Oncotarget

Research Papers:

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

Shuo Chen, Kai-Xuan Sun, Bo-Liang Liu, Zhi-Hong Zong and Yang Zhao _

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Oncotarget. 2016; 7:27538-27551. https://doi.org/10.18632/oncotarget.8485

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Abstract

Shuo Chen1, Kai-Xuan Sun1, Bo-Liang Liu1, Zhi-Hong Zong2, Yang Zhao1

1Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China

2Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang 100013, China

Correspondence to:

Yang Zhao, e-mail: [email protected]

Keywords: endometrial carcinoma, GSK-3β, microRNA-129, AZD 1080, tumorigenesis and progression

Received: December 18, 2015     Accepted: March 16, 2016     Published: March 30, 2016

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.


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