Abstract
We have previously demonstrated that the transition of melanoma to the metastatic phenotype is associated with a loss of expression of the transcription factor AP-2. To further investigate the role of AP-2 in the progression of human melanoma, we attempted to inactivate AP-2 in primary cutaneous SB-2 melanoma cells by using a dominant-negative AP-2, or AP-2B, gene. AP-2B is an alternatively spliced AP-2 variant capable of inhibiting AP-2 trans-activator function. Stable transfection of primary cutaneous melanoma SB-2 cells with the dominant-negative AP-2B gene was confirmed by RT–PCR and Northern blot analyses. Electromobility shift assay using nuclear extracts from these cell lines demonstrated decreased functional binding of AP-2B-transfected cells to the AP-2 consensus binding sequence compared with neo-transfected controls. In addition, CAT activity driven by a construct containing the AP-2 consensus binding sequence was downregulated in the AP-2B transfected cells, indicating AP-2 activity was quenched in the transfected cells. Orthotopic (subcutaneous) injection of the dominant-negative (AP-2B)-transfected cell lines into nude mice increased their tumorigenicity compared to control neo-transfected cells. The AP-2B-transfected cells displayed an increase in MMP-2 expression (by Northern blot) and MMP-2 activity (by zymography), which resulted in an increase in invasiveness through Matrigel-coated filters. The AP-2B-transfected tumors also displayed an increase in MMP-2 expression, microvessel density, and angiogenesis in vivo. These results demonstrate that inactivation of AP-2 contributes to the progression of melanoma, at least partially via deregulation of the MMP-2 gene.
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Acknowledgements
The authors thank Dr Michael Tainsky for the expression vectors used in this study and the Department of Scientific Publications for editorial assistance. This work was supported in part by an award from The University of Texas M.D. Anderson Physician-Scientist Program (JE Gershenwald), NIH grant CA76098 (M Bar-Eli), and NIH T-32 grant CA09599 (WE Sumner).
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Gershenwald, J., Sumner, W., Calderone, T. et al. Dominant-negative transcription factor AP-2 augments SB-2 melanoma tumor growth in vivo. Oncogene 20, 3363–3375 (2001). https://doi.org/10.1038/sj.onc.1204450
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DOI: https://doi.org/10.1038/sj.onc.1204450
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