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TheTANGOgene was originally identified as a new family member of the melanoma inhibitory activity gene family. The gene codes for a 14 kDa protein of so far unknown function. In our study we revealed that TANGO was downregulated or lost in 9 melanoma cell lines when compared to normal melanocytes and in most of the 8 tumor samples analyzed. The losses were associated with advanced stage of the disease. These results were confirmedin situby immunohistochemistry on 10 paraffin-embedded sections of human malignant melanoma primary tumors and melanoma skin metastases. A small reduction of TANGO was also seen in different benign and atypical nevi when compared to normal skin. For functional analysis of TANGO we evaluated TANGO re-expressing melanoma cell clones and antisense TANGO cell clones with a complete loss of TANGO. Functional assays with TANGO transfected or treated cell lines revealed that TANGO expression reduces motility, whereas reduction of TANGO enhances migration. Our studies, therefore, indicate that reduction of TANGO expression contributes to tumor progression. These results taken together provide the first indications for a tumor suppressor role of TANGO gene in human malignant melanoma.