The oncoprotein HBXIP promotes human breast cancer growth through down-regulating p53 via miR-18b/MDM2 and pAKT/MDM2 pathways
The oncoprotein HBXIP promotes human breast cancer growth through down-regulating p53 via miR-18b/MDM2 and pAKT/MDM2 pathways
复制标题
癌蛋白 HBXIP 通过 miR-18b/MDM2 和 pAKT/MDM2 通路下调 p53，促进人类乳腺癌生长
DOI：
10.1038/s41401-018-0034-6
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发表时间：
2018-11-01
影响因子：
8.2
通讯作者：
Ye, Li-hong
中科院分区：
文献类型：
--
作者：
Li, Hang;Wang, Zhen;Ye, Li-hong
哺乳动物B型肝炎X相互作用蛋白（HBXIP）是一种18 kDa的蛋白质，其通过作为致癌转录共激活因子调节大量转录因子如TF-IID、E2 F1、SP 1、STAT 3、c-Myc和LXR，并且在乳腺癌的发展中起重要作用。我们以前发现HBXIP作为一种癌蛋白，可以通过共激活p53增强MDM 2的启动子活性，促进乳腺癌中MDM 2的转录。在这项研究中，我们研究了HBXIP在体外和体内调节人乳腺癌MCF-7细胞中MDM 2/p53相互作用的分子机制。我们发现HBXIP可以通过诱导miR-18 b的DNA甲基化来上调MDM 2，从而抑制miR-18 b的表达，导致乳腺癌细胞中p53的减弱。此外，HBXIP可通过增加pAKT水平促进MDM 2磷酸化，并与pMDM 2结合，增强MDM 2与p53的相互作用，从而下调乳腺癌细胞中p53的表达。在MCF-7乳腺癌异种移植裸鼠中，我们还观察到HBXIP的过表达通过miR-18 b/MDM 2和pAKT/MDM 2途径促进乳腺癌生长。总之，癌蛋白HBXIP抑制miR-18 b以升高MDM 2，并激活pAKT以磷酸化MDM 2，从而增强MDM 2与p53之间的相互作用，导致p53降解，从而促进乳腺癌生长。我们的研究结果揭示了乳腺癌发展过程中p53下调的新机制。
Mammalian hepatitis B X-interacting protein (HBXIP) is an 18-kDa protein that regulates a large number of transcription factors such as TF-IID, E2F1, SP1, STAT3, c-Myc, and LXR by serving as an oncogenic transcription coactivator and plays an important role in the development of breast cancer. We previously showed that HBXIP as an oncoprotein could enhance the promoter activity of MDM2 through coactivating p53, promoting the MDM2 transcription in breast cancer. In this study we investigated the molecular mechanisms underlying the modulation of MDM2/p53 interaction by HBXIP in human breast cancer MCF-7 cells in vitro and in vivo. We showed that HBXIP could up-regulate MDM2 through inducing DNA methylation of miR-18b, thus suppressing the miR-18b expression, leading to the attenuation of p53 in breast cancer cells. In addition, HBXIP could promote the phosphorylation of MDM2 by increasing the level of pAKT and bind to pMDM2, subsequently enhancing the interaction between MDM2 and p53 for the down-regulation of p53 in breast cancer cells. In MCF-7 breast cancer xenograft nude mice, we also observed that overexpression of HBXIP promoted breast cancer growth through the miR-18b/MDM2 and pAKT/MDM2 pathways. In conclusion, oncoprotein HBXIP suppresses miR-18b to elevate MDM2 and activates pAKT to phosphorylate MDM2 for enhancing the interaction between MDM2 and p53, leading to p53 degradation in promotion of breast cancer growth. Our findings shed light on a novel mechanism of p53 down-regulation during the development of breast cancer.