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Nuclear expression of the ubiquitin ligase seven in absentia homolog (SIAH)-1 induces proliferation and migration of liver cancer cells

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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 c...

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Main Authors: Brauckhoff, Antje (Author) , Malz, Mona (Author) , Tschaharganeh, Darjus-Felix (Author) , Malek, Nisar Peter (Author) , Weber, Achim (Author) , Riener, Marc-Oliver (Author) , Soll, Christopher (Author) , Samarin, Jana (Author) , Bissinger, Michaela (Author) , Schmidt, Jan (Author) , Longerich, Thomas (Author) , Ehemann, Volker (Author) , Schirmacher, Peter (Author) , Breuhahn, Kai (Author)
Format: Article (Journal)
Language:English
Published: 26 February 2011
In: Journal of hepatology
Year: 2011, Volume: 55, Issue: 5, Pages: 1049-1057
ISSN:1600-0641
DOI:10.1016/j.jhep.2011.02.019
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.jhep.2011.02.019
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0168827811002042
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Author Notes:Antje Brauckhoff, Mona Malz, Darjus Tschaharganeh, Nisar Malek, Achim Weber, Marc-Oliver Riener, Christopher Soll, Jana Samarin, Michaela Bissinger, Jan Schmidt, Thomas Longerich, Volker Ehemann, Peter Schirmacher, Kai Breuhahn
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Summary: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.
Item Description:Gesehen am 03.06.2022
Physical Description:Online Resource
ISSN:1600-0641
DOI:10.1016/j.jhep.2011.02.019

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