Unknown,Transcriptomics,Genomics,Proteomics

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Microarray analysis of gene expression differences in prostate specific antigen negative (PSA-ve) cells versus PSA+ve cells in human prostate cancer (HPCa) samples

ABSTRACT: Prostate cancer (PCa) is heterogeneous containing both phenotypically differentiated and undifferentiated tumor cells. An important unanswered question is whether these two populations of PCa cells are functionally different. Here we report the distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (i.e., PSA+) and low (PSA-/lo) levels of the differentiation marker PSA (prostatespecific antigen). PSA-/lo PCa cells are quiescent and resistant to multiple stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity in male mice. They preferentially express stem cell-associated genes and can undergo asymmetric cell division generating PSA+ cells. Importantly, PSA-/lo PCa cells can initiate robust tumor development in castrated hosts, survive androgen deprivation, and harbor highly tumorigenic castration-resistant PCa cells that can be further enriched using the ALDH+CD44+α2β1+ phenotype. In contrast, PSA+ PCa cells possess more limited tumor-propagating capacity, mainly undergo symmetric division, and are sensitive to castration. Together, our study suggests that PSA-/lo and PSA+ PCa cells are functionally distinct and PSA-/lo cells may represent one critical source of castration-resistant PCa cells. There are 4 sets of human samples in this study corresponding to 4 different prostate cancer patients labeled as HPCa46T, HPCa47T, HPCa49T and HPCa51T. Each set includes 3 technical triplicates (except HPCa46T) that were performed on dual color arrays and each individual array includes comparisons between PSA- (Cy5) and PSA+ (Cy3) cells of the respective patient prostate tumor.

ORGANISM(S): Homo sapiens

SUBMITTER: Dean Tang

PROVIDER: E-GEOD-35733 | 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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Microarray analysis of gene expression differences in prostate specific antigen negative (PSA-ve) cells versus PSA+ve cells in human prostate cancer (HPCa) samples

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