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转录因子 AP4 通过调控 表达促进致癌表型和顺铂耐药性。

The Transcription Factor AP4 Promotes Oncogenic Phenotypes and Cisplatin Resistance by Regulating Expression.

机构信息

Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China.

出版信息

Mol Cancer Res. 2018 May;16(5):857-868. doi: 10.1158/1541-7786.MCR-17-0519. Epub 2018 Jan 29.

Abstract

Lysosomal-associated protein transmembrane-4 beta (LAPTM4B) is a novel oncogene, whose overexpression is involved in cancer occurrence and progression. However, the mechanism of LAPTM4B transcriptional regulation remains unclear. In this study, the results of transcription factor (TF) profiling plate arrays indicated that AP4 was a potential transcription factor regulating LAPTM4B expression. LAPTM4B was positively correlated with AP4 and they were both associated with poor overall and disease-free survival. Luciferase and electrophoretic mobility shift assay assays confirmed that AP4 directly bound to the polymorphism region of LAPTM4B promoter and modulated its transcription. Functionally, AP4 promoted cell proliferation, migration, invasion, and assisted drug resistance in part through upregulation of LAPTM4B. Taken together, these findings identify LAPTM4B as a direct AP4 target gene and the interaction of AP4 and LAPTM4B plays an important role in breast cancer progression. This study demonstrates that AP4 promotes cell growth, migration, invasion, and cisplatin resistance through upregulation of LAPTM4B expression, thus representing an attractive therapeutic target for breast cancer. .

摘要

溶酶体相关蛋白跨膜 4β(LAPTM4B)是一种新的癌基因,其过表达参与了癌症的发生和进展。然而,LAPTM4B 转录调控的机制尚不清楚。在这项研究中,转录因子(TF)谱板分析的结果表明,AP4 是一种潜在的调节 LAPTM4B 表达的转录因子。LAPTM4B 与 AP4 呈正相关,且均与总生存期和无病生存期不良相关。荧光素酶和电泳迁移率变动分析实验证实,AP4 直接结合到 LAPTM4B 启动子的多态性区域,并调节其转录。在功能上,AP4 通过上调 LAPTM4B 促进细胞增殖、迁移、侵袭,并辅助耐药。总之,这些发现表明 LAPTM4B 是 AP4 的直接靶基因,AP4 和 LAPTM4B 的相互作用在乳腺癌进展中起着重要作用。本研究表明,AP4 通过上调 LAPTM4B 的表达促进细胞生长、迁移、侵袭和顺铂耐药,因此代表了乳腺癌有吸引力的治疗靶点。

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