Role of Secreted Frizzled-Related Protein 3 in Human Renal Cell Carcinoma

The secreted frizzled-related protein (sFRP) family plays an important role in the inhibition of the Wnt signaling pathway in various cancers. The functional significance of Wnt antagonist sFRP3 has not been investigated in renal cancer. We performed tissue microarray and found that the level of sFRP3 protein was high in normal kidney, low in primary renal cancer tissues, and high in metastatic renal cancer tissues. Therefore, we hypothesized that sFRP3 may play an important role in metastatic renal cancer. To test this hypothesis, we performed a series of experiments to determine the role of sFRP3 using primary and metastatic renal cancer cell lines. Functional analysis showed increased numbers of viable and invaded cells and tube formation and decreased numbers of apoptotic cells in the sFRP3-transfected renal cancer cell line A498. Promotion of tumor growth was also observed in nude mice injected with sFRP3-transfected A498 cells. In contrast, the number of viable cells and invasive cells was decreased in sFRP3 mRNA knockdown metastatic cells (ACHN and Hs891.T). To investigate the mechanism of sFRP3 function, we performed microarray analysis to see which genes were upregulated or downregulated by sFRP3 expression. Among these genes, MMP-3 and ANGPT1 were significantly upregulated in sFRP3-transfected cells. In conclusion, this is the first report to show that sFRP3 expression promotes cell growth, invasion, and inhibition of apoptosis in renal cancer cells. Cancer Res; 70(5); 1896-905. (C) 2010 AACR.