A nuclear shift of GSK3β protein is an independent prognostic factor in prostate cancer
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Till Eichenauer1,2,*, Mohammad Hussein1,*, Claudia Hube-Magg1, Martina Kluth1, Franziska Büscheck1, Doris Höflmayer1, Maria Christina Tsourlakis1, Stefan Steurer1, Till S. Clauditz1, Andreas M. Luebke1, Eike Burandt1, Waldemar Wilczak1, Andrea Hinsch1, David Dum1, Burkhard Beyer3, Thomas Steuber3, Hartwig Huland3, Markus Graefen3, Ronald Simon1, Guido Sauter1, Nathaniel Melling4, Thorsten Schlomm5 and Sarah Minner1
1Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2Department of Urology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany
3Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
4Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
5Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany
*These authors contributed equally to this work
Ronald Simon, email: R.Simon@uke.de
Keywords: GSK3beta; prostate cancer; prognosis; immunohistochemistry
Received: January 16, 2019 Accepted: February 15, 2019 Published: March 01, 2019
Glycogen synthase kinase 3ß (GSK3ß) regulates many cancer relevant cellular processes and represents a potential therapeutic target. GSK3ß overexpression has been linked to adverse tumor features in many cancers, but its role in prostate cancer remains uncertain. We employed immunohistochemical GSK3ß expression analysis on a tissue microarray with 12,427 prostate cancers. Cytoplasmic and nuclear GSK3ß staining was separately analyzed. GSK3ß staining was absent in normal prostate epithelium, whereas 57% of 9,164 interpretable cancers showed detectable GSK3ß expression. Cytoplasmic staining was considered weak, moderate, and strong in 36%, 19.5% and 1.5% of tumors and was accompanied by nuclear GSK3ß staining in 47% of cases. Cytoplasmic GSK3ß staining as well as nuclear GSK3ß accumulation was associated with advanced tumor stage, high Gleason grade, presence of lymph node metastasis and early biochemical recurrence (p < 0.0001 each for cytoplasmic staining and nu-clear accumulation). Prognosis of GSK3ß positive cancers became particularly poor if nuclear GSK3ß staining was also seen (p < 0.0001). The prognostic impact of nuclear GSK3ß accumu-lation was independent of established preoperative and postoperative parameters in multivari-ate analyses (p < 0.0001). The significant association of GSK3ß expression with deletions of PTEN, 3p13 (p < 0.0001 each), 5q21 (p = 0.0014) and 6q15 (p = 0.0026) suggest a role of GSK3ß in the development of genomic instability. In summary, the results of our study identify GSK3ß as an independent prognostic marker in prostate cancer.
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