Prognostic relevance of increased Rac GTPase expression in prostate carcinomas
Prognostic relevance of increased Rac GTPase expression in prostate carcinomas
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DOI：
10.1677/erc-06-0036
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发表时间：
2007-06-01
影响因子：
3.9
通讯作者：
Gabbert, H. E.
中科院分区：
文献类型：
--
作者：
Engers, R.;Ziegler, S.;Gabbert, H. E.
Rho 样 GTPase 家族的 Rac 蛋白，包括普遍存在的 Rac1、造血特异性 Rac2 和最少特征的 Rac3，在致癌转化、肿瘤侵袭和转移中发挥着重要作用。然而，Rac 表达在人类肿瘤中的预后相关性尚未得到研究。在本研究中，通过半定量免疫组织化学分析了 60 个 R0 切除根治性前列腺切除术标本的良性分泌上皮、高级前列腺上皮内瘤变 (HG-PIN) 和前列腺癌中 Rac 蛋白的表达。因此，与良性分泌上皮相比，Rac 蛋白在 HG-PIN (P < 0.001) 和前列腺癌 (P < 0.001) 中显着强表达。因此，通过异构体特异性实时 PCR 分析的所有肿瘤组织 (n=7) 均表现出比相应良性对应物 (P=0.018) 显着更高的 Rac RNA 表达水平（即 Rac1 和 Rac3 表达水平之和），这似乎主要是由于通过免疫印迹验证的 Rac3 异构体表达增加所致。单变量分析显示，前列腺癌中 Rac 蛋白表达增加 (P=0.045)、术前前列腺特异性抗原水平 (P=0.044)、pT 分期 (P=0.002) 和 Gleason 评分 (P=0.001) 与无病生存 (DFS) 降低具有统计学显着相关性。即使在包括所有这四个因素的多变量分析中，Rac 蛋白表达增加的这种预后效应仍然显着（相对风险 = 3.22，95% 置信区间 = 1.04-10.00；P = 0.043）。总之，我们的数据表明，前列腺癌中 Rac 蛋白表达相对于相应良性分泌上皮的增加是 DFS 降低的独立预测因素，并且似乎主要是由于 Rac3 亚型表达增加所致。
Rac proteins of the Rho-like GTPase family, including the ubiquitous Rac1, the hernatopoiesisspecific Rac2, and the least-characterized Rac3 play a major role in oncogenic transformation, tumor invasion and metastasis. However, the prognostic relevance of Rac expression in human tumors has not been investigated yet. In the present study, Rac protein expression was analyzed in benign secretory epithelium, high-grade prostatic intraepitheliurn neoplasia (HG-PIN), and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochernistry. Thus, Rac proteins were significantly strongly expressed in HG-PIN (P < 0.001) and prostate carcinomas (P < 0.001) when compared with benign secretory epithelium. Accordingly, all tumor tissues analyzed by isoform-specific real-time PCR (n=7) exhibited significantly higher RNA expression levels of Rac (i.e. sum of Rac1 and Rac3 expression levels) than the respective benign counterparts (P=0.018) and this appeared to result mainly from increased expression of the Rac3 isoform as verified by immunoblotting. Univariate analyses showed statistically significant associations of increased Rac protein expression in prostate cancer (P=0.045), preoperative prostate-specific antigen levels (P= 0.044), pT stage (P=0.002), and Gleason score (P=0.001) with decreased disease-free survival (DFS). This prognostic effect of increased protein expression of Rac remained significant even in a multivariate analysis including all these four factors (relative risk=3.22, 95% confidence interval= 1.04-10.00; P=0.043). In conclusion, our data suggest that increased Rac protein expression in prostate cancer relative to the corresponding benign secretory epithelium is an independent predictor of decreased DFS and appears to result mainly from increased expression of the Rac3 isoform.