KISS1 is a metastasis suppressor gene that is lost in several malignancies, including bladder cancer. We tested the epigenetic silencing hypothesis and evaluated the biological influence of KISS1 methylation on its expression and clinical relevance in bladder cancer. KISS1 hypermethylation was frequent in bladder cancer cells analyzed by methylation-specific PCR and bisulfite sequencing and was associated with low gene expression, being restored in vitro by demethylating azacytidine. Hypermethylation was also frequently observed in a large series of bladder tumors (83.1%, n ؍ 804). KISS1 methylation was associated with increasing stage (P ؍ 0.001) and tumor grade (P ؍ 0.010). KISS1 methylation was associated with low KISS1 transcript expression by quantitative RT-PCR (P ؍ 0.037). KISS1 transcript expression was also associated with histopathological tumor stage (P < 0.0005). Low transcript expression alone (P ؍ 0.003) or combined with methylation (P ؍ 0.019) was associated with poor disease-specific survival (n ؍ 205).KISS1 transcript expression remained an independent prognosticator in multivariate analyses (P ؍ 0.017). KISS1 hypermethylation was identified in bladder cancer, providing a potential mechanistic explanation (epigenetic silencing) for the observed loss of KISS1 in uroepithelial malignancies. Associations of KISS1 methylation and its expression with histopathological variables and poor survival suggest the utility of incorporating KISS1 measurement using paraffin-embedded material for tumor stratification and clinical outcome prognosis of patients with uroepithelial neoplasias.
KiSS-1 is a metastasis suppressor gene reported to be involved in the progression of several solid neoplasias. The loss of KiSS-1 gene expression has been shown to be inversely correlated with increasing tumor stage, distant metastases, and poor overall survival in bladder tumors. To identify the molecular pathways associated with the metastasis suppressor role of KiSS-1 in bladder cancer, we carried out a proteomics analysis of bladder cancer cells (EJ138) transiently transfected with a vector encompassing the full-length KiSS-1 gene using an iTRAQ (isobaric tags for relative and absolute quantitation) approach. Protein extracts collected after 24-and 48-h transfection were fractionated and cleaved with trypsin, and the resulting peptides were labeled with iTRAQ reagents. The Bladder cancer represents the fourth most common malignancy among men and the eighth cause of male cancer deaths (1). Bladder cancer can be classified based on the depth of invasion. Clinically, ϳ75% of transitional cell carcinomas (TCCs) 1 are non-muscle-invasive (pTis, pTa, and pT1), 20% are muscle infiltrating (pT2-pT4), and 5% are metastatic at the time of diagnosis (1). Low grade tumors are always papillary and usually non-invasive, whereas high grade tumors can be either papillary or non-papillary and are often invasive. Patients diagnosed with localized TCC have a 5-year relative survival rate over 90%. However, patients presenting with regional and distant metastatic disease spread have 5-year relative survival rates of lower than 50 and 10%, respectively (1). Bladder cancer progression and the development of secondary metastases follow complex sequential steps. The changes at the genetic and/or epigenetic level to the many genes involved in critical cell functions are not completely understood (2).KiSS-1 has been shown to suppress metastases without affecting tumorigenicity in melanoma and breast cancer cells (3-7). It maps to chromosome 1q32 (8) and is regulated by genes mapping to chromosome 6 (3-7). KiSS-1 encodes a 145-amino acid protein, which is processed into kisspeptins of several sizes (9 -11). Kisspeptins have been shown to control the onset of puberty and inhibit cancer metastasis of different tumor types (9 -11). Experimental and clinical studies indicate KiSS-1 to be a functionally active metastasis suppressor gene in several solid tumors (12-19). Molecular profiling analysis revealed that KiSS-1 was lost in advanced cell 1 The abbreviations used are: TCC, transitional cell carcinoma; EF, error factor; FDR, false discovery rate; iTRAQ, isobaric tags for relative and absolute quantitation; RB, retinoblastoma; TP53, tumor protein 53; CI, confidence interval; EV, empty vector; Ct, cycle threshold. Research
Small-cell carcinoma (SCC) of the urinary bladder is an infrequent neoplasia accounting for 0.5% of all tumors located at this level. There is a predilection for males over females with a 4:1 proportion and a median age of 66 years. In most cases, the initial diagnosis is made at the metastatic or progressive stage of the disease. For this study, we collected ten cases of SCC of the urinary bladder, diagnosed over a period of 16 years, to describe the morphological and immunocytochemical characteristics of these infrequent neoplasia. In all cases, clinical data such as age at presentation, personal background, clinical symptoms, stage, treatment, clinical outcome and present status were available. Primary antibodies included chromogranin, neuron-specific enolase, synaptophysin, PGP 9.5, HNK-1, cytokeratin 34betaE12, cytokeratin 20, thyroid transcription factor-1 (TTF-1), c-erbB2 (CB-11), p53 (DO7), and Ki67 (MIB-1). In addition to the expression of neural/neuroendocrine markers, immunostaining for p53 and c-erbB2 was found in 80% and 50% of cases, respectively. In this paper, we confirm the aggressive course of the neoplastic disease. The expression of c-erbB2 in 50% of cases opens up hypothetical new possibilities for the use of immunotherapy in such cases.
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