| Summary: | 碩士 === 中國醫藥大學 === 癌症生物學研究所 === 97 === The adenoviral type 5 E1A gene as an effective tumor suppression gene has been applied to multiple clinical trials for breast, ovarian and head/neck cancer. Recent studies have shown that the E1A gene therapy might be a promising strategy to enhance the sensitivity of tumor cells to chemotherapy. However, the role of E1A in mediating tumor metastasis still remains largely unexplored. MicroRNAs (miRNAs) are small non-coding RNAs that have been implicated in regulating diverse cellular pathways. First, we apply vector control transfected and E1A transfected cells for microRNA microarray analysis. From the array data, we find that E1A regulate several miRNA expression. Here we provide evidence that miR-520h, positively promotes cell motility, is down-regulated by E1A. The expression of miR-520h is downregulated in E1A-transfected cancer cells including breast and ovarian cancer. Using miRNA inhibitors, we demonstrate that certain cancer cell lines require the activity of miR-520h to promote migration and invasion in vitro. In the experimental metastasis animal model, we find that overexpression of miR-520h enhances cancer cell metastatic ability. From different miRNA target prediction database, we identify that protein phosphatase 2A catalytic subunit (PP2A/C) is one target gene of miR-520h. The miR-520h proceeds to inhibit translation of the messenger RNA encoding protein phosphatase 2A catalytic subunit (PP2A/C), resulting in activation of Akt and NF-κB signaling pathway. Furthermore, the inhibition of PP2A/C by miR-520h increases expression of well-characterized pro-metastatic gene, Twist, through NF-κB signaling pathway. Taken together, these results suggest that miR-520h is regulated by E1A and may play a key role in E1A-mediated metastasis suppression. Meanwhile, our results indicate that miR-520h is functionally linked to promote metastasis in cancer cells and therefore provide new insights into the role of E1A-mediated miRNA regulation in metastasis. Since it is hampered at present to stably silence miRNA over extended periods of time, these results also indicates that E1A gene therapy may serve as a miRNA inhibitor to stably silence oncogenic miRNA in malignant cancer.
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