Mechanism Study Of Aurora A In Endometrial Cancer Metastases And Chemoresistance

[Objective]Endometrial cancer (EMC) is one of the most common gynecologic malignancies in female genital tract. The mortality of EMC is related with local recurrence, metastases and chemoresistance. Therefore, the mechanism study of metastases and chemoresistance in endometrial cancer are desperately needed.Aurora A belongs to the serine/threonine kinases family, which plays vital roles in regulating centrosome function, spindle assembly, chromosome segregation and cytokinesis. Numbers of Aurora A inhibitors are being evaluated in clinical trials. Previous studies indicated that in endometrial cancer, the overexpression of Aurora A correlated with tumor grade and pathological characteristics. However, the mechanism remains unclear.Our study aims to elucidate the role of Aurora A/AKT/MMP-2, MMP-9 pathway in endometrial cancer and hopes to provide evidence for its clinical application in the diagnosis and treatment of endometrial cancer.[Methods]1. Quantitative real-time PCR(qRT-PCR),Western Blot and Immunohistochemistry were performed to analyze the expression of Aurora A mRNA and protein in endometrial cancer and normal endometrium tissues.2. Adenovirus and Aurora A specific inhibitor(MLN8237) were used to detect the influences of Aurora A on migration ability and chemoresistance according to CCK-8 and Migration Assay.3. qRT-PCR, Western Blot and Gelatin Zymography Assay were performed to elucidate the molecular mechanism of Aurora A in endometrial cancer.[Results]1. Aurora A is overexpressed in endometrial cancer compared with normal endometrium and correlated with clinical characteristics.2. Aurora A could induce the migration and chemoresistance in Ishikawa and HEC-1B cells. Conversely, MLN8237 could inhibit the ability of migration and chemoresistance.3. Aurora A could promote the mRNA expression of MMP-2, MMP-9 as well as the ratios of MMP-2/TIMP-2 and MMP-9/TIMP-1. What’s more, Aurora A could also induce the expression of MMP-2 and MMP-9 protein.4. The regulatory mechanism related to MMPs were investigated, we found the AKT (Ser473) (Thr308) were abnormally phosphorylated. Simultaneously, wortmannin (AKT or MMP-2/9 activity inhibitor) could reverse Aurora A control of metastases and chemoresistance.[Conclusion]Our present study suggests that Aurora A is overexpressed in endometrial cancer and could induce migration ability and chemoresistance. The molecular mechanism is attributed to abnormally activation of AKT/MMP-2, MMP-9 pathway.