To Investigate Synergistic Carcinogenesis Mechanisms of Foxm1, Mmp-2 and Aurora-A in Human Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is one of the commonest head and neck cancers. NPC has distinct etiology, pathology, treatment and outcome when compared with other head and neck cancers, which are mainly squamous cell carcinomas. NPC, a malignant tumor of the nasopharyngeal epithelium, is divided into 3 types. Recently administration of concurrent radio- and chemotherapy has achieved a dramatic improvement in patient survival rates. However, different response to therapy is still dependent upon individual variability. By means of molecular studies of cancers can lead us to find and design new drugs for molecular target therapy and may apply to the clinical treatment in NPC in the future. Aurora-A (Aurora A/AURKA/BTAK) is a member of the Aurora/Ipl1p family of cell cycle–regulating serine/threonine kinases and is localized at interphase and mitotic centrosomes and at the spindle poles where it regulates proper chromosome segregation and cytokinesis. Our previously studies demonstrated that Aurora-A is overexpressed in human NPC. A strong Aurora-A expression is significantly correlated with an advanced tumor stage, and the cumulative 5-year survival rate in NPC specimens. Until now, there is little information described what is the downstream target could be modulated byAurora-A to promotes cancer cell proliferation and metastasis in NPC.Hence, to map the potential signaling pathway or downstream regulator(s) participating in Aurora-A-elicited cancer progression of NPC, we employed publicly accessible microarray dataset of head and neck cancer to gain insight into the functional concordance of co-expressed genes. Among these candidate targets, the top candidate is FOXM1, which was highly positively correlated with the mRNA expression level of Aurora-A in head and neck cancer patients (Pearson’s correlation coefficient= 0.852, p＜0.001). Recently, there is a report indicated that MMP-2 could be modulated by FOXM1to promote human cancer development. Therefore, we will aim at determining whether there is a specific signaling pathway, Aurora-A/FOXM1/ MMP-2, in NPC. Our preliminary data indicated that 1) Aurora-A is highly expressed in NPC tissues by immunohistochemical stain, RT-PCR and western blotting approaches. 2) A strong Aurora-A expression is significantly correlated with the cumulative 5-year survival rate. 3)The mRNA and protein of FOXM1 were inhibited when cells knockdown endogenous Aurora-A byAurora-A-mediated siRNA. 4) the MMP-2 protein was suppressed, when endogenous FOXM1 was depleted by FOXM1-mediated siRNA. Taken together, these results raise the possibility that Aurora-Amodulated MMP-2 expression may be through increased FOXM1 expression in NPC tissues and cell lines. To determine the contribution of changes among FOXM1, MMP-2 and Aurora-A in NPC, in the first year, we will investigate FOXM1, MMP-2 and Aurora-A expression profiles in normal and NPC patients’ tissues by Q-RT-PCR and IHC approaches in the first year. In addition, we will also compile statistic what are the relationships of clinicopathological features when FOXM1, MMP-2 and Aurora-A expression in NPC specimens. In the second year, we will examine the biological functions and molecular mechanisms of Aurora-A regulated FOXM1 expression in NPC cell lines. In the third year, we will examine the biological functions and molecular mechanisms of FOXM1 regulated MMP-2 expression in NPC cell lines. The final goal of our studies is to find useful molecular markers for predicting treatment response and prognosis in NPC.

Project ID:PC10107-0350
External Project ID:NSC101-2314-B182A-138