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. 2003 Feb;162(2):609-17.
doi: 10.1016/S0002-9440(10)63854-0.

Tumor suppressor role of KiSS-1 in bladder cancer: loss of KiSS-1 expression is associated with bladder cancer progression and clinical outcome

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Tumor suppressor role of KiSS-1 in bladder cancer: loss of KiSS-1 expression is associated with bladder cancer progression and clinical outcome

Marta Sanchez-Carbayo et al. Am J Pathol. 2003 Feb.

Abstract

The expression profiles of nine bladder cancer cell lines were compared against a pool containing equal total RNA quantities of each of them. Lower expression of KiSS-1 was revealed in cells derived from the most advanced bladder tumors. When comparing 15 primary bladder tumors versus a pool of four bladder cancer cell lines, lower transcript levels of KiSS-1 were observed in the invasive bladder carcinomas as compared to superficial tumors. KiSS-1 expression ratios provided prognostic information. The expression pattern of KiSS-1 transcripts was analyzed using in situ hybridization in nine bladder cancer cells, paired normal urothelium and bladder tumor samples (n = 25), and tissue microarrays of bladder tumors (n = 173). We observed complete loss of KiSS-1 in all invasive tumors under study as compared to their respective normal urothelium. The expression of KiSS-1 was found to be significantly associated with histopathological stage. Patients with lower KiSS-1 expression showed a direct correlation with overall survival in a subset of bladder tumors whose follow-up was available (n = 69). We did not observe any significant differential KiSS-1 expression along cell cycle by sorting analysis. A potential tumor suppressor role in bladder cancer was revealed for KiSS-1. Moreover, it showed predictive value by identifying patients with poor outcome.

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Figures

Figure 1.
Figure 1.
Kaplan-Meier curves obtained from the survival analysis of R/G ratios of KiSS-1 in the patients with bladder tumors to whom cDNA microarrays were performed. Low expression of KiSS-1 is represented by bladder tumors displaying a R/G ratio <1.5 versus those patients with high expression of KiSS-1 and R/G ratio >1.5. KiSS-1 was found to be significantly associated with overall survival in this subset of 15 bladder lesions whose expression profiles were analyzed (P = 0.008) (median follow-up time, 2 months). No association with overall survival was found for the R/G ratios of 6q16.2-21.
Figure 2.
Figure 2.
Representative expression patterns of KiSS-1 in normal urothelium (A), and transitional superficial (B) and invasive (C) bladder tumors. High expression levels of KiSS-1 were observed in normal urothelium and superficial bladder tumors as compared to the invasive bladder tumor. There was a significant difference regarding the expression of KiSS-1 regarding tumor stage and grade. Original magnifications, ×200.
Figure 3.
Figure 3.
Kaplan-Meier curve obtained from the survival analysis of the expression of KiSS-1 in a subset of 69 bladder lesions contained in a tissue microarray. KiSS-1 expression was analyzed by in situ hybridization in this separate subset of patients whose median follow-up time of 36 months. KiSS-1 was found to be significantly associated with overall survival (P = 0.03).
Figure 4.
Figure 4.
A: Distribution of cell-cycle phases obtained from the cell-sorting analysis of RT4 and SCaBER. Cell-cycle-specific cytospins including cell-cycle subpopulations were obtained to evaluate the expression of KiSS-1 along cell cycle by in situ hybridization. B: Representative patterns of KiSS-1 in bladder cancer cell lines under study by in situ hybridization derived from a transitional superficial tumor (RT4) and a squamous bladder tumor (SCaBER). No differential expression of KiSS-1 by in situ hybridization was observed in these sorted cells spotted on cytospins containing enriched populations of each cell cycle phase. Original magnifications, ×200.

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