The Regulation of UPA and UPAR in Human Carcinoma Cells

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DESCRIPTION (provided by applicant): The overexpression of urokinase plasminogen activator (uPA) and its receptor (uPAR) is detected in various malignancies. Both in vitro and in vivo studies demonstrate that uPA/uPAR play an important role in tumor progression and metastasis. To define the mechanism responsible for high uPA/uPAR expression in invasive cancer cells, we previously showed that 1) the endogenous p38 MAPK activity is elevated in invasive cancer cells and is required for high uPA/uPAR expression; and 2) p38 MAPK maintains high uPA expression by promoting uPA mRNA stability. However, how p38 MAPK stabilizes uPA mRNA in invasive cancer cells remains unclear. In our preliminary studies, we identified an RNA-binding protein SECp43 that not only specifically interacts with p38a MAPK but also serves as a direct substrate of p38a MAPK in vitro. Overexpression of SECp43 destabilizes uPA mRNA while silencing SECp43 expression prolongs uPA mRNA half-life in p38 MAPK-inhibited condition, suggesting that SECp43 and p38a MAPK are functionally linked in regulating uPA mRNA stability. In further study, we found that SECp43 interacts with uPA mRNA stability in vivo and the region in uPA mRNA required for SECp43 interaction contains AU-rich element (ARE) motifs. Interestingly, we also found that cells with elevated p38 MAPK activity and uPA expression exhibit poor SECp43/uPA mRNA interaction and vice versa. These results suggest that p38a MAPK may stabilize uPA mRNA by impeding SECp43's ability to mediate uPA mRNA decay. This proposal seeks to capitalize on our previous work to 1) investigate how p38a MAPK regulates SECp43-mediated uPA mRNA decay; 2) determine the mechanisms involved in SECp43-mediated uPA mRNA turnover; and 3) determine how non-p38a-phosphorylable SECp43 affects tumor cell growth and metastasis. The proposed study should increase our understanding on p38 MAPK-mediated mRNA stabilization and mechanisms involved in elevated uPA/uPAR expression in invasive cancer cells. Also, gaining further understanding of the novel role of SECp43 in repressing uPA expression may lead to the development of a novel therapeutic approach to suppress tumor growth and metastasis.