title: Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis.
abstract: A chronic inflammatory microenvironment favors tumor progression through molecular mechanisms that are still incompletely defined. In inflammation-induced skin cancers, IL-1 receptor- or caspase-1-deficient mice, or mice specifically deficient for the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) in myeloid cells, had reduced tumor incidence, pointing to a role for IL-1 signaling and inflammasome activation in tumor development. However, mice fully deficient for ASC were not protected, and mice specifically deficient for ASC in keratinocytes developed more tumors than controls, suggesting that, in contrast to its proinflammatory role in myeloid cells, ASC acts as a tumor-suppressor in keratinocytes. Accordingly, ASC protein expression was lost in human cutaneous squamous cell carcinoma, but not in psoriatic skin lesions. Stimulation of primary mouse keratinocytes or the human keratinocyte cell line HaCaT with UVB induced an ASC-dependent phosphorylation of p53 and expression of p53 target genes. In HaCaT cells, ASC interacted with p53 at the endogenous level upon UVB irradiation. Thus, ASC in different tissues may influence tumor growth in opposite directions: it has a proinflammatory role in infiltrating cells that favors tumor development, but it also limits keratinocyte proliferation in response to noxious stimuli, possibly through p53 activation, which helps suppressing tumors.
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Drexler
authors.forename: Luca
authors.initials: L
authors.lastname: Bonsignore
authors.forename: Mark
authors.initials: M
authors.lastname: Masin
authors.forename: Aubry
authors.initials: A
authors.lastname: Tardivel
authors.forename: Rene
authors.initials: R
authors.lastname: Jackstadt
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Olaf
authors.initials: O
authors.lastname: Gross
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Amir S
authors.initials: AS
authors.lastname: Yazdi
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000172:deficiency / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000378:metabolism*; D015536:Down-Regulation; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D018307:Neoplasms, Squamous Cell / Q000473:pathology; D009928:Organ Specificity; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000378:metabolism; D012867:Skin / Q000473:pathology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D013755:Tetradecanoylphorbol Acetate; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C402202:PYCARD protein, human; C498534:Pycard protein, mouse; D017472:Receptors, Interleukin-1; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; D020170:Caspase 1; D013755:Tetradecanoylphorbol Acetate