Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors
Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors
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DOI：
10.1038/sj.onc.1209635
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发表时间：
2006-10-05
期刊：
影响因子：
8
通讯作者：
Sata, M.
中科院分区：
文献类型：
--
作者：
Yoshida, T.;Hisamoto, T.;Sata, M.
Ras/Raf-1/细胞外调节激酶（ERK）通路的异常激活已被证明参与人肝细胞癌（HCC）的进展。然而，ERK激活失调的机制知之甚少。最近，我们鉴定了具有Ena/血管扩张剂刺激的磷蛋白同源性-1结构域（Spred）的Sprouty相关蛋白作为Ras/Raf-1/ERK通路的生理抑制剂。在这项研究中，我们发现，Spred-1和-2在人肝癌组织中的表达水平经常下降，与邻近的非肿瘤组织相比。肝癌组织中Spred的表达水平与肿瘤的浸润和转移呈负相关。Spred-1的强制表达在体外和体内抑制HCC细胞增殖，这与ERK活化减少有关。Spred-1的过表达还降低了基质金属蛋白酶-9（MMP-9）和MMP-2的分泌，而MMP-9和MMP-2在肿瘤的侵袭和转移中起重要作用。此外，Spred-1还抑制生长因子介导的肝癌细胞运动。这些数据表明，Spred在HCC中表达的减少是获得恶性特征的原因之一。因此，Spred不仅可以作为一种新的预后因子，而且可以作为一种新的治疗靶点。
Aberrant activation of the Ras/Raf-1/extracellular-regulated kinase (ERK) pathway has been shown to be involved in the progression of human hepatocellular carcinoma (HCC). However, the mechanism of dysregulation of ERK activation is poorly understood. Recently, we identified Sprouty-related protein with Ena/vasodilator stimulated phosphoprotein homology-1 domain (Spred) as a physiological inhibitor of the Ras/Raf-1/ERK pathway. In this study, we found that the expression levels of Spred-1 and -2 in human HCC tissue were frequently decreased, comparing with those in adjacent non-tumorous tissue. Moreover, Spred expression levels in HCC tissue were inversely correlated with the incidence of tumor invasion and metastasis. Forced expression of Spred-1 inhibited HCC cell proliferation in vitro and in vivo, which was associated with reduced ERK activation. Spred-1 overexpression also reduced the secretion of matrix metalloproteinase-9 (MMP-9) and MMP-2, which play important roles in tumor invasion and metastasis. In addition, Spred-1 inhibited growth factor-mediated HCC cell motility. These data indicate that the reduction of Spred expression in HCC is one of the causes of the acquisition of malignant features. Thus, Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC.