Published online Apr 24, 2019. doi: 10.5306/wjco.v10.i4.166
Peer-review started: December 3, 2018
First decision: December 30, 2018
Revised: January 25, 2019
Accepted: February 27, 2019
Article in press: February 28, 2019
Published online: April 24, 2019
Aberrant activation of phosphorylated form of glycogen synthase kinase-3β [pS9GSK-3β (Serine 9 phosphorylation)] is known to trigger Wnt/β-catenin signal cascade but its clinicohistopathological implications in bladder carcinogenesis remain unknown.
To investigate the diagnostic and prognostic relevance of expressions of pS9GSK-3β, β-catenin and its target genes in the pathobiology of bladder cancer.
Bladder tumor tissues from ninety patients were analyzed for quantitative expression and cellular localization of pS9GSK-3β by immunohistochemical (IHC) staining. Real time-quantitative polymerase chain reaction and IHC were done to check the expression of β-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.
Aberrant (low or no membranous/high nuclear/high cytoplasmic) expression of pS9GSK-3β 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-3β and β–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-3β/β–catenin showed relevance with tumor stage, grade and type.
β–catenin and pS9GSK-3β 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-3β/β-catenin.
Core tip: Aberrant co-expression of phosphorylated form of glycogen synthase kinase-3β (pS9GSK-3β) and β–catenin proteins and their association with tumor stage, tumor type, smoking/tobacco chewing status and shorter overall survival probabilities of urinary bladder cancer patients validate them as potential markers of diagnostic/prognostic significance in disease pathogenesis. Observed histopathological association of nuclear Cyclin D1 identifies it as a marker of potential relevance in tumors with altered pS9GSK-3β/β-catenin proteins. These results rule out the possible post translational activation of target genes examined, by pS9GSK-3β/β-catenin/T-cell factor/lymphoid enhancer factor transcriptional complex in bladder tumorigenesis.