Abstract
Abstract Cysteine-rich 61 (CYR61) is involved in development and progression in different types of human cancer. Nonetheless, the role of CYR61 in bladder cancer has not been reported. In this study, we explored CYR61 expression in tumor tissues of urothelial carcinoma of bladder and evaluated its diagnostic potential for the muscle invasive bladder cancer in preoperative urine. The global gene expression analysis was applied with the tumor tissues of 16 non-muscle invasive bladder cancers (NMIBCs) and 14 muscle invasive bladder cancers (MIBCs) using microarrays (the Agilent). After bioinformatic analysis, 10 genes that their expression signatures showed significant differences between the invasive and non-invasive tumors were selected, and then verified using RT-qPCR in the aforementioned 30 bladder cancer samples. Seven out of the10 genes was further validated in an independent cohort of 54 bladder cancers (32 NMIBCs and 22 MIBCs). Among the 4 genes that sustained significantly associated with tumor invasiveness through the validation, CYR61 was investigated in protein level by immunohistochemistry (IHC) staining in 115 formalin-fixed paraffin-embedded tumor tissues (59 NMIBCs and 56 MIBCs); followed by enzyme-linked immune sorbent assay (ELISA) applied in preoperative urine sample of 104 patients with bladder cancer (21 NMIBCs and 83 MIBCs). The mRNA transcription of CYR61 was significantly up-regulated in tumor tissues of MIBCs compared to those NMIBCs (fold change>2.0 and P value < 0.001) in both the discovery phase (microarray study) and the validation phase. The IHC staining further confirmed that expression of CYR61 protein was significantly associated with MIBCs. An intensive expression of CYR61 was observed in 64.9% of MIBCs, but in only 17.2% of NMIBCs (p = 0.001). On the other hand, we did not find any association between CYR61 expression and other analyzed clinicopathologic parameters, such as tumor size, tumor grade, tumor recurrence, patient's age, gender, drinking or smoking. CYR61 protein levels in the urine collected from the preoperative patients were determined by ELISA and measured as the ratio of urinary creatinine. We found an average 2.5 fold CYR61 urinary content in the MIBCs than that in the NMIBCs (10.48±9.36 ng/mg VS 4.12±2.26 ng/mg, p<0.001). Urinary CYR61 had 87.0% sensitivity and 61.7% specificity to predicate MIBCs (AUC 0.815, 95% CI 0.722-0.908, p<0.001). In conclusion, aberrant over-expression of CYR61 was associated with muscle invasion of bladder urothelial carcinoma in both mRNA and protein levels. The abundance of CYR61 protein in urine sample could be a potential biomarker for preoperatively differentiating MIBCs or NMIBCs, while its merits still need further investigation in large cohorts of the bladder cancer. Citation Format: Huang Chen, Jianzhong Shou, Yu Liu, Wei Zheng, Hao Xi, Jianhui Ma, Yan ning Gao. Aberrant expression of CYR61 in bladder cancer and its preoperative diagnostic potential in muscle invasive bladder cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 552. doi:10.1158/1538-7445.AM2015-552
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