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Production of matrix metalloproteinases (MMPs) for degradation of extracellular matrix is a vital step in cancer metastasis. We investigated the effects of HPV16 oncoproteins (16E6, 16E6*I and 16E7), either individually or combined, on the transcription of 7  MMP s implicated in cervical cancer invasiveness. The levels of 7  MMPs  reported to be increased in cervical cancer were determined in C33A stably expressing different HPV16 oncoproteins using quantitative RT-PCR and compared with invasion ability of cell lines using  in vitro  invasion and wound healing assays. Overexpression of  MMP-2  and  MT1-MMP  was detected in HPV16E6E7 expressing cells which correlated with increased cell invasion. Combination of HPV oncoproteins always showed greater effects than its individual form. Inhibition of cell invasion using a specific MMP-2 inhibitor, OA-Hy, and anti-MT1-MMP antibody confirmed that invasion in these cells was dependent on both MMP-2 and MT1-MMP expression. Depletion of HPV16E6E7 by shRNA-mediated knock-down experiments resulted in decreased MMP-2 and MT1-MMP expression levels as well as reduced invasion ability which strongly suggested specific effects of HPV oncoproteins on both MMPs and on cell invasion. Immunohistochemistry study in invasive cervical cancers confirmed the enhanced  in vivo  expression of these two MMPs in HPV16-infected cells. In addition, possible sites required by HPV16E6E7 on the  MMP-2  and  MT1-MMP  promoters were investigated and PEA3 (at −552/−540 for  MMP-2 , −303 for  MT1-MMP ) and Sp1 (at −91 for  MMP-2,  −102 for  MT1-MMP ) binding sites were shown to be essential for mediating their transactivation activity. In conclusion, our study demonstrated that HPV16E6 and E7 oncoproteins cooperate in promoting cervical cancer invasiveness by specifically upregulating  MMP-2  and  MT1-MMP  transcription in a similar manner.

HPV16 Oncoproteins Promote Cervical Cancer Invasiveness by Upregulating Specific Matrix Metalloproteinases