Pinna, Federico (2009) Controllo della progressione del carcinoma epatocellulare umano da parte della degradazione dell'oncosoppressore DUSP1. Doctoral Thesis.
Sustained activation of extracellular signal-regulated kinase (ERK) has been previously detected in numerous tumors in the absence of RAS activating mutations. Here, we evaluated the effects of the functional interactions of ERK proteins with dualspecificity phosphatase 1 (DUSP1), a specific inhibitor of ERK, and S-phase kinase-associated protein 2 (SKP2)/CDC28 protein kinase 1b (CKS1) ubiquitin ligase complex in human hepatocellular carcinoma (HCC). Levels of DUSP1, as assessed by PCR and western blot analysis, were significantly higher in tumors with better prognosis when compared with both normal and non-tumorous surrounding livers, whereas DUSP1 protein expression sharply declined in all HCC with poorer prognosis. In the latter HCC subtype, DUSP1 inactivation was due to ERK/SKP2/CKS1-dependent ubiquitination. Noticeably, expression levels of DUSP1 inversely correlated with those of activated ERK as well as with proliferation index and microvessel density, and directly with apoptosis and survival rate. Subsequent functional studies revealed that DUSP1 reactivation led to suppression of ERK, CKS1 and SKP2 activity, inhibition of proliferation and induction of apoptosis in human hepatoma cell lines. Taken together, the present data indicate that ERK achieves unrestrained activity during HCC progression by triggering ubiquitin-mediated proteolysis of its specific inhibitor DUSP1. Thus, DUSP1 may represent a valuable prognostic marker and ERK, CKS1 or SKP2 potential therapeutic targets for human HCC.
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