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BackgroundTR4 nuclear receptor 4 (TR4) plays an important role in macrophages-associated foam cell formation of cardiovascular diseases and infiltrating macrophages are critical for prostate cancer (PCa) progression. However, the linkage of macrophages and TR4 and their impacts on PCa metastasis remains unclear.ResultsKnocking-down TR4 in human PCa cells (C4-2, CWR22Rv1), but not in human macrophages cells (THP-1), led to suppress the macrophages infiltration to PCa cells. The consequences of such suppression of the recruitment of macrophages toward PCa then resulted in suppressing the PCa cell invasion. Mechanism dissection found that knocking-down TR4 in PCa cells suppressed metastasis-related genes including MMP2, with induction of TIMP-1. Interruption assays using TIMP-1 neutralizing antibody could then reverse TR4-macrophage-mediated PCa invasion. IHC staining showed higher TR4 level, more macrophage infiltration, lower TIMP-1 and stronger MMP2/MMP9 in tumor tissues of the Gleason score 5 + 4 patients compared with the Gleason score 3 + 3 patients.ConclusionTargeting TR4 in prostate tumor microenvironment might represent a potential new therapeutic approach to better battle PCa metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-014-0281-1) contains supplementary material, which is available to authorized users.

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Testicular nuclear receptor 4 (TR4), also known as NR2C2 (nuclear receptor subfamily 2, group C, member 2), is a transcriptional factor and a member of the nuclear receptor family. TR4 was initially cloned from human and rat hypothalamus, prostate, and testes libraries. For almost two decades, its specific tissue distribution, genomic organization, and chromosomal assignment have been well investigated in humans and animals. However, it has been very difficult to study TR4's physiological functions due to a lack of specific ligands. Gene knock-out animal techniques provide an alternative approach for defining the biological functions of TR4. In vivo studies of TR4 gene knockout mice (TR4 −/− ) found that they display severe spinal curvature, subfertility, premature aging, and prostate prostatic intraepithelial neoplasia (PIN) development. Upstream modulators, downstream target gene regulation, feedback mechanisms, and differential modulation mediated by the recruitment of other nuclear receptors and coregulators have been identified in studies using the TR4 −/− phenotype. With the establishment of a tissue-specific TR4 −/− mouse model, research on TR4 will be more convenient in the future.