Aberrant expression of transforming growth factor‐β1 (TGF‐β1) is associated with renal cell carcinoma (RCC) progression by inducing cancer metastasis. However, the downstream effector(s) in TGF‐β signaling pathway is not fully characterized. In the present study, the elevation of secreted protein acidic and rich in cysteine (SPARC) as a TGF‐β regulated gene in RCC was identified by applying differentially expressed gene analysis and microarray analysis, we further confirmed this result in several RCC cell lines. Clinically, the expression of these two genes is positively correlated in RCC patient specimens. Furthermore, elevated SPARC expression is found in all the subtypes of RCC and positively correlated with the RCC stage and grade. In contrast, SPARC expression is inversely correlated with overall and disease‐free survival of patients with RCC, suggesting SPARC as a potent prognostic marker of RCC patient survival. Knocking down SPARC significantly inhibits RCC cell invasion and metastasis both in vitro and in vivo. Similarly, in vitro cell invasion can be diminished by using a specific monoclonal antibody. Mechanistically, SPARC activates protein kinase B (AKT) pathway leading to elevated expression of matrix metalloproteinase‐2 that can facilitate RCC invasion. Altogether, our data support that SPARC is a critical role of TGF‐β signaling network underlying RCC progression and a potential therapeutic target as well as a prognostic marker.

中文翻译：

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SPARC 是 TGF-β 诱导的肾癌转移的关键介质。

转化生长因子-β1 (TGF-β1) 的异常表达通过诱导癌症转移与肾细胞癌 (RCC) 进展相关。然而，TGF-β 信号通路中的下游效应子尚未完全表征。在本研究中，通过应用差异表达基因分析和微阵列分析，鉴定了 RCC 中分泌的酸性和富含半胱氨酸蛋白 (SPARC) 作为 TGF-β 调节基因的升高，我们在几种 RCC 细胞系中进一步证实了这一结果。临床上，这两个基因的表达在 RCC 患者标本中呈正相关。此外，在 RCC 的所有亚型中都发现了升高的 SPARC 表达，并且与 RCC 分期和等级呈正相关。相比之下，SPARC 表达与 RCC 患者的总体生存率和无病生存率呈负相关，表明 SPARC 是 RCC 患者生存的有效预后标志物。敲低 SPARC 显着抑制 RCC 细胞在体外和体内的侵袭和转移。同样，使用特异性单克隆抗体可以减少体外细胞侵袭。从机制上讲，SPARC 激活蛋白激酶 B (AKT) 通路，导致基质金属蛋白酶-2 的表达升高，从而促进 RCC 侵袭。总而言之，我们的数据支持 SPARC 是 RCC 进展背后的 TGF-β 信号网络的关键作用，是潜在的治疗靶点和预后标志物。使用特异性单克隆抗体可以减少体外细胞侵袭。从机制上讲，SPARC 激活蛋白激酶 B (AKT) 通路，导致基质金属蛋白酶-2 的表达升高，从而促进 RCC 侵袭。总而言之，我们的数据支持 SPARC 是 RCC 进展背后的 TGF-β 信号网络的关键作用，是潜在的治疗靶点和预后标志物。使用特异性单克隆抗体可以减少体外细胞侵袭。从机制上讲，SPARC 激活蛋白激酶 B (AKT) 通路，导致基质金属蛋白酶-2 的表达升高，从而促进 RCC 侵袭。总而言之，我们的数据支持 SPARC 是 RCC 进展背后的 TGF-β 信号网络的关键作用，是潜在的治疗靶点和预后标志物。