SPARC is a key mediator of TGF-β-induced renal cancer metastasis
SPARC is a key mediator of TGF-β-induced renal cancer metastasis
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TGF-β诱导肾癌转移的关键介导因子
DOI：
10.1002/jcp.29975
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发表时间：
2020-08-11
影响因子：
5.6
通讯作者：
Tan, Wan-Long
中科院分区：
文献类型：
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作者：
Bao, Ji-Ming;Dang, Qiang;Tan, Wan-Long
转化生长因子- β 1 （tgf - β 1）的异常表达通过诱导肿瘤转移与肾细胞癌（RCC）进展相关。然而，tgf - β信号通路的下游效应因子尚未完全表征。本研究通过差异表达基因分析和微阵列分析，确定了RCC中分泌蛋白（secreted protein acid and rich In半胱氨酸，SPARC）作为tgf - β调控基因的升高，并在多个RCC细胞系中进一步证实了这一结果。在临床上，这两个基因的表达在RCC患者标本中呈正相关。此外，在所有类型的RCC中均发现SPARC表达升高，并与RCC分期和分级呈正相关。相反，SPARC表达与RCC患者的总体生存和无病生存呈负相关，表明SPARC是RCC患者生存的有效预后标志物。在体外和体内，敲除SPARC可显著抑制RCC细胞的侵袭和转移。同样地，体外细胞侵袭可以通过使用特定的单克隆抗体来减少。在机制上，SPARC激活蛋白激酶B （AKT）通路，导致基质金属蛋白酶-2表达升高，从而促进RCC侵袭。总之，我们的数据支持SPARC是tgf - β信号网络在RCC进展中的关键作用，是潜在的治疗靶点和预后标志物。
Aberrant expression of transforming growth factor-beta 1 (TGF-beta 1) is associated with renal cell carcinoma (RCC) progression by inducing cancer metastasis. However, the downstream effector(s) in TGF-beta signaling pathway is not fully characterized. In the present study, the elevation of secreted protein acidic and rich in cysteine (SPARC) as a TGF-beta 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-beta signaling network underlying RCC progression and a potential therapeutic target as well as a prognostic marker.