Systemic interferon-alpha (IFN-alpha) treatment leads to Stat3 inactivation in melanoma precursor lesions

Background: In the setting of familial melanoma, the presence of atypical n evi, which are the precursors of melanoma, is associated with a nearly 100% risk of developing primary melanoma by age 70. In patients with sporadic m elanoma, it is estimated that 40-60% of melanomas develop in contiguous ass ociation with atypical nevi. Currently, the only way, to prevent atypical n evi from progressing to melanoma is to monitor and excise them as soon as t hey exhibit changes in their clinical features. Activation of the transcrip tion factor, Stat3, has been linked to abnormal cell growth and transformat ion as well as to interferon alpha (IFN-alpha)-mediated growth suppression in vitro. Materials and Methods: To determine whether IFN-alpha, used for adjuvant th erapy of high-risk, resected melanoma, induces changes in Stat3 in atypical nevi, patients with a clinical history of melanoma who have multiple atypi cal nevi were treated for 3 months with low-dose IFN-alpha. Thereupon, the new technology of microscopic spectral imaging and biochemical assays such as electrophoretic mobility shift assays (EMSAs) and immunoblot analysis we re used for the study of atypical nevi, obtained before and after IFN-alpha treatment. Results: The results of the investigations provided evidence that, as a res ult of systemic IFN-alpha treatment, Stat1 and Stat3, which are constitutiv ely activated in melanoma precursor lesions, lose their ability to bind DNA , and as shown in the case of Stat3, become dephosphorylated. Conclusions: Unlike primary and metastatic melanomas, melanoma precursor le sions cannot be established as cell cultures. Thus, the only way to explore pathways and treatment regimens that might help prevent progression to mel anoma is within the context of a melanoma precursor lesion study conducted prospectively. The findings presented here suggest that down-regulation of the transcription factors Stat1 and Stat3 by systemic IFN-alpha treatment m ay represent a potential pathway to prevent the activation of gene(s) whose expression may be required for atypical nevus cells to progress to melanom a.