The role of glycogen synthase kinase-3β (GSK-3β) in endometrial carcinoma: A carcinogenesis, progression, prognosis, and target therapy marker.

Abstract

PURPOSE:

Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase involved in cancer development. Herein, we demonstrated the role of GSK-3β in endometrial cancer (EC) and identified new therapeutic targets.

RESULTS:

GSK-3β was overexpressed in EC tissues, and was positively correlated with International Federation of Gynecology and Obstetrics (FIGO) staging, dedifferentiation, and myometrial infiltration depth. Besides, GSK-3β overexpression predicted lower cumulative and relapse-free survival rate. si-GSK-3β transfection suppressed cell proliferation, migration, invasion, and promoted cell apoptosis through downregulating NF-kB, Cyclin D1 and MMP9 expression whereas upregulating P21 expression. Bioinformatic predictions and dual-luciferase reporter assays showed that GSK-3β was a possible target of miR-129. MiR-129 transfection reduced GSK-3β expression, and exhibited the same trend as si-GSK-3β transfection in cell function experiments. The nude mouse xenograft assay showed that miR-129 overexpression may suppress tumor growth through downregulating GSK-3β expression. Further studies showed that AZD1080, a GSK-3β inhibitor, could also inhibit EC cell proliferation, migration and invasion, while induced cell apoptosis through modulating relevant genes downstream of GSK-3β signaling.

EXPERIMENTAL DESIGN:

GSK-3β expression was determined in EC tissue and normal endometrial tissues by immunohistochemistry. After GSK-3β down-regulation by si-GSK-3β, microRNA-129 mimic transfection or GSK-3β inhibitor exposure, EC cell phenotypes and related molecules were examined.

CONCLUSIONS:

Our results demonstrate for the first time that GSK-3β may be a novel and important therapeutic target for the treatment of endometrial carcinoma. GSK-3β inhibitor AZD1080 may be an effective drug for treating endometrial carcinoma.

• Authors: Shuo Chen, Kai-Xuan Sun, Bo-Liang Liu, Zhi-Hong Zong, Yang Zhao
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 19 Pg. 27538-51 (May 10 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27050373 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• MicroRNAs
• Glycogen Synthase Kinase 3 beta

Topics

• Carcinogenesis
• Carcinoma, Endometrioid (enzymology, genetics, pathology)
• Disease Progression
• Endometrial Neoplasms (drug therapy, enzymology, genetics, pathology)
• Enzyme Inhibitors (pharmacology)
• Female
• Glycogen Synthase Kinase 3 beta (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Humans
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Molecular Targeted Therapy
• Prognosis
• Signal Transduction
• Transfection