Sulfatase-1 overexpression indicates poor prognosis in urothelial carcinoma of the urinary bladder and upper tract.

Wei-Ming Li,Hung-Lung Ke,Bi-Wen Yeh,Chien-Feng Li,Ching-Chia Li,Wen-Jeng Wu,Hsiang-Ying Lee,Hsin-Chih Yeh,Peir-In Liang,Chun-Nung Huang,Kei-Fu Yang,Yow-Ling Shiue,Ti-Chun Chan

doi:10.18632/oncotarget.17590

Abstract

Urothelial carcinoma (UC), arising from the urothelium of the urinary tract, can occur in the upper (UTUC) and the urinary bladder (UBUC). A representative molecular aberration for UC characteristics and prognosis remains unclear. Data mining of Gene Expression Omnibus focusing on UBUC, we identified sulfatase-1 (SULF1) upregulation is associated with UC progression. SULF1 controls the sulfation status of heparan sulfate proteoglycans and plays a role in tumor growth and metastasis, while its role is unexplored in UC. To first elucidate the clinical significance of SULF1 transcript expression, real-time quantitative RT-PCR was performed in a pilot study of 24 UTUC and 24 UBUC fresh samples. We identified that increased SULF1 transcript abundance was associated with higher primary tumor (pT) status. By testing SULF1 immunoexpression in independent UTUC and UBUC cohorts consisted of 340 and 295 cases, respectively, high SULF1 expression was significantly associated with advanced pT and nodal status, higher histological grade and presence of vascular invasion in both UTUC and UBUC. In multivariate survival analyses, high SULF1 expression was independently associated with worse DSS (UTUC hazard ratio [HR] = 3.574, P < 0.001; UBUC HR = 2.523, P = 0.011) and MeFS (UTUC HR = 3.233, P < 0.001; UBUC HR = 1.851, P = 0.021). Furthermore, depletion of SULF1 expression by using RNA interference leaded to impaired cell proliferative, migratory, and invasive abilities in vitro. In addition, we further confirmed oncogenic role of SULF1 with gain-of function experiments. In conclusion, our findings implicate the oncogenic role of SULF1 expression in UC, suggesting SULF1 as a prognostic and therapeutic target of UC.

Highlights

Urothelial carcinomas (UCs) arising from the transitional epithelium of the urinary tract are the fourth most common tumors after prostate, lung and colorectal cancers [1]
Data mining of Gene Expression Omnibus focusing on urinary bladder UCs (UBUCs), we identified sulfatase-1 (SULF1) upregulation is associated with UC progression
Using data mining from published transcriptomic datasets of UBUCs (GSE31684 and GSE32894), SULF1 and SULF2 were identified as significant genes showing upregulation during tumor progression among those associated with the heparan sulfate proteoglycan metabolic process (GO:0030201) (Figure 1, Supplementary Figure 1 and Table 1, Supplementary Table 1)

Summary

Introduction

Urothelial carcinomas (UCs) arising from the transitional epithelium of the urinary tract are the fourth most common tumors after prostate (or breast), lung and colorectal cancers [1]. These carcinomas grow in the upper urinary tract (pyelocaliceal cavities and ureter) or lower urinary tract (bladder and urethra). Bladder cancer is the most common malignancy of the urinary tract and accounts for 90–95% of UCs [2]. Upper tract urothelial carcinomas (UTUCs) are relatively rare compared with urinary bladder UCs (UBUCs) in Western society [3]. Identification of novel prognostic molecular markers for UC development and progression is needed

Methods

Results

Conclusion