Association of IFN-gamma signal transduction defects with impaired HLA class I antigen processing in melanoma cell lines.

ABSTRACT: Abnormalities in the constitutive and IFN-?-inducible HLA class I surface antigen expression of tumor cells is often associated with an impaired expression of components of the antigen processing machinery (APM). Hence, we analyzed whether there exists a link between the IFN-? signaling pathway, constitutive HLA class I APM component expression, and IFN-? resistance.The basal and IFN-?-inducible expression profiles of HLA class I APM and IFN-? signal transduction cascade components were assessed in melanoma cells by real-time PCR (RT-PCR), Western blot analysis and/or flow cytometry, the integrity of the Janus activated kinase (JAK) 2 locus by comparative genomic hybridization. JAK2 was transiently overexpressed in JAK2(-) cells. The effect of IFN-? on the cell growth was assessed by XTT [2,3-bis(2-methoxy-4-nitro-S-sulfophenynl)-H-tetrazolium-5-carboxanilide inner salt] assay.The analysis of 8 melanoma cell lines linked the IFN-? unresponsiveness of Colo 857 cells determined by lack of inducibility of HLA class I surface expression on IFN-? treatment to a deletion of JAK2 on chromosome 9, whereas other IFN-? signaling pathway components were not affected. In addition, the constitutive HLA class I APM component expression levels were significantly reduced in JAK2(-) cells. Furthermore, JAK2-deficient cells were also resistant to the antiproliferative effect of IFN-?. Transfection of wild-type JAK2 into JAK2(-) Colo 857 not only increased the basal APM expression but also restored their IFN-? sensitivity.Impaired JAK2 expression in melanoma cells leads to reduced basal expression of MHC class I APM components and impairs their IFN-? inducibility, suggesting that malfunctional IFN-? signaling might cause HLA class I abnormalities.

SUBMITTER: Respa A 

PROVIDER: S-EPMC3426200 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature