Liang Hai-qian, Wang Ren-jie, Diao Cai-feng, Li Jian-wei, Su Jing-liang, Zhang Sai
Department of Neurosurgery, Pingjin Hospital, Logistics College of Armed Police Forces, Tianjin, China, 300162.
Tianjin Saier-Biological Technology Company, Tianjin, China, 300353.
Oncotarget. 2015 Oct 6;6(30):29413-27. doi: 10.18632/oncotarget.5003.
Deregulation of the pituitary tumor transforming gene (PTTG1), a newly discovered oncogene, is a hallmark of various malignancies, including pituitary tumors. However, the mechanisms regulating PTTG1 expression are still needed to be explored. MicroRNAs (miRNAs) are a novel class of small RNA molecules that act as posttranscriptional regulators of gene expression and can play a significant role in tumor development. Here, we identified a series of miRNAs, namely, miR-329, miR-300, miR-381 and miR-655, which could target PTTG1 messenger RNA and inhibit its expression. Interestingly, all four miRNAs significantly that are downregulated in pituitary tumors were mapped to the 14q32.31 locus, which acts as a tumor suppressor in several cancers. Functional studies show that the PTTG1-targeting miRNAs inhibit proliferation, migration and invasion but induce apoptosis in GH3 and MMQ cells. Furthermore, overexpression of a PTTG1 expression vector lacking the 3'UTR partially reverses the tumor suppressive effects of these miRNAs. Next, we identified the promoter region of PTTG1-targeting miRNAs with binding sites for p53. In our hands, p53 transcriptionally activated the expression of these miRNAs in pituitary tumor cells. Finally, we found that PTTG1 could inhibit p53 transcriptional activity to the four miRNAs. These data indicate the existence of a feedback loop between PTTG1 targeting miRNAs, PTTG1 and p53 that promotes pituitary tumorigenesis. Together, these findings suggest that these PTTG1-targeting miRNAs are important players in the regulation of pituitary tumorigenesis and that these miRNAs may serve as valuable therapeutic targets for cancer treatment.
垂体肿瘤转化基因（PTTG1）是一种新发现的癌基因，其失调是包括垂体肿瘤在内的各种恶性肿瘤的一个标志。然而，调节PTTG1表达的机制仍有待探索。微小RNA（miRNA）是一类新型的小RNA分子，作为基因表达的转录后调节因子，在肿瘤发生中可发挥重要作用。在此，我们鉴定出一系列miRNA，即miR-329、miR-300、miR-381和miR-655，它们可靶向PTTG1信使RNA并抑制其表达。有趣的是，在垂体肿瘤中显著下调的所有这四种miRNA都定位于14q32.31位点，该位点在几种癌症中起肿瘤抑制作用。功能研究表明，靶向PTTG1的miRNA抑制GH3和MMQ细胞的增殖、迁移和侵袭，但诱导其凋亡。此外，缺乏3'UTR的PTTG1表达载体的过表达部分逆转了这些miRNA的肿瘤抑制作用。接下来，我们鉴定出靶向PTTG1的miRNA的启动子区域具有p53的结合位点。在我们的研究中，p53在垂体肿瘤细胞中转录激活这些miRNA的表达。最后，我们发现PTTG1可抑制p53对这四种miRNA的转录活性。这些数据表明在靶向PTTG1的miRNA、PTTG1和p53之间存在促进垂体肿瘤发生的反馈回路。总之，这些发现表明这些靶向PTTG1的miRNA是垂体肿瘤发生调控中的重要参与者，并且这些miRNA可能作为癌症治疗的有价值的治疗靶点。
