Abstract
Abstract The Retinal Determination Gene Network (RDGN), consisting of dachshund (dac), eyes absent (eya), and sin oculis (so), is best known for its role in eye specification. Recently, coordinate abnormal expression of the DACH1/Eya/Six complex has been observed in human tumors supporting a tumor promoting role of Six and Eya family members, and a tumor-suppressor function of DACH. Oncogenes sustain host-cell interactions, promoting invasiveness, recruiting inflammatory mediators and developing angiogenic networks. Ras and Myc promote tumor angiogenesis through up-regulation of VEGF and the inflammatory mediator, interleukin-8(IL-8) and interleukin-6 (IL-6). Altered expressions of the IL-6 and IL-8 genes are seen in many cancers including prostate cancer. Hormone-resistant prostate carcinoma cell lines produce large amounts of IL-6 and IL-8 compared to hormone responsive prostate cancer cell lines. The expression of IL-8 and IL-6 are linked to poor prognosis and metastatic phenotype in prostate cancer. Recent finding demonstrated that IL-6 regulates the dynamic equilibrium between cancer stem cells and non-stem cancer cells in human breast and prostate cancer. Moreover, IL-6 alone can transform non-tumorigenic benign prostate epithelial cells and further progress to invasive phenotype. We had previously reported that the expression of DACH1 was reduced in human prostate cancer and DACH1 inhibited androgen signaling transduction. To explore the role of DACH1 in androgen resistant prostate cancer, PC3 cells stably expressing DACH1 were established. DACH1 inhibited cellular proliferation evaluated by MTT assay and growth curve. Microarray analyses demonstrated DACH1 inhibited mRNA expression of GRO, IL-6, IL-8 by 75%, 80% and 90%, respectively. However, there was no change of mRNA expression for IL-6 and IL-8 receptor. Ectopic expression of DACH1 in PC-3 cells significantly decreased tumor growth compared with vector control group (p<0.001), and DS domain was required. It has been reported that stable expression IL-6 in SV40T immortalized non-tumorigenic prostate epithelial cell line p69 induced EMT and acquired malignant phenotypes through autocrine loop IL6 and IGF-1R signaling. To further test the functional interaction of DACH1 with IL-6, a table cells expressing IL-6 alone or IL-6 with DACH1 were deployed. Ectopic expression of DACH1 attenuated activation of IGF-1R by IL-6 as evaluated by phosphorylation of IGF-1R. Subcutaneous implantation study showed an in vivo tumor growth initiated by IL-6 in p69 was inhibited by more than 60% with the expression of DACH1. Together, our studies suggest that DACH1 is a potential tumor suppressor of prostate through repression of IL-6 signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-16. doi:1538-7445.AM2012-LB-16
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