Int J Clin Exp Pathol 2014;7(4):1695-1701 www.ijcep.com /ISSN:1936-2625/IJCEP1401041

Original Article SKIP expression is correlated with clinical prognosis in patients with bladder cancer Longwang Wang1*, Mei Zhang2*, Yong Wu1, Cheng Cheng1, Yawei Huang1, Zimin Shi1, Hongwei Huang1 Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; 2Department of Neurology, Wuhan Central Hospital, Hubei Province, 430014, China. *Equal contributors. 1

Received January 13, 2014; Accepted February 26, 2014; Epub March 15, 2014; Published April 1, 2014 Abstract: The Ski-interacting protein (SKIP) is a transcriptional cofactor distinct from other cofactors and is involved in regulation of many cancer-related proteins. However, its distribution and clinical significances in bladder cancer remains poorly understood. In this study, Quantitative real-time PCR and immunohistochemistry were performed to detect the expression of SKIP in clinical bladder cancer samples. In addition, the correlation of SKIP expression and clinicopathological features and clinical outcomes were analyzed. The expression levels of SKIP in clinical bladder cancer were much higher than that in paired adjacent noncancerous tissues. High expression of SKIP was closely related with histological grades and the poor prognosis of bladder cancer. Based on our data, we speculated that SKIP may be a potential prognostic marker in bladder cancer. Keywords: SKIP expression, prognosis, bladder cancer

Introduction Bladder cancer is the first and second most common malignancy of the urinary system in China and the USA, respectively [1]. Approximately 75% of patients with bladder cancer present as non-muscle invasive cancer (NMIBC) and the remaining 25% of BCs are muscle-invasive bladder cancer (MIBC) [2]. Although great progress has been made in the diagnosis and treatment of bladder cancer, tumor recurrence is still an annoying clinical problem. The reported recurrence rates of NMIBC after transurethral resection of bladder tumor (TUR-BT) are 10%~67% in 12 months [3, 4] and the cumulative 5-yr mortality rate is up to 30.2% [5]. Currently, there are no reliable biomarkers to predict the risk of recurrence and the prognosis of bladder cancer [6]. SKIP was originally found as a binding partner of the viral oncogene v-Ski in a yeast two-hybrid system. It was demonstrated to interact with a highly conserved region of Ski, which is thought to be important for Ski’s transforming activity [7]. Previous studies have shown that SKIP can combine with pRb to form a highly stable complex, which effectively inhibit pRb-induced tran-

scriptional repression and induce cell cycle activation [8]. SKIP also binds to Smad2,3 to enhance TGF-β-dependent transcription and may regulate cell growth and differentiation through the TGF-β pathway [9]. In addition, SKIP significantly overcomes both TGF-β1-induced uPA and MMP-9 promoter transactivation in the androgen-independent human prostate cancer cells [10]. Overall, these studies suggested that SKIP was a required transcriptional coactivator for many newly induced genes, which include interactions with VDR and RXR in a tripartite complex with SRCs [11], with androgen receptor in the nucleus and enhances AR-dependent transactivation, and so on [12]. Thus, SKIP appears to modulate a number of key signalling pathways involved in cell proliferation and differentiation, and as such may play a role in oncogenesis and tumor development. These properties of SKIP may become a novel therapeutic target in bladder cancer treatment. In the present study, we detected the expression of SKIP protein in clinical low and highgrade urothelial carcinoma samples, and the mRNA expression of SKIP in both bladder cancer and adjacent noncancerous tissues. In addition, we investigated the relationship of the

SKIP is a prognostic marker in bladder cancer Table 1. Expression of SKIP expression in bladder cancer patients according to clinicopathologic characteristics Expression of SKIP expression in bladder cancer patients according to clinicopathologic characteristics NO SKIP expression p High N (%) Low N (%) Sex 1.000 Male 55 17 38 Female 15 5 10 Age (y) 0.128 ≤45 9 5 4 >45 61 17 44 Differentiation 0.001* Grade 1/2 51 10 41 Grade 3 19 12 7 Tumor types 0.731 NMIBC 59 18 41 MIBC 11 4 7 Distant metastasis 0.448 61 18 43 + 9 4 5 Recurrence 0.004* 38 6 32 + 32 16 16 Statistical analyses were performed by the Pearson χ2 test * P45 vs ≤45) Differentiation (Grade 3 vs 1/2) SKIP (+ vs -)

OS Hazard ratio (95% CI) 1.117 (0.294-4.237) 1.019 (0.214-4.859) 6.338 (1.333-30.131)

P 0.981 0.871 0.020*

RFS Hazard ratio (95% CI) 1.248 (0.430-3.619) 1.133 (0.487-2.634) 2.697 (1.161-6.264)

P 0.683 0.772 0.021*

Statistical analyses were performed by the Cox regression analysis *P