Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA.
Cancer Res. 2010 Mar 1;70(5):1896-905. doi: 10.1158/0008-5472.CAN-09-3549. Epub 2010 Feb 16.
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.
分泌型卷曲相关蛋白（sFRP）家族在各种癌症中抑制 Wnt 信号通路中发挥着重要作用。Wnt 拮抗剂 sFRP3 在肾癌中的功能意义尚未得到研究。我们进行了组织微阵列分析，发现 sFRP3 蛋白水平在正常肾脏中较高，在原发性肾癌组织中较低，在转移性肾癌组织中较高。因此，我们假设 sFRP3 可能在转移性肾癌中发挥重要作用。为了验证这一假设，我们使用原发性和转移性肾癌细胞系进行了一系列实验来确定 sFRP3 的作用。功能分析显示，sFRP3 转染的肾癌细胞系 A498 中活细胞和侵袭细胞的数量增加，凋亡细胞的数量减少，管形成增加。在注射 sFRP3 转染的 A498 细胞的裸鼠中也观察到肿瘤生长的促进。相比之下，sFRP3 mRNA 敲低转移性细胞（ACHN 和 Hs891.T）中活细胞和侵袭细胞的数量减少。为了研究 sFRP3 功能的机制，我们进行了微阵列分析，以观察 sFRP3 表达上调或下调了哪些基因。在这些基因中，sFRP3 转染细胞中 MMP-3 和 ANGPT1 显著上调。总之，这是第一项表明 sFRP3 表达促进肾癌细胞生长、侵袭和抑制凋亡的报告。
