The role of glycogen synthase kinase-3β (GSK-3β) in endometrial carcinoma: A carcinogenesis, progression, prognosis, and target therapy marker.
The role of glycogen synthase kinase-3β (GSK-3β) in endometrial carcinoma: A carcinogenesis, progression, prognosis, and target therapy marker.
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糖原合酶激酶 3 β (GSK-3 β) 在子宫内膜癌中的作用：癌发生、进展、预后和靶向治疗标志物
DOI：
10.18632/oncotarget.8485
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发表时间：
2016-05-10
期刊：
影响因子：
--
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Chen S;Sun KX;Liu BL;Zong ZH;Zhao Y
糖原合成酶激酶-3 β（GSK-3β）是一种参与癌症发展的丝氨酸/苏氨酸激酶。在此，我们证明了GSK-3β在子宫内膜癌（EC）中的作用，并确定了新的治疗靶点。GSK-3β在EC组织中呈高表达，且与国际妇产科联盟（FIGO）分期、去分化程度、肌层浸润深度呈正相关。此外，GSK-3β过表达预测较低的累积和无复发生存率。si-GSK-3β转染可通过下调NF-κ B、Cyclin D1和MMP 9的表达，上调P21的表达，抑制细胞增殖、迁移、侵袭，促进细胞凋亡。生物信息学预测和双荧光素酶报告基因分析表明GSK-3β是miR-129的可能靶点。miR-129转染降低GSK-3β表达，并且在细胞功能实验中表现出与si-GSK-3β转染相同的趋势。裸鼠移植瘤实验表明，miR-129过表达可能通过下调GSK-3β表达抑制肿瘤生长。进一步研究发现，GSK-3β抑制剂AZD 1080还可抑制EC细胞增殖、迁移和侵袭，并通过调节GSK-3β信号下游相关基因诱导EC细胞凋亡。采用免疫组化法检测GSK-3β在EC组织和正常子宫内膜组织中的表达。通过si-GSK-3β、microRNA-129模拟物转染或GSK-3β抑制剂暴露下调GSK-3β后，检测EC细胞表型和相关分子。我们的研究结果首次表明GSK-3β可能是治疗子宫内膜癌的一个新的和重要的治疗靶点。GSK-3β抑制剂AZD 1080可能是治疗子宫内膜癌的有效药物。
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. 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. 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. 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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影响因子：
12.4
作者：
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