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

Kinoshita,Hiroki; Okabe,Hirohisa; Beppu,Toru; Chikamoto,Akira; Hayashi,Hiromitsu; Imai,Katsunori; Mima,Kosuke; Nakagawa,Shigeki; Yokoyama,Naomi; Ishiko,Takatoshi; Shinriki,Satoru; Jono,Hirofumi; Ando,Yukio; Baba,Hideo

doi:10.3892/mco.2013.68

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

Authors:
- Hiroki Kinoshita
- Hirohisa Okabe
- Toru Beppu
- Akira Chikamoto
- Hiromitsu Hayashi
- Katsunori Imai
- Kosuke Mima
- Shigeki Nakagawa
- Naomi Yokoyama
- Takatoshi Ishiko
- Satoru Shinriki
- Hirofumi Jono
- Yukio Ando
- Hideo Baba
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Affiliations: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan, Department of Multidisciplinary Treatment for Gastroenterological Cancer, Kumamoto University Hospital, Kumamoto 860-8556, Japan, Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan, Department of Pharmacy, Kumamoto University Hospital, Kumamoto 860-8556, Japan, Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
Published online on: January 14, 2013 https://doi.org/10.3892/mco.2013.68
Pages: 309-314

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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.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics. CA Cancer J Clin. 62:10–29. 2012.
2	Carr BI: Hepatocellular carcinoma: current management and future trends. Gastroenterology. 127:S218–S224. 2004. View Article : Google Scholar : PubMed/NCBI
3	Bignell GR, Warren W, Seal S, et al: Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet. 25:160–165. 2000. View Article : Google Scholar : PubMed/NCBI
4	Jin W, Chang M, Paul EM, et al: Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J Clin Invest. 118:1858–1866. 2008. View Article : Google Scholar : PubMed/NCBI
5	Reiley WW, Jin W, Lee AJ, et al: Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med. 204:1475–1485. 2007. View Article : Google Scholar : PubMed/NCBI
6	Wright A, Reiley WW, Chang M, et al: Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD. Dev Cell. 13:705–716. 2007. View Article : Google Scholar : PubMed/NCBI
7	Zhang J, Stirling B, Temmerman ST, et al: Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice. J Clin Invest. 116:3042–3049. 2006. View Article : Google Scholar : PubMed/NCBI
8	Brummelkamp TR, Nijman SM, Dirac AM and Bernards R: Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature. 424:797–801. 2003. View Article : Google Scholar : PubMed/NCBI
9	Kovalenko A, Chable-Bessia C, Cantarella G, et al: The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature. 424:801–805. 2003. View Article : Google Scholar : PubMed/NCBI
10	Trompouki E, Tsagaratou A, Kosmidis SK, et al: Truncation of the catalytic domain of the cylindromatosis tumor suppressor impairs lung maturation. Neoplasia. 11:469–476. 2009.PubMed/NCBI
11	Lim JH, Jono H, Komatsu K, et al: CYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt. Nat Commun. 3:7712012.
12	Jenner MW, Leone PE, Walker BA, et al: Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma. Blood. 110:3291–3300. 2007. View Article : Google Scholar : PubMed/NCBI
13	Annunziata CM, Davis RE, Demchenko Y, et al: Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 12:115–130. 2007. View Article : Google Scholar : PubMed/NCBI
14	Keats JJ, Fonseca R, Chesi M, et al: Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 12:131–144. 2007. View Article : Google Scholar : PubMed/NCBI
15	Hashimoto K, Mori N, Tamesa T, et al: Analysis of DNA copy number aberrations in hepatitis C virus-associated hepatocellular carcinomas by conventional CGH and array CGH. Mod Pathol. 17:617–622. 2004. View Article : Google Scholar : PubMed/NCBI
16	Hirai Y, Kawamata Y, Takeshima N, et al: Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix. Int J Oncol. 24:977–986. 2004.PubMed/NCBI
17	Ströbel P, Zettl A, Ren Z, et al: Spiradenocylindroma of the kidney: clinical and genetic findings suggesting a role of somatic mutation of the CYLD1 gene in the oncogenesis of an unusual renal neoplasm. Am J Surg Pathol. 26:119–124. 2002.PubMed/NCBI
18	Hellerbrand C, Bumes E, Bataille F, et al: Reduced expression of CYLD in human colon and hepatocellular carcinomas. Carcinogenesis. 28:21–27. 2007. View Article : Google Scholar : PubMed/NCBI
19	Massoumi R, Kuphal S, Hellerbrand C, et al: Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma. J Exp Med. 206:221–232. 2009. View Article : Google Scholar : PubMed/NCBI
20	Okabe H, Beppu T, Ueda M, et al: Identification of CXCL5/ENA-78 as a factor involved in the interaction between cholangiocarcinoma cells and cancer-associated fibroblasts. Int J Cancer. Feb 15–2012.(Epub ahead of print).
21	Fu LY, Jia HL, Dong QZ, et al: Suitable reference genes for real-time PCR in human HBV-related hepatocellular carcinoma with different clinical prognoses. BMC Cancer. 9:492009. View Article : Google Scholar
22	Okabe H, Beppu T, Hayashi H, et al: Hepatic stellate cells may relate to progression of intrahepatic cholangiocarcinoma. Ann Surg Oncol. 16:2555–2564. 2009. View Article : Google Scholar : PubMed/NCBI
23	Lee JS and Thorgeirsson SS: Functional and genomic implications of global gene expression profiles in cell lines from human hepatocellular cancer. Hepatology. 35:1134–1143. 2002. View Article : Google Scholar : PubMed/NCBI
24	Nikolaou K, Tsagaratou A, Eftychi C, et al: Inactivation of the deubiquitinase CYLD in hepatocytes causes apoptosis, inflammation, fibrosis, and cancer. Cancer Cell. 21:738–750. 2012. View Article : Google Scholar : PubMed/NCBI