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The role of relaxin in prostate cancer Thompson, Vanessa Camille

Abstract

Prostate cancer is the leading cause of cancer in men, and there is currently a lack of novel treatment options for this disease. Relaxin, part of the insulin superfamily, is a potent peptide hormone normally produced and secreted by the human prostate. cDNA and tissue microarray analyses, indicated that relaxin is highly overexpressed in prostate cancer progression to androgen independence (AI), and is negatively regulated by androgens. Characterization of the relaxin receptor, LGR7, in xenografts and human patient tissue microarrays (TMAs) indicated that LGR7 is expressed in the stroma and epithelia, suggesting that relaxin may act in an autocrine and/or paracrine fashion. Relaxin is known to increase angiogenesis through upregulation of vascular endothelial growth factor, and matrix metalloproteases. To elucidate novel pathways that may be upregulated by relaxin in prostate cancer, the effects of relaxin overexpression in the LNCaP prostate cancer xenograft model were analysed by gene expression microarrays. A novel discovery is that the protocadherinY (PCDHY)/Wnt pathway is upregulated by relaxin, resulting in β-catenin translocation from the cell membrane to the cytoplasm and upregulation of Wnt11, which can stimulate proliferation, transformation, and migration. Relaxin is well characterized in the uterus and ovary to increase insulin-like growth factor-I (IGF-I); relaxin may also increase IGF-I in prostate cancer. Since IGF-I and various other growth factor signaling is mediated by insulin receptor substrate-2 (IRS-2), and IGF-I signaling is important in prostate cancer progression to AI, we investigated the role of IRS-2 in LNCaP cells. IRS-2 mRNA is dramatically upregulated by androgens, and decreased by IGF-I in androgen treated cells. IRS-2 was knocked down using IRS-2 siRNA to explore the interaction between the IGF axis and androgen signalling. Combined IGF-I and androgen treatment reduced transcription of androgen regulated genes, prostate specific antigen, insulin degrading enzyme, vascular endothelial growth factor, and clusterin. This indicates that in the presence of IGF-I treatment, IRS-2 mRNA is required for normal androgen mediated transcription. Due to the potential for relaxin to induce proliferation and metastases, and the necessity of IRS-2 to mediate androgen action, relaxin and IRS-2 are intriguing targets for novel, targeted therapeutics for prostate cancer.

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