title: Absent in Melanoma 2 (AIM2) is an important mediator of interferon-dependent and -independent HLA-DRA and HLA-DRB gene expression in colorectal cancers.
abstract: Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible, nuclear proteins, associated with both, infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, we and others have previously demonstrated a high frequency of AIM2-alterations in microsatellite unstable (MSI-H) tumors. To further elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive target genes by microarray based gene expression profiling of 22 244 human genes. A total of 111 transcripts were significantly upregulated, whereas 80 transcripts turned out to be significantly downregulated in HCT116 cells, constitutively expressing AIM2, compared with AIM2-negative cells. Among the upregulated genes that were validated by quantitative PCR and western blotting we recognized several interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA), as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in 10 different IFN-γ treated colorectal cancer cell lines. Moreover, small interfering RNA-mediated knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB and CIITA in IFN-γ-treated cells. IFN-γ independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon doxycyclin-regulated transient induction of AIM2. Luciferase reporter assays revealed induction of the HLA-DR promoter upon AIM2 transfection in different cell lines. STAT-signaling was not involved in IFN-γ independent induction of ISGs, arguing against participation of cytokines released in an autostimulating manner. Our data indicate that AIM2 mediates both IFN-γ dependent and independent induction of several ISGs, including genes encoding the major histocompatibility complex (MHC) class II antigens HLA-DR-α and -β. This suggests a novel role of the IFN/AIM2/ISG cascade likewise in cancer cells.
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: N
authors.initials: N
authors.lastname: Gretz
authors.forename: J
authors.initials: J
authors.lastname: Gebert
authors.forename: S
authors.initials: S
authors.lastname: Dihlmann
mesh_terms: D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins; D015870:Gene Expression / Q000187:drug effects; D059805:HLA-DR alpha-Chains / Q000235:genetics*; D059806:HLA-DR beta-Chains / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D050791:STAT Transcription Factors / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics
chemical_list: C410167:AIM2 protein, human; D004268:DNA-Binding Proteins; D059805:HLA-DR alpha-Chains; D059806:HLA-DR beta-Chains; D053583:Interleukin-1beta; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D050791:STAT Transcription Factors; D015534:Trans-Activators; D007371:Interferon-gamma; D020170:Caspase 1