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: Stefan K Drexler, Luca Bonsignore, Mark Masin, Aubry Tardivel, Rene Jackstadt, Heiko Hermeking, Pascal Schneider, Olaf Gross, Jurg Tschopp, Amir S Yazdi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 45 Pg. 18384-9 (Nov 06 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 23090995 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Cytokines
• Cytoskeletal Proteins
• Inflammasomes
• PYCARD protein, human
• Pycard protein, mouse
• Receptors, Interleukin-1
• Tumor Suppressor Protein p53
• 9,10-Dimethyl-1,2-benzanthracene
• Caspase 1
• Tetradecanoylphorbol Acetate

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Caspase 1 (deficiency, metabolism)
• Cell Proliferation
• Cell Transformation, Neoplastic (pathology)
• Cytokines (biosynthesis)
• Cytoskeletal Proteins (deficiency, metabolism)
• Down-Regulation
• Epithelium (metabolism, pathology)
• Humans
• Inflammasomes (metabolism)
• Inflammation (pathology)
• Keratinocytes (metabolism, pathology)
• Mice
• Mice, Knockout
• Myeloid Cells (metabolism, pathology)
• Neoplasms, Squamous Cell (pathology)
• Organ Specificity
• Receptors, Interleukin-1 (deficiency, metabolism)
• Skin (pathology)
• Skin Neoplasms (metabolism, pathology, prevention & control)
• Tetradecanoylphorbol Acetate
• Tumor Microenvironment
• Tumor Suppressor Protein p53 (metabolism)