Abstract 1998: Deficient expression of oncogenic Wip1 (PPM1D) negatively regulates melanoma progression and metastasis

PPM1D belongs to the magnesium-dependent serine/threonine phosphatase family. It is well demonstrated that PPM1D amplification and overexpression is a frequent event in many human cancer types; however, its role in melanoma development and metastasis is not yet defined. The objectives of this study were to evaluate the role of Wip1 in melanoma progression and to evaluate correlations between Wip1 expression and clinical pathological parameters, such as grade and metastasis. In order to investigate the role of Wip1 in melanoma progression, we crossed Grm1 transgenic (TG3) mice, a well-characterized mouse model for melanoma, with Wip1 null mice (PPM1D-/-) to generate TG3:PPM1D-/- mice, and observed the rate of spontaneous melanoma formation. Compared with TG3 mice, TG3:PPM1D-/- mice exhibited dramatic reductions in melanoma incidence and metastasis to lymph nodes, lungs, liver and spleen. In addition, in-vitro down-regulation of Wip1 in Mass20 melanoma cells significantly decreased cellular proliferation and migration. Further, human melanoma tissue microarrays (TMAs) were used to determine PPM1D mRNA and protein expression levels in human tumors at different stages of progression. In situ staining of PPM1D mRNA and its corresponding protein Wip1 in human melanoma TMAs revealed higher expression levels in at least ∼50% of the metastatic tumors analyzed. Overall, our results demonstrate abundant expression of Wip1 in late stage/high grade melanoma and suggest that therapeutic strategies targeting Wip1 in individuals with select tumor subtypes might improve the survival advantage in Wip1-positive melanoma patients. However, further studies are required to elucidate the interactions between Wip1 signaling and established pathways of melanoma progression. Note: This abstract was not presented at the meeting. Citation Format: Bo-Hyun Moon, Shubhankar Suman, Henghong Li, Qian Yang, Steven J. Strawn, Janine LoBello, Sharlyn J. Mazur, Ettore Appella, Suzie Chen, Albert J. Fornace. Deficient expression of oncogenic Wip1 (PPM1D) negatively regulates melanoma progression and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1998. doi:10.1158/1538-7445.AM2014-1998