate Cox regression analysis revealed that the level of DHCR24 expression is an independent predictor of progression (hazard ratio, 5.464; 95 % confidence interval, 1.746–17.099; P = 0.004). The results of immunohistochemical staining were generally concordant with mRNA expression levels. Enforced expression of DHCR24 caused proliferation, adhesion, and migration, while DHCR24 loss resulted in slower proliferation and a reduction in cell viabilities compared with control cells.
DHCR24 was found to be closely associated with progression among patients with NMIUC and showed aggressive properties in human UC cells.
KeywordsHT1376 Cell SW780 Cell Urothelial Carcinoma Desmosterol U18666A
This work was supported in part by a grant from the National Cancer Institute (P30CA072720). It was also supported in part by generous grants from the Tanzman Foundation, Jon Runyan’s Score for the Cure, and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education Science and Technology (2008–0062611) and supported by a grant from the Next-Generation BioGreen 21 Program (PJ009621), Rural Development Administration, Republic of Korea. The biospecimens for this study were provided by the Chungbuk National University Hospital, a member of the National Biobank of Korea, which is supported by the Ministry of Health, Welfare and Family Affairs. All samples derived from the National Biobank of Korea were obtained with informed consent under institutional review board–approved protocols.
The authors declare no conflict of interest.
- 16.Sobin LH, Gospodariwicz M, Wittekind C (eds). TNM classification of malignant tumors. UICC International Union Against Cancer,7th Edition. Wiley-Blackwell, 2009Google Scholar
- 19.Huang WC, Chan ST, Yang TL, Tzeng CC, Chen CC. Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel alpha-methylene-gamma-butyrolactone derivatives. Carcinogenesis. 2004;25:1925–34.PubMedCrossRefGoogle Scholar
- 20.Oh JH, Park EJ, Park JW, Lee J, Lee SH, Kwon TK. A novel cyclin-dependent kinase inhibitor down-regulates tumor necrosis factor-alpha (TNF-alpha)-induced expression of cell adhesion molecules by inhibition of NF-kappaB activation in human pulmonary epithelial cells. Int Immunopharmacol. 2010;10:572–9.PubMedCrossRefGoogle Scholar
- 22.Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49:466–5.PubMedCrossRefGoogle Scholar