Coherent Expression Chromosome Cluster Analysis Reveals DifferentialRegulatory Functions of Amino-Terminal and Distal ParathyroidHormone-Related Protein Domains in Prostate Carcinoma

[摘要] Parathyroid hormone-related protein (PTHrP) has a number ofcancer-related actions. While best known for causing hypercalcemiaof malignancy, it also has effects on cancer cell growth,apoptosis, and angiogenesis. Studying the actions of PTHrP inhuman cancer is complicated because there are three isoforms andmany derived peptides. Several peptides are biologically active atknown or presumed cell surface receptors; in addition, thePTHrP-derived molecules can exert effects at the cell nucleus. Toaddress this complexity, we studied gene expression in a DU 145prostate cancer cell line that was stably transfected with controlvector, PTHrP 1-173 and PTHrP 33-173. With this model, regulatoryeffects of the amino-terminal portion of PTHrP would result onlyfrom transduction with the full-length molecule, while effectspertaining to distal sequences would be evident with eitherconstruct. Analysis of the expression profiles by microarraysdemonstrated nonoverlapping groups of differentially expressedgenes. Amino-terminal PTHrP affected groups of genes involved inapoptosis, prostaglandin and sex steroid metabolism, cell-matrixinteractions, and cell differentiation, while PTHrP 33-173 causedsubstantial increases in MHC class I antigen expression. This workdemonstrates the distinct biological actions of the amino-terminuscompared to distal mid-molecule or carboxy-terminal sequences ofPTHrP in prostate carcinoma cells and provides targets for furtherstudy of the malignant process.

[学科分类] 基础医学