Abstract
BackgroundWhile prostate cancer can often manifest as an indolent disease, the development of locally-advanced or metastatic disease can cause significant morbidity or mortality. Elucidation of molecular mechanisms contributing to disease progression is crucial for more accurate prognostication and effective treatments. R-Spondin 3 (RSPO3) is a protein previously implicated in the progression of colorectal and lung cancers. However, a role for RSPO3 in prostate cancer prognosis and behaviour has not been explored.MethodsWe compare the relative levels of RSPO3 expression between normal prostate tissue and prostate cancer in two independent patient cohorts (Taylor and GSE70768—Cambridge). We also examine the association of biochemical relapse with RSPO3 levels in these cohorts. For elucidation of the biological effect of RSPO3, we use siRNA technology to reduce the levels of RSPO3 in established prostate cancer cell lines, and perform in vitro proliferation, invasion, western blotting for EMT markers and clonogenic survival assays for radiation resistance. Furthermore, we show consequences of RSPO3 knockdown in an established chick chorioallantoic membrane (CAM) assay model of metastasis.ResultsRSPO3 levels are lower in prostate cancer than normal prostate, with a tendency for further loss in metastatic disease. Patients with lower RSPO3 expression have lower rates of biochemical relapse-free survival. SiRNA-mediated loss of RSPO3 results in no change to clonogenic survival and a lower proliferative rate, but increased invasiveness in vitro with induction of epithelial–mesenchymal transition (EMT) markers. Consistent with these results, lower RSPO3 expression translates to greater metastatic capacity in the CAM assay. Together, our preclinical findings identify a role of RSPO3 downregulation in prostate cancer invasiveness, and provide a potential explanation for how RSPO3 functions as a positive prognostic marker in prostate cancer.
Highlights
Prostate cancer is the second most common malignancy of males, and the fifth leading cause of cancer death worldwide [1]
R-Spondin 3 (RSPO3) expression is decreased in prostate cancer and prognosticates poorer biochemical relapse‐free survival Given the previous reports outlining overexpression of RSPO3 in various cancers, we sought to investigate whether RSPO3 overexpression is observed in patient cohorts of human prostate cancer using Oncomine Platform, a repository of gene expression datasets
There is a general trend towards lower RSPO3 expression with greater Gleason grade (Fig. 1a bottom left and bottom right panels), despite small (See figure on page.) Fig. 1 RSPO3 levels are lower in human prostate carcinoma, and RSPO3 is associated with reduced biochemical relapse-free survival. a Expression levels of RSPO3 in two cohorts of prostate cancer patients
Summary
Prostate cancer is the second most common malignancy of males, and the fifth leading cause of cancer death worldwide [1]. An estimated 1.1 million men were diagnosed with prostate cancer in 2012 across the world [1] While this disease can follow an indolent course, a substantial number of patients develop locally advanced or metastatic disease with associated morbidity and mortality. Wnt activation results in rescue of β-catenin molecule from degradation by. Upregulation of various players in Wnt signaling (including Wnt ligands, receptors, and regulator molecules) has been observed in certain prostate tumours or stroma [2]. In addition to the complexity contributed by conflicting roles of the same WNT ligand, there exist other Wnt ligands with potentially separate biological contributions to prostate cancer. While prostate cancer can often manifest as an indolent disease, the development of locally-advanced or metastatic disease can cause significant morbidity or mortality. A role for RSPO3 in prostate cancer prognosis and behaviour has not been explored
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