Retrospective Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Apr 24, 2019; 10(4): 166-182
Published online Apr 24, 2019. doi: 10.5306/wjco.v10.i4.166
Clinicohistopathological implications of phosphoserine 9 glycogen synthase kinase-3β/ β-catenin in urinary bladder cancer patients
Niharika Maurya, Rinni Singh, Apul Goel, Atin Singhai, Uday Pratap Singh, Vinita Agrawal, Minal Garg
Niharika Maurya, Rinni Singh, Minal Garg, Department of Biochemistry, Lucknow University, Lucknow 226007, India
Apul Goel, Department of Urology, King George Medical University, Lucknow 226003, India
Atin Singhai, Department of Pathology, King George Medical University, Lucknow 226003, India
Uday Pratap Singh, Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
Vinita Agrawal, Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
Author contributions: All authors contributed to this paper; all the authors have agreed with the submission in its present form.
Institutional review board statement: Studies were approved by the appropriate institutional research ethics committee and were performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Ethical clearance was obtained from Bioethics Cell, Institutional Ethics Committee (IEC), KGMU (Reference no. 77th ECM II A/P14) and SGPGIMS (Reference no. 2014-166-CP-80), Lucknow, India.
Informed consent statement: Subjects were not required to give informed consent to the study because the analysis used anonymous data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: All the authors of the study declare no potential conflict-of-interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Minal Garg, MSc, PhD, Assistant Professor, Department of Biochemistry, Lucknow University, Lucknow 226007, India. minal14@yahoo.com
Telephone: +91-522-2348968 Fax: +91-522-2348968
Received: December 2, 2018
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
Abstract
BACKGROUND

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.

AIM

To investigate the diagnostic and prognostic relevance of expressions of pS9GSK-3β, β-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-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.

RESULTS

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.

CONCLUSION

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.

Keywords: Pathobiology, Target genes, Tumor stage and grade, Wnt/β–catenin signal cascade, Urothelial carcinoma of bladder

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.