Inactivation of the Deubiquitinase CYLD in Hepatocytes Causes Apoptosis, Inflammation, Fibrosis, and Cancer

Nikolaou, Kostas C.; Tsagaratou, Ageliki; Eftychi, Christina; Kollias, George; Mosialos, George; Talianidis, Iannis

doi:10.1016/j.ccr.2012.04.026

Cited by 125 publications

(140 citation statements)

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“…Hepatocyte-specific inactivation of NEMO (IKK-g) or TAK1, the upstream activators of NF-kB, resulted in spontaneous hepatocyte death, liver inflammation, and fibrosis, as well as the development of HCC (43)(44)(45). Interestingly, constitutive hyperactivation of TAK1 in Cyld-deficient hepatocytes displayed similar effects (46). Taken together, the above studies reinforced the established view that NF-kB signaling plays a central role in linking chronic inflammation to tumorigenesis.…”

Section: Signal Transduction Pathways Establish Communication Betweensupporting

confidence: 73%

Molecular Pathways: The Complex Roles of Inflammation Pathways in the Development and Treatment of Liver Cancer

Nikolaou

Sarris

Talianidis

2013

Clinical Cancer Research

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Inflammatory signals from the surrounding microenvironment play important roles in tumor promotion. Key inflammatory mediators and pathways that induce and sustain tumorigenesis have recently been identified in many different cancers. Hepatocellular carcinoma is a paradigm for inflammation-induced cancer, as it most frequently develops in the setting of chronic hepatitis, consecutive cellular damage, and compensatory regeneration. Recent studies revealed that liver damage-mediated inflammation and carcinogenesis are triggered by a complex cross-talk between NF-kB, c-jun-NH 2 -kinase, and STAT3 signaling pathways. Molecular dissection of the mechanisms involved in the interplay between these pathways identified promising new targets for therapeutic intervention. Targeting different components of the signaling cascades may provide efficient means for blocking the apparently irreversible sequence of events initiated by chronic liver inflammation and culminating in liver cancer.

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Section: Signal Transduction Pathways Establish Communication Betweensupporting

confidence: 73%

Molecular Pathways: The Complex Roles of Inflammation Pathways in the Development and Treatment of Liver Cancer

Nikolaou

Sarris

Talianidis

2013

Clinical Cancer Research

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“…As a result, this promoted progressive fibrosis and inflammation, resulting in cancer development (24). Although CYLD expression was expected to be potentially associated with certain types of carcinogenesis from viral hepatitis or liver cirrhosis due to chronic inflammation, no correlation was observed between CYLD expression and non-tumor liver tissue.…”

Section: Cyld (T/n Ratio) -------------------------------------------mentioning

confidence: 81%

CYLD downregulation is correlated with tumor development in patients with hepatocellular carcinoma

Kinoshita

Okabe

Beppu

et al. 2013

Molecular and Clinical Oncology

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Abstract. The cylindromatosis (CYLD) gene is involved in tumor progression by acting as a negative regulator of nuclear factor-κB (NF-κΒ). However, the clinical significance of CYLD in patients with hepatocellular carcinoma (HCC) remains unclear. To demonstrate the clinical significance of CYLD expression, we analyzed CYLD gene expression in 124 paired HCC and non-tumor tissues using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). CYLD gene expression was detected in the patients and the cut-off value was determined by the median value of tumor-to-non-tumor (T/N) ratio. qRT-PCR analysis showed that a low CYLD expression was associated with a high serum α-fetoprotein (AFP) value. Patients in the low CYLD expression group exhibited poorer overall survival compared to those in the high expression group (P=0.0406). Protein expression of CYLD was also investigated in 70 patients with HCC using immunohistochemistry. The findings showed that CYLD protein expression in tumor tissue was associated with CYLD gene expression (P=0.031). The findings of the present study suggest that CYLD is clinically associated with tumor development in HCC patients. IntroductionHepatocellular carcinoma (HCC) is one of the most common gastrointestinal malignancies and constitutes the leading cause of cancer-related mortality in East Asia and South Africa (1). Currently, the first-line treatment for HCC is liver transplantation or surgical resection (2). However, the overall survival rate after curative therapy is not satisfactory due to the highly chemoresistant nature of this tumor and the frequent intrahepatic recurrence. Identification of the genes responsible for the onset and progression of HCC as well as comprehension of the clinical significance of these genes are critical for the development of successful therapies.The cylindromatosis (CYLD) gene was originally identified as a tumor suppressor, the mutation of which predisposes patients to the development of tumors of hair follicles (cylindromas) (3). It has been reported that CYLD acts as a negative regulator of the nuclear factor-κB (NF-κB) signaling pathway by deubiquitinating NF-κB essential modulator (NEMO), IκB kinase (IKK)-γ, and IKK upstream regulators, including the tumor necrosis factor (TNF), receptor-associated factor 2 (TRAF2), TRAF6, TRAF7 and receptor-interacting protein 1 (RIP1) (4-10). CYLD also regulates transforming growth factor-β (TGF-β) signaling via the deubiquitination of Akt in lung fibrosis (11).Recent studies have demonstrated that CYLD deficiency may promote the development of several types of cancer in addition to skin tumors caused by mutations and loss of the heterozygosity (LOH) of CYLD. LOH of chromosome 16q, which includes the CYLD gene, has been detected in a large proportion of multiple myeloma cases and has been associated with poor overall survival (12)(13)(14). Comparative genomic hybridization (CGH) assays have also suggested potential genetic abnormalities of CYLD (reduction in copy number) in HCC, uterine carcinoma a...

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“…In striking contrast to mice deficient in CYLD, mice expressing a truncated form of CYLD lacking exon 9, which ablates its enzymatic activity, die shortly after birth due to lung dysfunction [95]. Mice expressing this truncated version of CYLD in the liver develop progressive fibrosis, inflammation, enhanced hepatocyte apoptosis and formation of cancer foci and these events are prevented by concomitant ablation of TNFR1 [96]. Finally, mice expressing catalytically inactive CYLD lacking the last 20 amino acids are partially protected from necroptotic cell death in FADD-deficient enterocytes [97] and keratinocytes [98], a condition that is partially, but not exclusively, mediated by TNF.…”

Section: Author Manuscriptmentioning

confidence: 99%

Formation and removal of poly‐ubiquitin chains in the regulation of tumor necrosis factor‐induced gene activation and cell death

et al. 2016

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Tumor necrosis factor (TNF) is a potent cytokine known for its involvement in inflammation, repression of tumorigenesis and activation of immune cells. Consequently, accurate regulation of the TNF signaling pathway is crucial to prevent potent noxious effects of TNF. These pathological conditions include chronic inflammation, septic shock, cachexia and cancer. The TNF signaling cascade utilizes a complex network of post-translational modifications to control the cellular response following its activation. Next to phosphorylation, the ubiquitination of signaling complex components is probably the most important modification. This process is mediated by a specialist class of enzymes, the ubiquitin ligases. Equally important is the class of dedicated ubiquitin-specific proteases, the deubiquitinases. Together with ubiquitin binding proteins, this ubiquitinationdeubiquitination system enables the dynamics of signaling complexes. In TNF signaling these dynamics translate into the precise regulation of the induction of gene activation or cell death. Here we review and discuss the current knowledge of TNF signaling regulation by the ubiquitin system.

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Inactivation of the Deubiquitinase CYLD in Hepatocytes Causes Apoptosis, Inflammation, Fibrosis, and Cancer

Cited by 125 publications

References 50 publications

Molecular Pathways: The Complex Roles of Inflammation Pathways in the Development and Treatment of Liver Cancer

Molecular Pathways: The Complex Roles of Inflammation Pathways in the Development and Treatment of Liver Cancer

CYLD downregulation is correlated with tumor development in patients with hepatocellular carcinoma

Formation and removal of poly‐ubiquitin chains in the regulation of tumor necrosis factor‐induced gene activation and cell death

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