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Nuclear expression of the deubiquitinase CYLD is associated with improved survival in human hepatocellular carcinoma.

Welte S, Urbanik T, Elßner C, Kautz N, Koehler BC, Waldburger N, Bermejo JL, Pinna F, Weiss KH, Schemmer P, Jaeger D, Longerich T, Breuhahn K, Schulze-Bergkamen H - PLoS ONE (2014)

Bottom Line: Nuclear CYLD staining strongly correlated with tumor grading (P<0.001) and Ki67 positivity (P = 0.005). nucCYLD+ 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.

View Article: PubMed Central - PubMed

Affiliation: National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany.

ABSTRACT

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 immunohistochemical (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%, nucCYLD+). 13 out of 52 nucCYLD+ patients (25%) showed a lack of cytoplasmic CYLD expression. nucCYLD+ was associated with prolonged overall survival in patients after resection or liver transplantation (P = 0.007). 5-year overall survival rates were 63% in nucCYLD+ vs. 26% in nucCYLD- patients. Nuclear CYLD staining strongly correlated with tumor grading (P<0.001) and Ki67 positivity (P = 0.005). nucCYLD+ 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.

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Correlation of CYLD expression with outcome after liver resection vs. liver transplantation.(A) Kaplan-Meier analysis for overall survival (OS) of patients receiving liver resection with positive (nucCYLD+, N = 33) and negative nuclear CYLD expression (nucCYLD−; N = 29; P = 0.1). (B) OS of patients receiving liver transplantation with positive (nucCYLD+; N = 16) or negative nuclear CYLD expression (nucCYLD−; N = 11; P = 0.04).
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pone-0110591-g004: Correlation of CYLD expression with outcome after liver resection vs. liver transplantation.(A) Kaplan-Meier analysis for overall survival (OS) of patients receiving liver resection with positive (nucCYLD+, N = 33) and negative nuclear CYLD expression (nucCYLD−; N = 29; P = 0.1). (B) OS of patients receiving liver transplantation with positive (nucCYLD+; N = 16) or negative nuclear CYLD expression (nucCYLD−; N = 11; P = 0.04).

Mentions: In the multiple Cox regression analysis, tumor size and CHILD score were independent prognostic factors (P = 0.01, HR = 0.34 and P = 0.04, HR = 0.4, Table 3). nucCYLD+ did not prove to be an independent prognostic parameter (P = 0.27, Table 3). cyt°CYLD− patients showed non-significant differences for overall survival compared to the cyt°CYLD+ group (IHS<6, P = 0.6, Fig. 3B, HR = 1.2, respectively) Importantly, nucCYLD+ was significantly associated with improved OS in Kaplan-Meier analysis (nucCYLD+: 1-/3-/5-year OS rates 81/73/63% vs.nucCYLD−: 75/50/26%, P = 0.007, Fig. 3A). The analysis was repeated with patients divided according to their surgical procedure (liver resection vs. liver transplantation). Patients in the nucCYLD+ group after liver resection showed a non-significant differences for OS, compared to the nucCYLD− group (nucCYLD+: 1-/3-/5-year survival rates 77/64/59% vs.nucCYLD−: 75/50/20%, P = 0.1, Fig. 4A). In patients after liver transplantation, nucCYLD+ was associated with longer OS compared to nucCYLD−, and a log-rank test confirmed significance (nucCYLD+: 1-/3-/5-year survival rates 94/94/77% vs.nucCYLD: 73/55/41%, P = 0.04, Fig. 4B). Analyzing CYLD expression in all subgroups (nucCYLD+/cyt°CYLD−, nucCYLD+/cyt°CYLD+, nucCYLD−/cyt°CYLD+ and nucCYLD−/cyt°CYLD−), no significant differences for overall survival were detected by the Kaplan-Meier approach. Among the subgroups, nucCYLD+/cyt°CYLD− had the most favourable 5-year survival rate (P = 0.06; Fig.1).


Nuclear expression of the deubiquitinase CYLD is associated with improved survival in human hepatocellular carcinoma.

Welte S, Urbanik T, Elßner C, Kautz N, Koehler BC, Waldburger N, Bermejo JL, Pinna F, Weiss KH, Schemmer P, Jaeger D, Longerich T, Breuhahn K, Schulze-Bergkamen H - PLoS ONE (2014)

Correlation of CYLD expression with outcome after liver resection vs. liver transplantation.(A) Kaplan-Meier analysis for overall survival (OS) of patients receiving liver resection with positive (nucCYLD+, N = 33) and negative nuclear CYLD expression (nucCYLD−; N = 29; P = 0.1). (B) OS of patients receiving liver transplantation with positive (nucCYLD+; N = 16) or negative nuclear CYLD expression (nucCYLD−; N = 11; P = 0.04).
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pone-0110591-g004: Correlation of CYLD expression with outcome after liver resection vs. liver transplantation.(A) Kaplan-Meier analysis for overall survival (OS) of patients receiving liver resection with positive (nucCYLD+, N = 33) and negative nuclear CYLD expression (nucCYLD−; N = 29; P = 0.1). (B) OS of patients receiving liver transplantation with positive (nucCYLD+; N = 16) or negative nuclear CYLD expression (nucCYLD−; N = 11; P = 0.04).
Mentions: In the multiple Cox regression analysis, tumor size and CHILD score were independent prognostic factors (P = 0.01, HR = 0.34 and P = 0.04, HR = 0.4, Table 3). nucCYLD+ did not prove to be an independent prognostic parameter (P = 0.27, Table 3). cyt°CYLD− patients showed non-significant differences for overall survival compared to the cyt°CYLD+ group (IHS<6, P = 0.6, Fig. 3B, HR = 1.2, respectively) Importantly, nucCYLD+ was significantly associated with improved OS in Kaplan-Meier analysis (nucCYLD+: 1-/3-/5-year OS rates 81/73/63% vs.nucCYLD−: 75/50/26%, P = 0.007, Fig. 3A). The analysis was repeated with patients divided according to their surgical procedure (liver resection vs. liver transplantation). Patients in the nucCYLD+ group after liver resection showed a non-significant differences for OS, compared to the nucCYLD− group (nucCYLD+: 1-/3-/5-year survival rates 77/64/59% vs.nucCYLD−: 75/50/20%, P = 0.1, Fig. 4A). In patients after liver transplantation, nucCYLD+ was associated with longer OS compared to nucCYLD−, and a log-rank test confirmed significance (nucCYLD+: 1-/3-/5-year survival rates 94/94/77% vs.nucCYLD: 73/55/41%, P = 0.04, Fig. 4B). Analyzing CYLD expression in all subgroups (nucCYLD+/cyt°CYLD−, nucCYLD+/cyt°CYLD+, nucCYLD−/cyt°CYLD+ and nucCYLD−/cyt°CYLD−), no significant differences for overall survival were detected by the Kaplan-Meier approach. Among the subgroups, nucCYLD+/cyt°CYLD− had the most favourable 5-year survival rate (P = 0.06; Fig.1).

Bottom Line: Nuclear CYLD staining strongly correlated with tumor grading (P<0.001) and Ki67 positivity (P = 0.005). nucCYLD+ 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.

View Article: PubMed Central - PubMed

Affiliation: National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany.

ABSTRACT

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 immunohistochemical (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%, nucCYLD+). 13 out of 52 nucCYLD+ patients (25%) showed a lack of cytoplasmic CYLD expression. nucCYLD+ was associated with prolonged overall survival in patients after resection or liver transplantation (P = 0.007). 5-year overall survival rates were 63% in nucCYLD+ vs. 26% in nucCYLD- patients. Nuclear CYLD staining strongly correlated with tumor grading (P<0.001) and Ki67 positivity (P = 0.005). nucCYLD+ 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.

Show MeSH
Related in: MedlinePlus