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microRNA-132-3p 通过调节乳腺癌中溶酶体相关蛋白跨膜 4β 抑制肿瘤恶性进展。

MicroRNA-132-3p inhibits tumor malignant progression by regulating lysosomal-associated protein transmembrane 4 beta in breast cancer.

机构信息

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

出版信息

Cancer Sci. 2019 Oct;110(10):3098-3109. doi: 10.1111/cas.14164. Epub 2019 Aug 19.

Abstract

Lysosomal-associated protein transmembrane 4 beta (LAPTM4B), a proto-oncogene, has been shown to be a positive modulator in cancer progression. However, the mechanism of LAPTM4B regulation is not fully elucidated. Aberrant microRNAs (miRNAs) can regulate gene expression by interfering with target transcripts and/or translation to exert tumor-suppressive or oncogenic effects in breast cancer. In the present study, miR-132-3p, which was predicted by relevant software, was confirmed to directly bind to the 3' untranslated region (3'UTR) of LAPTM4B and negatively regulate its expression in luciferase reporter and western blot assays. Subsequently, we validated that miR-132-3p was downregulated in breast cancer tissues. Receiver-operating characteristic curve analysis indicated that miR-132-3p had accurate diagnostic value, and a Kaplan-Meier and Cox regression model showed that miR-132-3p was a potential prognostic marker for recurrence, showing low levels in breast cancer patients. In addition, we showed that miR-132-3p was inversely correlated with LAPTM4B expression in the above samples. Functionally, miR-132-3p suppressed the migration and invasion of breast carcinoma cells through LAPTM4B by mediating epithelial-mesenchymal transition signals, and partially reversed the carcinogenic effects of LAPTM4B by inhibiting the PI3K-AKT-mTOR signaling pathway. Taken together, these findings provide the first comprehensive analysis of miR-132-3p as a direct LAPTM4B-targeted miRNA, and shed light on miR-132-3p/LAPTM4B as a significant functional axis involved in the oncogenesis and metastasis of breast cancer.

摘要

溶酶体相关蛋白跨膜 4β(LAPTM4B)是一种原癌基因,已被证明是癌症进展的正向调节剂。然而,LAPTM4B 调节的机制尚未完全阐明。异常的 microRNAs(miRNAs)可以通过干扰靶转录物和/或翻译来调节基因表达,从而在乳腺癌中发挥肿瘤抑制或致癌作用。在本研究中,通过相关软件预测的 miR-132-3p 被证实可以直接结合 LAPTM4B 的 3'非翻译区(3'UTR)并在荧光素酶报告基因和 Western blot 实验中负调控其表达。随后,我们验证了 miR-132-3p 在乳腺癌组织中下调。受试者工作特征曲线分析表明,miR-132-3p 具有准确的诊断价值,Kaplan-Meier 和 Cox 回归模型表明,miR-132-3p 是乳腺癌患者复发的潜在预后标志物,其水平较低。此外,我们还表明,miR-132-3p 与上述样本中 LAPTM4B 的表达呈负相关。功能上,miR-132-3p 通过介导上皮-间充质转化信号抑制乳腺癌细胞的迁移和侵袭,通过抑制 PI3K-AKT-mTOR 信号通路部分逆转 LAPTM4B 的致癌作用。综上所述,这些发现提供了 miR-132-3p 作为直接靶向 LAPTM4B 的 miRNA 的全面分析,并阐明了 miR-132-3p/LAPTM4B 作为涉及乳腺癌发生和转移的重要功能轴。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c678/6778625/94ce01524957/CAS-110-3098-g001.jpg

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