Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Sox9 mediated differential gene expression was assessed in prostaspheres derived from urogenital sinus epithelial cells

ABSTRACT: Prostate cancer is one of the most common malignancies and the second leading cause of death from cancer in men. The molecular mechanisms driving prostate carcinogenesis are complex; with several lines of evidence suggesting that the re-expression of conserved developmental programs play a key role. Through conditional gene targeting and organ grafting, we describe conserved roles for the transcription factor Sox9 in the initiation of both prostate organogenesis and prostate carcinogenesis in murine models. Abrogation of Sox9 expression prior to the initiation of androgen signaling blocks the initiation of prostate development. Similarly, Sox9 deletion in two genetic models of prostate cancer (TRAMP and Hi-Myc) blocks cancer initiation. Expression profiling of Sox9-null prostate epithelial cells reveals that the role of Sox9 in the initiation of prostate development may relate to its regulation of multiple cytokeratins and/or calcium-related proteins. Due to its essential role in cancer initiation, manipulation of Sox9 targets in at-risk men may prove useful in the chemoprevention of prostate cancer. Sox9 differential gene expression in prostaspheres derived from the urogenital sinus epithelium was assessed by tow-colors direct comparisons of labeled moieties. Hybridizations were performed on the Agilent (Santa Clara, CA) Whole Mouse Genome DNA microarray (mgug4122a). Sox9 targets were assessed in murine prostate epithelial cells with targeted deletion.

ORGANISM(S): Mus musculus

SUBMITTER: Luigi Marchionni

PROVIDER: E-GEOD-35419 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Full title: Comprehensive Characterization of Three-Dimensional Models for Prostate Cancer Growth and Invasion in Laminin-rich Extracellular Matrix Prostate Cancer (PrCa) cells undergo acinar morphogenesis and spheroid formation in three-dimensional (3D) culture, supported by laminin-rich extracellular matrix (lrECM, Matrigel). We developed miniaturized 3D model systems that facilitate investigation of morphogenesis and invasion of normal and PrCa cell lines in lrECM. Primary and non-transformed cell lines formed round structures with strong cell-cell contacts and epithelial polarization, lumen and a complete basal lamina (BL). In contrast, most PrCa cell lines formed either defective, “mass” spheroids with incomplete BL, or invasive “stellate” structures. The bioinformatic analyses of genome-wide mRNA expression data revealed massive alteration of key functional and signaling pathways in 3D cultures, with lipid and steroid metabolism, epigenetic reprogramming, and differentiation-related transcription factors induced across all cell lines by lrECM. In invasive cells, AKT, PI3Kinase, mTOR, and hedgehog signaling pathways were most highly activated, validated by small molecule inhibitors compounds specifically targeting key regulatory molecules. Compounds against AKT and PI3kinase pathways were significantly more effective in invasive cells, compared to mass or round/normal phenotype spheroids, and monolayer culture. A severe morphologic conversion was observed in PC-3 and PC-3M cells, transforming initially round, normal-appearing epithelial spheroids into rapidly invading cell masses. Markers for EMT (epithelial-mesenchymal transition) were highly expressed already in early stage, round spheroids prior to invasive conversion, and were not further increased in invasive cells. This indicates that PrCa cells can display extraordinary plasticity. EMT may be involved in providing a metastable genotype that allows morphological transformation, but is not be required for invasive processes themselves. Total RNA was obtained from non-transformed prostate epithelial cells and prostate cancer cells cultured in monolayer and three-dimensional laminin-rich extracellular matrix (growth factor-reduced Matrigel).

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Sox9 mediated differential gene expression was assessed in prostaspheres derived from urogenital sinus epithelial cells

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