CyclinE2-3'UTR竞争性结合miR-30e上调Notch1促进鼻咽癌转移的机制研究

Recent studies revealed that deregulation of gene 3'untranslated regions play important roles in cancinogenesis, acting as oncogenes or tumor suppressor genes.Our previous study showed that cyclin E2-3'UTR is overexpressed in nasopharyngeal carcinoma tissues. Overexpression of cyclin E2-3'UTR in nasopharyngeal carcinoma cells enhanced biological activity of motility and invasiveness.Further Study showed that cyclin E2-3'UTR and Notch1-3'UTR share several miR-30e binding sites.What is more,luciferase results showed that cyclin E2-3'UTR decreased the inhibitory effect of miR-30e on Notch1. Therefore,we propose the new mechanism that cyclin E2-3'UTR modulates Notch1 expression through binding miR-30e competitively thus decreases the inhibitory effect of miR-30e on Notch1 and promotes nasopharyngeal carcinoma progression. This study is aimed at exploring function and mechanism of cyclin E2-3'UTR in vitro and in vivo, gaining the evidence of cyclin E2-3'UTR up-regulating Notch1 expression through competitively binding of miR-30e,and providing theoretical evidence for nasopharyngeal carcinoma targeting therapy.

最近研究表明基因3'UTR在肿瘤的发生发展及预后中起到非常重要的作用。我们预实验发现上调Cyclin E2-3'UTR表达能使鼻咽癌细胞迁移能力增强。荧光素酶实验证实Cyclin E2-3'UTR与Notch1-3'UTR均为miRNA miR-30e的靶序列，并且荧光素酶实验证实了Cyclin E2-3'UTR降低miR-30e对Notch1的抑制作用。由此，我们提出Cyclin E2-3'UTR促进鼻咽癌转移的新机制，即：Cyclin E2-3'UTR通过竞争性结合miR-30e，减少了miR-30e对Notch1的抑制作用，从而促进鼻咽癌演进和转移。本研究拟在体内外实验水平研究Cyclin E2-3'UTR的功能，获得Cyclin E2-3'UTR通过竞争性结合miR-30e，上调Notch1表达的可靠依据，分析Cyclin E2-3'UTR与鼻咽癌临床病理指标的关系，指导临床实践。

研究表明基因3'UTR在肿瘤的发生发展及预后中起到非常重要的作用。我们发现上调Cyclin E2-3'UTR表达能使鼻咽癌细胞迁移能力增强，并且将稳定过表达CyclinE2-3’UTR的鼻咽癌细胞裸鼠尾静脉注射后肺内转移瘤形成率增加，足垫淋巴转移模型中癌细胞向前哨淋巴结转移能力增强。荧光素酶实验证实Cyclin E2-3'UTR与NOTCH1-3'UTR均为miRNA miR-30e的靶序列，并且荧光素酶实验证实了Cyclin E2-3'UTR降低miR-30e对NOTCH1的抑制作用。由此，我们提出Cyclin E2-3'UTR促进鼻咽癌转移的新机制，即：Cyclin E2-3'UTR通过竞争性结合miR-30e，减少了miR-30e对NOTCH1的抑制作用，从而促进鼻咽癌演进和转移。本研究通过体内外实验水平研究Cyclin E2-3'UTR的功能，获得了Cyclin E2-3'UTR通过竞争性结合miR-30e，上调NOTCH1表达的可靠依据，发现Cyclin E2-3'UTR在鼻咽癌中高频地过表达，CyclinE2-3’UTR过表达与鼻咽癌患者淋巴结转移相关。