title: The tumour suppressor Fhit positively regulates MHC class I expression on cancer cells.
abstract: MHC class I (MHC-I) molecules are ubiquitously expressed on the cells of an organism. Study of the regulation of these molecules in normal and disease conditions is important. In tumour cells, the expression of MHC-I molecules is very frequently lost, allowing these cells to evade the immune response. Cancers of different histology have shown total loss of MHC-I molecule expression, due to a coordinated transcriptional down-regulation of various antigen-processing machinery (APM) components and/or MHC-I heavy chains. The mechanisms responsible for these alterations remain unclear. We determined the possible genes involved by comparing MHC-I-positive with MHC-I-negative murine metastases derived from the same fibrosarcoma tumour clone. MHC-I-negative metastases showed transcriptional down-regulation of APM and MHC-I heavy chains. The use of microarrays and subtraction cDNA libraries revealed four candidate genes responsible for this alteration, but two of them were ruled out by real-time RT-PCR analyses. The other two genes, AP-2α and Fhit tumour suppressors, were studied by using siRNA to silence their expression in a MHC-I-positive metastatic cell line. AP-2α inhibition did not modify transcriptional expression of APM components or MHC-I heavy chains or surface expression of MHC-I. In contrast, silencing of the Fhit gene produced the transcriptional down-regulation of APM components and MHC-I heavy chains and decreased MHC-I surface expression. Moreover, transfection of Fhit in MHC-I-negative tumour cell lines restored MHC-I cell surface expression. These data indicate that defects in Fhit expression may promote MHC-I down-regulation in cancer cells and allow escape from immunosurveillance(#).
authors.affiliation: Servicio de Análisis Clínicos & Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Romero
authors.forename: Marisol
authors.initials: M
authors.lastname: Martinez
authors.forename: Cristina
authors.initials: C
authors.lastname: Garrido
authors.forename: Antonia
authors.initials: A
authors.lastname: Collado
authors.forename: Ignacio
authors.initials: I
authors.lastname: Algarra
authors.forename: Federico
authors.initials: F
authors.lastname: Garrido
authors.forename: Angel M
authors.initials: AM
authors.lastname: Garcia-Lora
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017951:Antigen Presentation; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D019139:Tumor Escape; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D015395:Histocompatibility Antigens Class I; D007143:Immunoglobulin Heavy Chains; D009363:Neoplasm Proteins; D050656:Transcription Factor AP-2; D000099170:Bis(5'-adenosyl)triphosphatase