Interferon-induced tumor-suppressive activity of Absent in Melanoma 2 (AIM2) in gastrointestinal cancers

• Antragstellerin: Professorin Dr. Susanne Dihlmann
• Fachliche Zuordnung: Pathologie
• Förderung: Förderung von 2008 bis 2011
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 92054903

During carcinogenesis tumor cells are continuously exposed to different types of immune cells. Some of these cells release interferons (IFNs), a family of cytokines that mediate pro-and antiinflammatory as well as tumor-suppressive functions. Although the receptors and intracellular signaling components of the IFN-signaling pathway are well understood, little is known about the function of IFN-induced target genes and their role in tumor suppression. We recently examined in detail alterations of the absent in melanoma 2 (AIM2) gene that belongs to the HIN-200 family of IFNinducible proteins. AIM2 shows a high frequency of frameshift mutations in microsatellite unstable (MSI-H) colorectal, gastric, and endometrial tumors. In addition, it is affected by other mutations and promoter silencing in primary colon cancers and cell lines, suggesting that its inactivation might be involved in tumor escape mechanisms. Supporting evidence came from stable restoration of recombinant AIM2 in AIM2-deficient cells which clearly suppressed colony formation, cell proliferation and viability by reducing endogenous and TNF-α stimulated nuclear factor kappa B (NF-kB) signaling activity. Interestingly, there was no evidence for the (A9) frameshift mutation to affect any of the analyzed AIM2 functions. Microarray-based differential expression analysis revealed substantial AIM2- induced up-regulation of genes involved in immunomodulation, such as IFN-responsive, -inducing or - enhancing genes, and genes involved in cell-cell signaling. Moreover, a great number of genes that was down-regulated upon constitutive AIM2 expression point to a role of AIM2 in regulation of cancer related lipid metabolism. The studies applied for here aim to understand the tumor suppressive mechanism of AIM2 in more detail. Accordingly, both, downstream effects and upstream mechanisms of AIM2 expression will be analyzed. In particular, we will characterize AIM2-responsive target genes to link IFN-mediated anti-tumor effects, cell differentiation and cancer related metabolism. In addition, AIM2-responsiveness to other cytokines and JAK/STAT-mediated activation of AIM2 expression will be studied to link cytokine signaling to induction of AIM2. Our studies shall add to understanding cytokine (IFN and others) -mediated anti-tumor effects and putative tumor escape mechanisms thereby providing the basis for development of novel anti-cancer therapies.

• DFG-Verfahren: Sachbeihilfen