Biological and clinical significance of GSK-3beta in mantle cell lymphoma--an immunohistochemical study.
GSK-3beta, a biologically important signalling protein, is regulated by the Wnt canonical and the PI3K/Akt pathways. We recently reported that mantle cell lymphoma (MCL) frequently shows evidence of GSK-3beta inactivation, since GSK-3beta is phoshorylated at its functionally critical serine 9 residue in all MCL cell lines and the majority of MCL tumors examined. To further assess the clinical and biological significance of GSK-3beta inactivation in MCL, we employed immunohistochemistry to assess the expression of the phosphorylated/inactive form of GSK-3beta (pGSK-3beta) in 83 paraffin-embedded tumors, and correlated its expression with various biological and clinical parameters. Dichotomizing pGSK-3beta into 2 groups produced twenty-seven (32.5%) tumors assessed as negative and fifty-six (67.5%) as positive. Positive pGSK-3beta expression correlated significantly with positive nuclear expression of beta-catenin and high expression of cyclin D1 (p = 0.0025, 0.0032 Fisher's exact, respectively), both of which have been previously shown to be regulated by GSK-3beta regarding their expression levels and/or sub cellular localization in-vitro. However, no significant correlation was found between pGSK-3beta and Ki67. Of the clinical parameters, continuous pGSK-3beta status had a significant correlation with absolute lymphocyte count in blood (p = 0.0011, Spearman) and negative pGSK-3beta expression was significantly correlated with a longer overall survival (p= 0.045, HR = 1.89), but not with age at diagnosis, clinical stage or the international prognostic index. To conclude, our results support the concept that GSK-3beta inactivation, found in approximately two-thirds of MCL tumors, is biologically and clinically important in MCL.
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Randy
R
Chung
Anthea C
AC
Peters
Hanan
H
Armanious
Mona
M
Anand
Pascal
P
Gelebart
Raymond
R
Lai
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012044:Regression Analysis; D012189:Retrospective Studies; D015996:Survival Rate; D051176:beta Catenin / Q000378:metabolism
D051176:beta Catenin; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
GSK-3β; Mantle cell lymphoma; immunohistochemistry