Limits...
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: The relationship with clinicopathological parameters was investigated.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.

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

Survival of HCC patients after liver surgery according to subcellular CYLD expression.Kaplan-Meier analysis (N = 95) for overall survival (OS) of patients receiving liver resection, for the following subgroups: (nucCYLD+/cyt°CYLD−, nucCYLD+/cyt°CYLD+, nucCYLD−/cyt°CYLD+ and nucCYLD−/cyt°CYLD− (P = 0.06). Positive nuclear (nucCYLD+) and cytoplasmic (cyt°CYLD+) CYLD staining was defined as an immunohistochemical score (IHS) ≥3 for nucCYLD+ and ≥6 for cyt°CYLD+ (IHS ranging from 0 to 12, obtained by multiplication of the intensity and the quantity score).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4199737&req=5

pone-0110591-g001: Survival of HCC patients after liver surgery according to subcellular CYLD expression.Kaplan-Meier analysis (N = 95) for overall survival (OS) of patients receiving liver resection, for the following subgroups: (nucCYLD+/cyt°CYLD−, nucCYLD+/cyt°CYLD+, nucCYLD−/cyt°CYLD+ and nucCYLD−/cyt°CYLD− (P = 0.06). Positive nuclear (nucCYLD+) and cytoplasmic (cyt°CYLD+) CYLD staining was defined as an immunohistochemical score (IHS) ≥3 for nucCYLD+ and ≥6 for cyt°CYLD+ (IHS ranging from 0 to 12, obtained by multiplication of the intensity and the quantity score).

Mentions: Downregulation of the deubiquitinase CYLD has been described as a frequent event in human HCC [10], [11]. In addition, CYLD deletion led to HCC development in murine knockout models [13], [14]. However, only little is known about subcellular CYLD localization and its association to the outcome of HCC patients. In order to assess CYLD expression, we analyzed 95 HCC tissue samples (N = 67 derived from liver resection, N = 28 from liver transplantation, respectively). Patients' characteristics concerning etiology, gender, and tumor stage are listed in Table 1. Subcellular CYLD expression was assessed (Fig. 1 and 2A, upper panels). 70 patients (74%) showed high nuclear and/or cytoplasmic CYLD expression, referred as totalCYLD+. In 25 patients (26%), only minor or absent CYLD expression was detected, both nuclear and cytoplasmic, referred as totalCYLD−. 52 patients (55%) showed positive nuclear staining for CYLD (nucCYLD+). Among them, 39 (75%) were also positive for cytoplasmic expression (nucCYLD+/cyt°CYLD+, Fig. 1). There was a positive correlation between nucCYLD+ and cyt°CYLD+ (P = 0.001). To figure out differences in CYLD expression between patients treated with resection or transplantation, we compared subcellular CYLD expression in these two groups. CYLD expression levels for patients treated with resection or transplantation were similar (data not shown).


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)

Survival of HCC patients after liver surgery according to subcellular CYLD expression.Kaplan-Meier analysis (N = 95) for overall survival (OS) of patients receiving liver resection, for the following subgroups: (nucCYLD+/cyt°CYLD−, nucCYLD+/cyt°CYLD+, nucCYLD−/cyt°CYLD+ and nucCYLD−/cyt°CYLD− (P = 0.06). Positive nuclear (nucCYLD+) and cytoplasmic (cyt°CYLD+) CYLD staining was defined as an immunohistochemical score (IHS) ≥3 for nucCYLD+ and ≥6 for cyt°CYLD+ (IHS ranging from 0 to 12, obtained by multiplication of the intensity and the quantity score).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199737&req=5

pone-0110591-g001: Survival of HCC patients after liver surgery according to subcellular CYLD expression.Kaplan-Meier analysis (N = 95) for overall survival (OS) of patients receiving liver resection, for the following subgroups: (nucCYLD+/cyt°CYLD−, nucCYLD+/cyt°CYLD+, nucCYLD−/cyt°CYLD+ and nucCYLD−/cyt°CYLD− (P = 0.06). Positive nuclear (nucCYLD+) and cytoplasmic (cyt°CYLD+) CYLD staining was defined as an immunohistochemical score (IHS) ≥3 for nucCYLD+ and ≥6 for cyt°CYLD+ (IHS ranging from 0 to 12, obtained by multiplication of the intensity and the quantity score).
Mentions: Downregulation of the deubiquitinase CYLD has been described as a frequent event in human HCC [10], [11]. In addition, CYLD deletion led to HCC development in murine knockout models [13], [14]. However, only little is known about subcellular CYLD localization and its association to the outcome of HCC patients. In order to assess CYLD expression, we analyzed 95 HCC tissue samples (N = 67 derived from liver resection, N = 28 from liver transplantation, respectively). Patients' characteristics concerning etiology, gender, and tumor stage are listed in Table 1. Subcellular CYLD expression was assessed (Fig. 1 and 2A, upper panels). 70 patients (74%) showed high nuclear and/or cytoplasmic CYLD expression, referred as totalCYLD+. In 25 patients (26%), only minor or absent CYLD expression was detected, both nuclear and cytoplasmic, referred as totalCYLD−. 52 patients (55%) showed positive nuclear staining for CYLD (nucCYLD+). Among them, 39 (75%) were also positive for cytoplasmic expression (nucCYLD+/cyt°CYLD+, Fig. 1). There was a positive correlation between nucCYLD+ and cyt°CYLD+ (P = 0.001). To figure out differences in CYLD expression between patients treated with resection or transplantation, we compared subcellular CYLD expression in these two groups. CYLD expression levels for patients treated with resection or transplantation were similar (data not shown).

Bottom Line: The relationship with clinicopathological parameters was investigated.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.

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