A Regulatory Loop Involving miR-22, Sp1, and c-Myc Modulates CD147 Expression in Breast Cancer Invasion and Metastasis
A Regulatory Loop Involving miR-22, Sp1, and c-Myc Modulates CD147 Expression in Breast Cancer Invasion and Metastasis
复制标题
DOI：
10.1158/0008-5472.can-13-3555
复制
发表时间：
2014-07-15
期刊：
影响因子：
11.2
通讯作者：
Chen, Zhi-Nan
中科院分区：
文献类型：
--
作者：
Kong, Ling-Min;Liao, Cheng-Gong;Chen, Zhi-Nan
乳腺癌是女性中最常见的癌症，其转移过程仍然知之甚少。CD 147在乳腺癌中上调，并与肿瘤进展相关，但对其调控机制知之甚少。本研究证实CD 147在乳腺癌组织和细胞系中过表达，且高表达与肿瘤的侵袭和转移相关。我们还发现转录因子Sp1和c-Myc可以与CD 147启动子结合并增强其表达。CD 147 mRNA有一个748 bp的30个非翻译区（UTR），有许多miRNA靶位点，表明可能受miRNA调控。我们发现miR-22通过直接靶向CD 147 30 UTR抑制CD 147表达。我们还确定miR-22可以通过下调Sp1表达间接参与CD 147调节。miR-22可以与Sp1形成一个自身调节环，Sp1通过与miR-22启动子结合来抑制miR-22的转录。结合c-Myc介导的miR-22表达抑制，我们的研究确定了一个调控CD 147基因转录的miR-22/Sp1/c-Myc网络。此外，miR-22过表达通过靶向CD 147在体外和体内抑制乳腺癌细胞的侵袭、转移和增殖。此外，我们发现miR-22在乳腺癌组织中显著下调，并且其表达与患者的肿瘤淋巴结转移阶段和淋巴结转移呈负相关。我们的研究提供了第一个证据，证明miR-22/Sp1/c-Myc网络调节乳腺癌中CD 147的上调，并且miR-22抑制乳腺癌的侵袭和转移能力。(C)2014年AACR。
Breast cancer is the most common cancer in women for which the metastatic process is still poorly understood. CD147 is upregulated in breast cancer and has been associated with tumor progression, but little is known about its regulatory mechanisms. In this study, we demonstrated that CD147 was overexpressed in breast cancer tissues and cell lines, and the high expression correlated with tumor invasion and metastasis. We also found that the transcription factors Sp1 and c-Myc could bind to the CD147 promoter and enhance its expression. The CD147 mRNA has a 748-bp 30-untranslated region (UTR) with many miRNA target sites, suggesting possible regulation by miRNAs. We discovered that miR-22 repressed CD147 expression by directly targeting the CD147 30UTR. We also determined that miR-22 could indirectly participate in CD147 modulation by downregulating Sp1 expression. miR-22 could form an autoregulatory loop with Sp1, which repressed miR-22 transcription by binding to the miR-22 promoter. Together with the c-Myc-mediated inhibition of miR-22 expression, our investigation identified a miR-22/Sp1/c-Myc network that regulates CD147 gene transcription. In addition, miR-22 overexpression suppressed breast cancer cell invasion, metastasis, and proliferation by targeting CD147 in vitro and in vivo. Furthermore, we found that miR-22 was significantly downregulated in breast cancer tissues and that its expression was inversely correlated with the tumor-node-metastasis stage and lymphatic metastasis in patients. Our study provides the first evidence that an miR-22/Sp1/c-Myc network regulates CD147 upregulation in breast cancer and that miR-22 represses breast cancer invasive and metastatic capacities. (C) 2014 AACR.