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Global expression changes of LNCaP and PC3 cells in response to acute Notch activation

ABSTRACT: Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We report here that Notch1 expression is significantly reduced in a substantial fraction of human PCas, while it is unaffected or even increased in others. Global analysis of gene expression shows that increased Notch1 expression in PCa cells or samples, while counteracting to a significant extent the abnormal program of gene expression that is characteristically altered in clinically occurring tumors, enhances some other aberrant aspects of this program. In particular, down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity. While control of p21Cip1/WAF1 expression by increased Notch1 activity through a Smad3-dependent mechanism can explain the growth inhibitory effects, pro-oncogenic genes, like EPAS1 and CXCL6, are concomitantly up-regulated by Notch in PCa cell lines resistant to Notch1 growth inhibition, in agreement with enhanced tumorigenic behavior.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74631 | GEO | 2017/03/08

SECONDARY ACCESSION(S): PRJNA301039

REPOSITORIES: GEO

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Project description:Uterine receptivity implies a dialogue between the hormonally primed maternal endometrium and the free-floating blastocyst. Endometrial stromal cells proliferate, avert apoptosis, and undergo decidualization in preparation for implantation; however, the molecular mechanisms that underlie differentiation into the decidual phenotype remain largely undefined. The Notch family of transmembrane receptors transduce extracellular signals responsible for cell survival, cell-to-cell communication, and trans-differentiation, all fundamental processes for decidualization and pregnancy. Using a murine artificial decidualization model, pharmacological inhibition of Notch signaling by gamma-secretase inhibition resulted in significantly decreased deciduoma. Furthermore, a progesterone receptor (PR)-Cre Notch1 bigenic (Notch1d/d) confirmed a Notch1-dependant hypomorphic decidual phenotype. Microarray and pathway analysis, following Notch1 ablation, demonstrated significantly altered signaling repertoire. Concomitantly, hierarchical clustering demonstrated Notch1-dependent differences in gene expression. Uteri deprived of Notch1 signaling demonstrated decreased cellular proliferation; namely, reduced proliferation-specific antigen, Ki67, altered p21, cdk6, and cyclinD activity, and increased apoptotic-profile, augmented cleaved caspase-3, Bad, and attenuated Bcl2. Demonstrated here, the pre-implantation uterus relies on Notch signaling to inhibit apoptosis of stromal fibroblasts and regulate cell cycle progression, which together promotes successful decidualization. In summary, Notch1 signaling modulates multiple signaling mechanisms crucial for decidualization and we provide greater perspective to the coordination of multiple signaling modalities required during decidualization RNA samples from 3-5 separate mice were extracted. All mRNA quantities were normalized against 18S gene expression. Gene expression levels were measured by real-time RT-PCR SYBR Green analysis using the ABI Prism 7700 Sequence Detector System according to manufacturer’s instructions (Applied Biosystems).

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Global expression changes of LNCaP and PC3 cells in response to acute Notch activation

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