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1.
J Hepatol ; 55(5): 1049-57, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21356256

ABSTRACT

BACKGROUND & AIMS: Differential expression of tumor-relevant proteins based on aberrant proteasomal degradation may contribute to human (hepato)carcinogenesis. Recently, we identified the E3 ubiquitin ligase seven in absentia homolog (SIAH)-1 as frequently dysregulated in human hepatocellular carcinoma (HCC). We therefore systematically analyzed the expression, functional relevance, as well as possible downstream effectors of SIAH-1 in human liver carcinogenesis. METHODS: SIAH-1 expression was analyzed at the transcript and protein levels in human hepatocarcinogenesis and in HCC cells. Proliferation, apoptosis, and migration of different HCC cell lines were examined after siRNA-mediated inhibition of SIAH-1. In order to identify downstream effectors that mediate SIAH-1 effects, correlative analyses of protein expression profiles were performed. RESULTS: In HCC tissues both reduction of cytoplasmic SIAH-1 and especially its nuclear accumulation positively correlated with HCC progression. RNA interference revealed that nuclear expression of SIAH-1 predominantly supported HCC cell proliferation and migration while only moderately affecting anti-apoptosis. In de-differentiated human HCCs, nuclear SIAH-1 accumulation significantly correlated with the expression of the transcription factor far-upstream element (FUSE)-binding protein (FBP)-3. In vitro, SIAH-1 positively and indirectly regulated FBP-3 which itself primarily supported HCC cell proliferation. Indeed, high level expression of FBP-3 in human HCCs significantly correlated with reduced overall survival of patients. CONCLUSIONS: Nuclear accumulation of the E3 ubiquitin ligase SIAH-1 supports different pro-tumorigenic cellular processes associated with tumor growth and tumor cell dissemination in human hepatocarcinogenesis. It promotes HCC cell proliferation by at least partly employing the transcription factor FBP-3. Therefore, interference with SIAH-1 activity represents a promising approach to suppress HCC growth.


Subject(s)
Carcinoma, Hepatocellular/genetics , Cell Transformation, Neoplastic/metabolism , Liver Neoplasms/genetics , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Apoptosis , Carcinoma, Hepatocellular/enzymology , Cell Line, Tumor , Cell Movement , Cell Nucleus/metabolism , Cell Proliferation , Cytoplasm/metabolism , DNA-Binding Proteins/metabolism , Down-Regulation , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Liver Neoplasms/enzymology , Nuclear Proteins/antagonists & inhibitors , RNA, Small Interfering/genetics , Statistics, Nonparametric , Transcription Factors/metabolism , Transfection , Ubiquitin-Protein Ligases/antagonists & inhibitors
2.
Clin Cancer Res ; 15(2): 650-9, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-19147771

ABSTRACT

PURPOSE: The death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R) are involved in immune surveillance and tumor development. Here, we studied a possible association between the expression of TRAIL/TRAIL-Rs and the prognosis in patients with renal cell carcinomas (RCC). EXPERIMENTAL DESIGN: A tissue microarray containing RCC tumor tissue samples and corresponding normal tissue samples from 838 patients was generated. Expression of TRAIL and TRAIL-Rs was examined by immunohistochemistry and the effect of TRAIL and TRAIL-R expression on disease-specific survival was assessed. RESULTS: High TRAIL-R2 expression levels were associated with high-grade RCCs (P < 0.001) and correlated negatively with disease-specific survival (P = 0.01). Similarly, high TRAIL expression was associated with a shorter disease-specific survival (P = 0.01). In contrast, low TRAIL-R4 expression was associated with high-stage RCCs (P < 0.001) as well as with the incidence of distant metastasis (P = 0.03) and correlated negatively with disease-specific survival (P = 0.02). In patients without distant metastasis, multivariate Cox regression analyses revealed that TRAIL-R2 and TRAIL are independent prognostic factors for cancer-specific survival (in addition to tumor extent, regional lymph node metastasis, grade of malignancy, and type of surgery). CONCLUSION: High TRAIL-R2, high TRAIL, and low TRAIL-R4 expression levels are associated with a worse disease-specific survival in patients with RCCs. Therefore, the assessment of TRAIL/TRAIL-R expression offers valuable prognostic information that could be used to select patients for adjuvant therapy studies. Moreover, our findings are of relevance for a potential experimental therapeutic administration of TRAIL-R agonists in patients with RCCs.


Subject(s)
Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/metabolism , Gene Expression Regulation, Neoplastic , Kidney Neoplasms/diagnosis , Kidney Neoplasms/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , TNF-Related Apoptosis-Inducing Ligand/metabolism , Aged , Female , Gene Expression Profiling , Humans , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Prognosis , Proportional Hazards Models , Treatment Outcome
3.
Hepatology ; 46(3): 759-68, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17663418

ABSTRACT

UNLABELLED: The microtubule (MT)-destabilizing protein stathmin/Op18 has previously been described to be negatively regulated by p53 and to be highly expressed in several tumor entities. However, little is known about its expression profile, functional or therapeutic relevance, and regulation in human hepatocarcinogenesis. Here we demonstrate cytoplasmic overexpression of stathmin in premalignant lesions (dysplastic nodules; DNs) and hepatocellular carcinomas (HCCs), which significantly correlated with tumor progression, proliferation, and activation of other protumorigenic factors (e.g., nuclear p53). Inhibition of stathmin expression by gene-specific short interfering RNA (siRNA) was associated with a significant reduction of MT-dependent cellular functions such as tumor cell viability, proliferation, migration, and increased apoptosis in HCC cells. Loss of stathmin expression increased responsiveness of tumor cells to the treatment with cytostatic drugs targeting MT-stability (paclitaxel, vinblastine) and to DNA cross-linking agents (cisplatin). Surprisingly, inducible expression of p53(wt) in p53-negative HCC cells as well as a reduction of p53(wt) by siRNA in p53(wt)-positive cells did not alter stathmin expression. However, stathmin was down-regulated after siRNA-based reduction of p53(mut/Y220C) and p53(mut/R213Q) expression in different tumor cell types. CONCLUSION: Our results demonstrate that overexpression of stathmin is an early protumorigenic event in human hepatocarcinogenesis, and its up-regulation can be mediated by gain-of-function mutations in p53. Thus, stathmin represents a potential therapeutic target, for example, by increasing responsiveness of tumor cells to treatment with chemotherapeutic agents after reduction of stathmin bioactivity.


Subject(s)
Carcinoma, Hepatocellular/etiology , Cell Transformation, Neoplastic/metabolism , Liver Neoplasms/etiology , Stathmin/metabolism , Tumor Suppressor Protein p53/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival , Cell Transformation, Neoplastic/pathology , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , RNA, Small Interfering/pharmacology , Stathmin/antagonists & inhibitors , Stathmin/genetics , Tumor Suppressor Protein p53/antagonists & inhibitors
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