Abstract
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.
Highlights
Cell proliferation is a highly regulated process with multiple levels of control in normal cells, and dysregulated proliferation is one of the most important biological features of cancer
Actin-stress fiber formation has been shown frequently in invasive and metastatic lesions of many cancers. These findings suggest that activation of the Ras/Raf-1/ERK pathway is associated with malignant phenotypes of tumors, and the status of this pathway may reflect the prognosis of an hepatocellular carcinoma (HCC) patient
We found that the expression of stimulated phosphoprotein homology-1 domain (Spred)-1 and that of Spred-2 were simultaneously decreased in HCC tissue compared with adjacent non-tumorous tissue in about 70% of HCC patients
Summary
Cell proliferation is a highly regulated process with multiple levels of control in normal cells, and dysregulated proliferation is one of the most important biological features of cancer. Expression of Sprouty-related protein with Ena/ vasodilator-stimulated phosphoprotein homology-1 domains and extracellular-regulated kinase activation in human human hepatocellular carcinoma tissue First, we confirmed that ERK activation levels were higher in HCC tissues than in non-tumorous regions, which is consistent with previous reports (Ito et al, 1998). Spred is necessary to prevent the progression to aggressive tumor T Yoshida et al Figure 1 Extracellular-regulated kinase (ERK) activation and reduction of Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred) expression in human hepatocellular carcinoma (HCC). Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain-1 inhibits human hepatocellular carcinoma cell tumorigenesis We investigated whether Spreds exhibit inhibitory action on HCC cell growth, invasion and metastasis. Spred is necessary to prevent the progression to aggressive tumor T Yoshida et al Akt pathway (Figure 3a) These findings suggest that Spred regulates HCC cell migration mainly through the Ras/Raf-1/ERK pathway
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