Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix

Hirai, Yasuo; Kawamata, Yasutaka; Takeshima, Nobuhiro; Furuta, Reiko; Kitagawa, Tomoyuki; Kawaguchi, Tokuichi; Hasumi, Katsuhiko; Sugai, Sachiko; Noda, Tetsuo

doi:10.3892/ijo.24.4.977

Cited by 30 publications

(27 citation statements)

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“…Mice in which CYLD is knocked out are prone to chemical tumorigenesis [50], and CYLD levels are downregulated in diverse tumor types [51,52]. In addition, it has recently been established that the CYLD gene product is a DUB that removes lysine 63-linked ubiquitin chains from TRAF2, blocking its ability to activate the IκB kinase, IKK, thereby inhibiting activation of the transcription factor nuclear factor (NF)-κB, which would otherwise lead to anti-apoptotic gene expression and a survival phenotype [53].…”

Section: Tumor Suppressor Cylindromatosis Genementioning

confidence: 99%

Deubiquitinating Enzymes as Novel Anticancer Targets

et al. 2007

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Tagging proteins with mono-or poly-ubiquitin is now recognized as a multifaceted and universal means of regulating cell growth and physiology. It does so by controlling the cellular lifetime of nearly all eukaryotic proteins and the cellular localization of many critical proteins. Enzymes of the ubiquitin pathway add (ligases) or remove (deubiquitinases [DUBs]) ubiquitin tags to or from their target proteins in a selective fashion. Similarly to the kinases and their corresponding phosphatases, ubiquitin ligases and DUBs have become actively studied molecular oncology targets for drug discovery. Approximately 79 functional DUBs exist in the human proteome, suggesting that selective intervention is a reasonable therapeutic objective, with the goal of downregulating or ablating oncogene products or, alternatively, upregulating or sparing tumor suppressors. In the following review, this fascinating class of regulatory enzymes will be described, and specific examples of DUBs that are viable targets for anticancer therapy will be considered. Keywordsassociated molecule with the SH3-domain of STAM; cylindromatosis gene; deubiquitinating enzymes; isopeptidase; proteasomal degradation; ubiquitin; ubiquitin-specific protease 2a; ubiquitinspecific protease 7; ubiquitin-specific protease 20 Ubiquitin & ubiquitin-like proteinsThe content of most proteins in the cell is regulated by the ubiquitin-proteasomal pathway [1]. Ubiquitin and ubiquitin-like proteins (UBLs), such as SUMO, NEDD8, ISG15 and FAT10, regulate proteins via additional mechanisms, for example, intracellular compartmentation, signal transduction and the regulation of some E3 ligases [2]. Degradation of a targeted protein by the ubiquitin system involves the activation of ubiquitin by the enzyme E1, which links the ubiquitin C-terminus to a cysteine side chain of the enzyme in an ATP-dependent manner [1]. Activated ubiquitin is transferred as a thioester to enzyme E2, which catalyzes ubiquitin †Author for correspondence: Progenra, Inc., 271A Great Valley Parkway,

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Section: Tumor Suppressor Cylindromatosis Genementioning

confidence: 99%

Deubiquitinating Enzymes as Novel Anticancer Targets

et al. 2007

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“…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 and renal cancer (15)(16)(17). Moreover, suppressed CYLD gene expression may contribute to tumor development in colon cancer, hepatocellular carcinoma and melanoma (18,19 The aim of this study was to investigate the clinical importance of the CYLD gene by analyzing 124 consecutive patients with HCC who were treated with hepatic resection.…”

Section: Introductionmentioning

confidence: 99%

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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“…Cylindromas are usually benign, although occasionally they can malignize (Durani et al, 2001;De Francesco et al, 2005). Additional studies have associated Cyld downregulation with the development of other types of human cancer including tumors of colon, lung and kidney, as well as melanomas and cervical and hepatocellular carcinomas (Strobel et al, 2002;Hashimoto et al, 2004;Hirai et al, 2004;Costello et al, 2005;Hellerbrand et al, 2007;Keats et al, 2007;Zhong et al, 2007;Massoumi et al, 2009). In the case of multiple myeloma and melanoma, it has been shown that its grade of malignancy is directly related with the silencing of CYLD, being of poor prognosis those tumors with lower expression level of CYLD (Annunziata et al, 2007;Jenner et al, 2007;Massoumi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

et al. 2010

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In this study, we demonstrate that the expression in tumorigenic epidermal cells of a catalytically inactive form of CYLD (CYLD C/S ) that mimics the identified mutations of cyld in human tumors and competes with the endogenous CYLD results in enhanced cell proliferation and inhibition of apoptosis; it also stimulates cell migration and induces the expression of angiogenic factors, including vascular endothelial growth factor-A. Altogether, these characteristics indicate an increased oncogenicity of the tumorigenic epidermal CYLD C/S mutant cells in vitro. Moreover, we show the increase in malignancy of epidermal squamous cell carcinomas that express the CYLD C/S transgene in an in vivo xenograft model. Tumors carrying the mutated CYLD C/S exhibit a fast growth, are poorly differentiated and present a robust angiogenesis. CYLD C/S tumors are also characterized by their elevated proliferation rate and decreased apoptosis. In contrast with previous studies showing the development of benign tumors by mutations in the CYLD gene, here we provide evidence that the occurrence of mutations in the CYLD gene in tumorigenic epidermal cells (carrying previous mutations) increases the aggressiveness of carcinomas, mainly through enhancement of the expression of angiogenic factors, having therefore a key role in epidermal cancer malignancy.

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Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix

Cited by 30 publications

References 0 publications

Deubiquitinating Enzymes as Novel Anticancer Targets

Deubiquitinating Enzymes as Novel Anticancer Targets

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

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

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