RESUMEN
BACKGROUND: Aberrant activation of phosphorylated form of glycogen synthase kinase-3ß [pS9GSK-3ß (Serine 9 phosphorylation)] is known to trigger Wnt/ß-catenin signal cascade but its clinicohistopathological implications in bladder carcinogenesis remain unknown. AIM: To investigate the diagnostic and prognostic relevance of expressions of pS9GSK-3ß, ß-catenin and its target genes in the pathobiology of bladder cancer. METHODS: Bladder tumor tissues from ninety patients were analyzed for quantitative expression and cellular localization of pS9GSK-3ß by immunohistochemical (IHC) staining. Real time-quantitative polymerase chain reaction and IHC were done to check the expression of ß-catenin, Cyclin D1, Snail and Slug at transcriptome and protein level respectively. Clinicohistopathological variables were obtained from histology reports, follow up and OPD visits of patients. Expressions of the markers were statistically correlated with these variables to determine their significance in clinical setting. Results were analysed using SPSS 20.0 software. RESULTS: Aberrant (low or no membranous/high nuclear/high cytoplasmic) expression of pS9GSK-3ß was noted in 51% patients and found to be significantly associated with tumor stage and tumor grade (P = 0.01 and 0.04; Mann Whitney U test). Thirty one percent tumors exhibited aberrant co-expression of pS9GSK-3ß and ß-catenin proteins and showed strong statistical association with tumor stage, tumor type, smoking/tobacco chewing status (P = 0.01, 0.02 and 0.04, Mann-Whitney U test) and shorter overall survival probabilities of patients (P = 0.02; Kaplan Meier test). Nuclear immunostaining of Cyclin D1 in tumors with altered pS9GSK-3ß/ß-catenin showed relevance with tumor stage, grade and type. CONCLUSION: ß-catenin and pS9GSK-3ß proteins are identified as markers of diagnostic/prognostic significance in disease pathogenesis. Observed histopathological association of Cyclin D1 identifies it as marker of potential relevance in tumors with altered pS9GSK-3ß/ß-catenin.
RESUMEN
Urothelial carcinoma of the bladder (UCB) shows different biological outcomes, diverse biological propensities for invading the muscularis as well as epithelial-to-mesenchymal transition (EMT), a dynamic key event during developmental processes, wound healing, and tissue repair. The EMT core molecules include EMT-activating transcription factors (EMT-ATFs), and a host of downstream effectors and target genes including extracellular inducers and growth factors. Here, we describe molecular regulatory determinants of mesenchymal-to-epithelial transition (MET) and more specifically EMT that allows a subset of urothelial cancer cells to gain mesenchymal traits with self-renewal potential. EMT accelerates tumor progression and poses a clinical challenge to anticancer therapies. Targeting the populations of tumor-initiating cells and those with a metastable phenotype provide the basis for the development of more reliable risk assessment of tumor progression and risk, and better treatment strategies of UCB.
Asunto(s)
Carcinoma de Células Transicionales/etiología , Transición Epitelial-Mesenquimal , Neoplasias de la Vejiga Urinaria/etiología , Animales , Carcinogénesis , HumanosRESUMEN
INTRODUCTION: Epithelial-to-mesenchymal transition (EMT) is a dynamic process in the pathogenesis of urinary bladder cancer. Despite significant advancements in its diagnosis and treatment, the outcomes have more or less remained the same. In the present study, the expression of EMT markers was investigated to evaluate its prognostic significance in patients with non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: The present study was undertaken to examine the expression of EMT markers, including E-cadherin, N-cadherin, vimentin, Snail, Twist, Zeb, and Slug, on 28 bladder tumor tissues (15 cases of NMIBC and 13 of MIBC) using reverse transcription-polymerase chain reaction. Immunohistochemical (IHC) staining was performed to check the protein expression and localization of E-cadherin, N-cadherin, vimentin, Snail, and Slug. RESULTS: At the message level, reduced expression of E-cadherin correlated with gender (P = .004), enhanced expression of N-cadherin correlated with stage and age (P = .02, for both), and increased expression of EMT transcription factors correlated significantly with stage, grade, or age. Inverse correlation of reduced levels of E-cadherin were observed with new expression of N-cadherin (P = .001; Mann-Whitney U test) and vimentin (P = .001; Mann-Whitney U test). On IHC, novel expression of vimentin and N-cadherin was associated with enhanced expression of Snail and Slug (P = .005; Wilcoxon signed rank test). CONCLUSION: Molecular validation of the EMT marker profile proved to be a sensitive and an effective prognostic tool for objective and systematic investigation of EMT function in the pathogenesis of urinary bladder cancer. Nevertheless, further studies are required with a greater number of clinical samples.