Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of CHUK deleted mouse keratinocytes compared to wild type mouse keratinocytes

ABSTRACT: It has long been known that excessive mitotic activity due to H-Ras can block keratinocyte differentiation and cause skin cancer. It is not clear, however, whether there are any innate surveillants that ensure keratinocytes undergoing terminal differentiation, preventing the disease. IKKÎ± induces keratinocyte terminal differentiation and its reduction promotes skin tumor development. However, its nature function in skin cancer is unknown. Here we found that mice with IKKÎ± deletion in keratinocytes or in hair follicle keratinocytes developed a thickened epidermis and spontaneous squamous cell-like carcinomas. Inactivation of epidermal growth factor receptor (EGFR) or reintroduction of IKKÎ± inhibited excessive mitosis, induced terminal differentiation, and prevented skin cancer through an EGFR-driven autocrine loop in mice. Thus, IKKÎ± serves as an innate surveillant. Experiment Overall Design: The differences in gene expression profiles of CHUK deleted mouse keratinocytes compared to wild type mouse keratinocytes were analyzed using two dual-channel agilent microarrays in duplicates.

ORGANISM(S): Mus musculus

SUBMITTER: Yinling Hu

PROVIDER: E-GEOD-12111 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:15-Lipoxygenase 2 (15-LOX2), a human-specific lipid-peroxidizing enzyme, is mainly expressed in luminal compartment of the normal prostate and often decreased or lost in prostate cancer (PCa). Previous studies from our lab implicate 15-LOX2 as a functional tumor suppressor. To better understand the biological role of 15-LOX2 in vivo, we established prostate-specific 15-LOX2 transgenic mice using the ARR2PB promoter. Unexpectedly, 15-LOX2 expression resulted in age-dependent prostatic hyperplasia. Interestingly, transgenic expression of 15-LOX2sv-b, a splice variant that lacks the arachidonic acid metabolizing activity, also induced hyperplasia and enlargement of the prostate. Prostatic hyperplasia induced by both 15-LOX2 and 15-LOX2sv-b was associated with an increase in proliferative (i..e., Ki67+) and luminal cells but 15-LOX2-induced hyperplasia was also accompanied by a prominent increase in basal cells. Microarray analysis revealed distinct gene expression profiles that could help explain the prostate phenotypes. Strikingly, 15-LOX2 (but not 15-LOX2sv-b) transgenic prostate showed up-regulation of several well-known stem/progenitor cell molecules including Sca-1, Trop2, p63 and Psca. Prostatic hyperplasia caused by both 15-LOX2 and 15-LOX2sv-b did not progress to PCa over >5 years of observations. Mechanistically, hyperplastic prostate lobes (especially those of the 15-LOX2 mice) showed a dramatic increase in senescent cells revealed by increased SA-ßgal, HP1, and p27Kip1 staining. Collectively, our results suggest that 15-LOX2 expression in mouse prostate leads to hyperplasia that activates the senescence checkpoint, which may in turn function as a barrier to tumor development. RNA was isolated from combined prostatic lobes of 6 mice (to reduce inter-animal variation) from ~2.5 month old (young; y) 15-LOX2 (line fl26), 15-LOX2sv-b (line svb9), wild type (wt) and ~15 month old (old; o) wt mice and hybridized onto Agilent's whole mouse genome oligoarrays arrays (G4122A) in fl26y(vs)wty, svb9y(vs)wty and wto(vs)wty combinations. The hybridizations were carried out in duplicates using an independent set of samples (biological replicates).

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Transcription profiling of CHUK deleted mouse keratinocytes compared to wild type mouse keratinocytes

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