Open AccessNuclear Expression of the Deubiquitinase CYLD Is Associated with Improved Survival in Human Hepatocellular Carcinoma
Author(s) -
Stefan Welte,
Toni Urbanik,
Christin Elßner,
Nicole Kautz,
Bruno Christian Koehler,
Nina Waldburger,
Justo Lorenzo Bermejo,
Federico Pinna,
Karl-Heinz Weiss,
Peter Schemmer,
Dirk Jaeger,
Thomas Longerich,
Kai Breuhahn,
Henning SchulzeBergkamen
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0110591
Subject(s) - immunohistochemistry , hepatocellular carcinoma , deubiquitinating enzyme , transplantation , liver transplantation , pathology , biology , cancer research , cell culture , medicine , ubiquitin , gene , biochemistry , genetics
Background & Aims The deubiquitinase CYLD removes (K-63)-linked polyubiquitin chains from proteins involved in NF-κB, Wnt/ß-catenin and Bcl-3 signaling. Reduced CYLD expression has been reported in different tumor entities, including hepatocellular carcinoma (HCC). Furthermore, loss of CYLD has been shown to contribute to HCC development in knockout animal models. This study aimed to assess subcellular CYLD expression in tumor tissues and its prognostic significance in HCC patients undergoing liver resection or liver transplantation. Methods Subcellular localization of CYLD was assessed by immunohistochemistry in tumor tissues of 95 HCC patients undergoing liver resection or transplantation. Positive nuclear CYLD staining was defined as an immunhistochemical (IHC) score ≥3. Positive cytoplasmic CYLD staining was defined as an IHC score ≥6. The relationship with clinicopathological parameters was investigated. Cell culture experiments were performed to analyze subcellular CYLD expression in vitro . Results Cytoplasmic CYLD expression was observed in 57 out of 95 (60%) HCC specimens ( cyt °CYLD + ). Nuclear CYLD staining was positive in 52 out of 95 specimens (55%, nuc CYLD + ). 13 out of 52 nuc CYLD + patients (25%) showed a lack of cytoplasmic CYLD expression. nuc CYLD + was associated with prolonged overall survival in patients after resection or liver transplantation ( P = 0.007). 5-year overall survival rates were 63% in nuc CYLD + vs. 26% in nuc CYLD - patients. Nuclear CYLD staining strongly correlated with tumor grading ( P <0.001) and Ki67 positivity ( P = 0.005). nuc CYLD + did not prove to be an independent prognostic parameter. In vitro , Huh7, Hep3B and HepG2 showed reduced CYLD levels compared to the non-malignant liver cell line THLE-2. Induction of CYLD expression by doxorubicin treatment led to increased cytoplasmic and nuclear expression of CYLD. Conclusions Expression of nuclear CYLD is a novel prognostic factor for improved survival in patients with HCC undergoing liver resection or transplantation.