Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA110469 | ENA |
REPOSITORIES: ENA
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Project description:Peroxisome proliferator-activated receptor-gamma (PPARg) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Following conditional prostatic epithelial knockout of PPARg in mice we observed focal hyperplasia of the epithelium which developed to mouse prostatic intraepithelial neoplasia (mPIN), becoming progressively more severe with time. We selectively knocked down PPARg2 isoform in wild-type mouse prostatic epithelial cells and examined the consequences of this in a tissue recombination model. Histopathologically the results resembled the conditional PPARg KO mouse prostates. Electron microscopy showed accumulated defective lysosomes and autophagic vacuoles in both of PPARg- and g2- deficient cells. Gene expression profiling indicated a major dysregulation of cell cycle control and metabolic signaling networks related to peroxisomal and lysosomal maturation, lipid oxidation and degradation. We conclude that PPARg maintains the maturation and turnover of peroxisomes and lysosomes in prostate epithelium. Disruption of PPARg signaling results in autophagy and oxidative stress during mPIN pathogenesis. The mPrE-PPARg knockout and mPrE-PPARg2 shRNA cells were compared to wildtype mPrE cells. Time (3 days culture) and cell types (x 4) were tested.
2010-05-18 | E-GEOD-13867 | biostudies-arrayexpress
Project description:Peroxisome proliferator-activated receptor-gamma (PPARg) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Following conditional prostatic epithelial knockout of PPARg in mice we observed focal hyperplasia of the epithelium which developed to mouse prostatic intraepithelial neoplasia (mPIN), becoming progressively more severe with time. We selectively knocked down PPARg2 isoform in wild-type mouse prostatic epithelial cells and examined the consequences of this in a tissue recombination model. Histopathologically the results resembled the conditional PPARg KO mouse prostates. Electron microscopy showed accumulated defective lysosomes and autophagic vacuoles in both of PPARg- and g2- deficient cells. Gene expression profiling indicated a major dysregulation of cell cycle control and metabolic signaling networks related to peroxisomal and lysosomal maturation, lipid oxidation and degradation. We conclude that PPARg maintains the maturation and turnover of peroxisomes and lysosomes in prostate epithelium. Disruption of PPARg signaling results in autophagy and oxidative stress during mPIN pathogenesis.
2009-12-07 | GSE13867 | GEO
Project description:Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development.
2022-07-14 | GSE164970 | GEO
Project description:Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development.
2022-07-14 | GSE164969 | GEO
Project description:Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development.
2022-07-14 | GSE164968 | GEO
Project description:Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development.
2022-07-14 | GSE164967 | GEO
Project description:A high fat diet and obesity have been linked to the development of metabolic dysfunction and the promotion of multiple cancers in mice and men. The causative cellular signals are multifactorial and not completely understood. Previous studies have shown that metabolic dysfunction leads to activation of the AKT and PKC pathways. Both signaling pathways are inhibited by the dual specificity phosphatase, INPP4B, which dephosphorylates PI(3,4)P2, an activator of AKT, and PI(4,5)P2, an activator of the PLC/PKC pathway. We established that INPP4B signaling protects mice from metabolic dysfunction. Inpp4b-/- male mice had accelerated activation of SREBF1 in liver which, along with the high fat diet, caused increased expression and activity of PPARG and other lipogenic pathways leading non-alcoholic fatty liver disease (NAFLD), type II diabetes, expansion and inflammation of WAT, and systemic and localized prostate inflammation that drives the development of high-grade prostatic intraepithelial neoplasia (PIN).
2021-02-04 | GSE134466 | GEO
Project description:Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe the first mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia, and invasive poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor (AR) signaling, effectively uncoupling the normal negative feedback between these two pathways. Associated RNA-seq data deposited in GEO: GSE94839.
2017-03-20 | PXD005309 | Pride
Project description:Protein homeostasis, or proteostasis is critical for organelle function, including mitochondria, but its role in cancer is controversial. Here, we show that transgenic mice expressing the mitochondrial chaperone, TRAP1 in the prostate develop prostatic hyperplasia and cellular atypia. When examined on a Pten+/- background, a common alteration in prostate cancer patients, TRAP1 transgenic mice showed accelerated incidence of invasive prostatic adenocarcinoma, characterized by increased cell proliferation and reduced apoptosis, in situ. Conversely, homozygous deletion of TRAP1 delays prostatic tumorigenesis in Pten+/- mice, without affecting hyperplasia or prostatic intraepithelial neoplasia (PIN). Global RNA sequencing and reverse phase protein array profiling of Pten+/--TRAP1 transgenic tumors reveals modulation of oncogenic networks of cell proliferation, apoptosis, cell motility, DNA damage and metabolism. Mechanistically, reconstitution of Pten+/- prostatic epithelial cells with TRAP1 results in increased cell proliferation, reduced apoptosis, heightened cell invasion, and no changes in mitochondrial bioenergetics. Therefore, TRAP1 promotes invasive prostate cancer, and provides an “actionable” therapeutic target in patients with advanced disease.
2017-05-11 | GSE81316 | GEO
Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of prostatic precancerous lesions to malignant tumors provides a broad time-frame for strategies targeting disease emergence. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on prostates of genetically-engineered Pten(i)pe- /- mice. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells during disease progression. Luminal HIF1A enhances glucose metabolism and promotes a PIN-derived secretome that increases the recruitment of myeloid-derived suppressor cells, thus dampening immune surveillance. Moreover, pharmacological inhibition of HIF1A induces apoptosis in early PIN lesions, and slows the proliferation of late ones. Therefore, our study identifies HIF1A as a target for PCa prevention. Importantly, we also demonstrate that HIF1A signaling correlates with the emergence of prostatic luminal cells expressing TGM2, the expression of which predicts early relapse after primary intervention in PCa patients.
2022-06-07 | GSE186419 | GEO