Signaling strength determines proapoptotic functions of STING
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE100411 | GEO | 2017/06/24
SECONDARY ACCESSION(S): PRJNA391688
REPOSITORIES: GEO
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Project description:Hepatocellular carcinoma (HCC) emerges from chronic inflammation to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that while p62 positively regulates STING ubiquitination by TRIM32 by displacing NBR1, which results in the activation of the interferon (IFN) cascade, NBR1 prevents TRIM32 interaction with and the activation of STING, leading to impaired IFN synthesis. NBR1 also antagonizes STING function by promoting its trafficking from the Golgi to the endosome-lysosomal degradative cascade independent of autophagy. Importantly, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs. The upregulation of the STING-IFN pathway by NBR1 deficiency enhances the anti-tumor response mediated by CD8+ T cells. These results identify NBR1 as a synthetic vulnerability of p62-deficiency in HSCs. NBR1 loss, by promoting the STING/IFN pathway, boosts anti-tumor CD8+ T cell responses to restrain HCC.
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Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from DMBA or acetone treated wild type (WT) or STING deficient (SKO) mouse skin or skin tumor was examined for gene expression.
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