Journal
CARCINOGENESIS
Volume 29, Issue 10, Pages 1930-1937Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgn176
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Funding
- Sun Yat-sen University 985 Program Initiation Fund
- National Nature Science Foundation of China [30772476]
- Guangzhou S T Fund [031403]
- Guangdong Medical Science Fund [B2008056]
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Mitotic serine/threonine kinase Aurora-A (Aur-A) plays a critical role in regulating centrosome segregation and spindle assemble. Aur-A overexpression causes excessive centrosome duplication and abnormal spindle structure, leading to tumor malignant progression. Here, we investigated Aur-A expression in nasopharyngeal carcinoma (NPC) and the association between Aur-A and NPC invasiveness. We showed that overexpression of Aur-A in tumor tissues was correlated with cranial bone invasion and clinical stage in NPC patients. Suppression of Aur-A by either selective Aurora inhibitory VX-680 or small-interfering RNA caused G(2)/M arrest and apoptotic cell death in NPC CNE-2 cells. Significantly, inhibition of Aur-A suppressed CNE-2 cell invasion and restored membrane expression of epithelial markers, E-cadherin and beta-catenin, suggesting a reversed epithelial -mesenchymal transition process in cancer cells. In addition, we found that Aur-A-regulated epithelial -mesenchymal transition and invasion were mediated by mitogen-activated protein kinase (MAPK) phosphorylation. Moreover, suppression of MAP kinase by small-interfering RNA or its upstream MEK1/2-selective inhibitor U0126 abrogated cell invasion enhanced by Aur-A overexpression. On the other hand, forced overexpression of constitutively active form of MEK1/ 2, MEK2DD, in CNE-2 cancer cells rescued cell invasive ability suppressed by VX-680-imposed Aur-A inhibition. Our results indicated that Aur-A acted through a downstream MAP kinase pathway to promote epithelial mesenchymal transition and invasiveness in nasopharyngeal tumorigenesis. Small chemical inhibitor VX-680 may offer as a promising molecular targeting agent in human NPC.
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