Constitutive activation of glycogen synthase kinase-3beta correlates with better prognosis and cyclin-dependent kinase inhibitors in human gastric cancer.
BACKGROUND
Aberrant regulation of glycogen synthase kinase-3beta (GSK-3beta) has been implicated in several human cancers; however, it has not been reported in the gastric cancer tissues to date. The present study was performed to determine the expression status of active form of GSK-3beta phosphorylated at Tyr216 (pGSK-3beta) and its relationship with other tumor-associated proteins in human gastric cancers.


METHODS
Immunohistochemistry was performed on tissue array slides containing 281 human gastric carcinoma specimens. In addition, gastric cancer cells were cultured and treated with a GSK-3beta inhibitor lithium chloride (LiCl) for immunoblot analysis.


RESULTS
We found that pGSK-3beta was expressed in 129 (46%) of 281 cases examined, and was higher in the early-stages of pathologic tumor-node-metastasis (P < 0.001). The expression of pGSK-3beta inversely correlated with lymphatic invasion (P < 0.001) and lymph node metastasis (P < 0.001) and correlated with a longer patient survival (P < 0.001). In addition, pGSK-3beta expression positively correlated with that of p16, p21, p27, p53, APC, PTEN, MGMT, SMAD4, or KAI1 (P < 0.05), but not with that of cyclin D1. This was confirmed by immunoblot analysis using SNU-668 gastric cancer cells treated with LiCl.


CONCLUSIONS
GSK-3beta activation was frequently observed in early-stage gastric carcinoma and was significantly correlated with better prognosis. Thus, these findings suggest that GSK-3beta activation is a useful prognostic marker for the early-stage gastric cancer.
Cho
Yu Jin
YJ
Department of Anatomy, Seoul National University College of Medicine, Chongno-gu, Seoul, Korea. dslanat@snu.ac.kr
Kim
Ji Hun
JH
Yoon
Jiyeon
J
Cho
Sung Jin
SJ
Ko
Young San
YS
Park
Jong-Wan
JW
Lee
Hye Seung
HS
Lee
Hee Eun
HE
Kim
Woo Ho
WH
Lee
Byung Lan
BL
D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D011379:Prognosis; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride