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Interferon-γ (IFN-γ) has been found to be antiproliferative and antitumoral in malignant mesothelioma (MM), but the MM cell response to IFN-γ has not been fully characterized so far. We investigated gene expression profiles in human MM cell lines (HMCLs) exposed to IFN-γ. Four HMCLs showing different sensitivities to the antiproliferative effect of IFN-γ, two of them presenting a defect in the JAK/STAT signaling pathway, were treated with 500 IU/mL of IFN-γ. Gene expression patterns were studied at 6 and 72 hours after exposure to the IFN-γ, using a cDNA array technique. Six genes were studied with real-time reverse transcription–polymerase chain reaction. The gene expression profiles in response to IFN-γ were shown to differ in different HMCLs. Numerous genes involved in cell proliferation and cell adhesion were regulated by IFN-γ in JAK/STAT-deficient HMCLs. Genes possibly involved in regulation of cell proliferation included CDC2, PLK1, and IGFBP4, as well as several genes involved in cell–cell interactions and cell adhesion. The cDNA array technique revealed differences in expression pathways, especially those involved in cell growth, cell adhesion, and cell proliferation, between IFN-γ–resistant and –sensitive MM cell lines. We found that the changes in gene expression profiles of HMCLs exposed to IFN-γ were also related to features other than the antiproliferative response. [Copyright &y& Elsevier]