Expression of the human Cathepsin L inhibitor hurpin in mice: skin alterations and increased carcinogenesis.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE5236 | GEO | 2007/08/18
SECONDARY ACCESSION(S): PRJNA96445
REPOSITORIES: GEO
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Project description:Aim of this study was to identify gene expression differences in the skin of hurpin (=headpin=serpinB13) transgenic mice in comparison to wildtype mice. Experiment Overall Design: Comparison of 4 transgenic mice with 3 wildtype mice. One wildtye sample was used two times. Experiment Overall Design: Age: 8 month. Experiment Overall Design: Gender: mixed (male and female)
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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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Project description:Female FVB/N and Tg.Ac (hemizygotes) mice 3-5 weeks of age were purchased from Harlan UK and Taconic UK, respectively. The mice were contained in an isolator and maintained at 19C with 50% relative humidity and a 12-hour light-dark cycle. Following a 1 week acclimatisation period the dorsal skin of the mice was shaved (approximately 8cm2 area) 2 days prior to commencing treatment. FVB/N mice (5 per group) were treated with dimethylbenz[a]anthracene (DMBA) (10ug/200ul in acetone) or vehicle control one week before promotion with TPA. TPA (2.5ug/200ul in acetone) was applied to the back of both FVB/N and Tg.Ac mice (5 per group) twice a week for up to 14 weeks; control mice received acetone. Mice were shaved and examined weekly for the presence of papillomas. At each time point (FVB/N mice 2, 4, 6 and 14 weeks of TPA promotion and Tg.Ac mice 4 days, 1, 2 and 9 weeks of TPA promotion) the mice were killed by cervical dislocation and the dorsal skin removed, a representative portion was fixed in 10% neutral buffered formalin and retained for histological analysis; the remainder was snap frozen in liquid nitrogen.
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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
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