We have previously described the human homolog of a rat metastasis-associated molecule, hC4.4 A, with a weak homology to the urokinase-type plasminogen activator receptor. By the restricted expression in nontransformed tissues as opposed to expression in roughly 50% of a variety of carcinoma lines of different origins, a possible correlation between hC4.4 A and tumor progression emerged. This was explored in more detail in melanoma by quantitative polymerase chain reaction and in situ hybridization. As shown before, normal human skin weakly expresses hC4.4 A. Melanocytes and nevi are negative, but up to 60% of primary malignant melanoma and 100% of lymph node and skin metastases of melanoma are hC4.4 A positive. Signal intensity in both polymerase chain reaction and in situ hybridization varied considerably between individual samples, which is indicative for regulated expression of hC4.4 A. To test the hypothesis, melanoma lines were incubated with human serum. Whereas expression of hC4.4 was not influenced by heat-inactivated human serum, all melanoma lines responded to noninactivated human serum with upregulation of hC4.4 A expression. Regulated expression with highest level expression on metastases is a feature that hC4.4 A shares with the urokinase-type plasminogen activator receptor. This feature points towards functional activity of hC4.4 A in tumor progression.