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CYLD controls c-MYC expression through the JNK-dependent signaling pathway in hepatocellular carcinoma.

Rajeswara, Pannem Rao LU ; Dorn, Christoph ; Ahlqvist, Kristofer LU ; Bosserhoff, Anja K ; Hellerbrand, Claus and Massoumi, Ramin LU (2014) In Carcinogenesis 35(2). p.461-468
Abstract
Post-translational modification of different proteins via direct ubiquitin attachment is vital for mediating various cellular processes. CYLD, a deubiquitination enzyme, is able to cleave the polyubiquitin chains from the substrate, and to regulate different signaling pathways. Loss, or reduced expression, of CYLD is observed in different types of human cancer, such as hepatocellular carcinoma (HCC). However, the molecular mechanism by which CYLD affects cancerogenesis has to date not been unveiled. The aim of the present study was to examine how CYLD regulates cellular functions and signaling pathways during hepatocancerogenesis. We found that mice lacking CYLD were highly susceptible to chemically induced liver cancer. The mechanism... (More)
Post-translational modification of different proteins via direct ubiquitin attachment is vital for mediating various cellular processes. CYLD, a deubiquitination enzyme, is able to cleave the polyubiquitin chains from the substrate, and to regulate different signaling pathways. Loss, or reduced expression, of CYLD is observed in different types of human cancer, such as hepatocellular carcinoma (HCC). However, the molecular mechanism by which CYLD affects cancerogenesis has to date not been unveiled. The aim of the present study was to examine how CYLD regulates cellular functions and signaling pathways during hepatocancerogenesis. We found that mice lacking CYLD were highly susceptible to chemically induced liver cancer. The mechanism behind proved to be an elevated proliferation rate of hepatocytes, owing to sustained JNK1-mediated signaling via ubiquitination of TRAF2 and expression of c-MYC. Overexpression of wild type CYLD in an HCC cell lines prevented cell proliferation, without affecting apoptosis, adhesion, and migration. A combined immunohistochemical and tissue microarray analysis of 81 human HCC tissues revealed that CYLD expression is negatively correlated with expression of proliferation marker Ki-67 and c-MYC. To conclude, we found that downregulation of CYLD induces tumor cell proliferation, consequently contributing to the aggressive growth of HCC. Our findings suggest that CYLD holds potential to serve as a marker for HCC progression, and its link to c-MYC via JNK1 may provide the foundation for new therapeutic strategies for HCC-patients. (Less)
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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Carcinogenesis
volume
35
issue
2
pages
461 - 468
publisher
Oxford University Press
external identifiers
  • pmid:24104553
  • wos:000331272100024
  • scopus:84893089028
  • pmid:24104553
ISSN
0143-3334
DOI
10.1093/carcin/bgt335
language
English
LU publication?
yes
id
d0d78b93-4d26-4536-b871-5fa1962934d5 (old id 4143529)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24104553?dopt=Abstract
date added to LUP
2016-04-01 10:45:18
date last changed
2022-05-06 01:10:34
@article{d0d78b93-4d26-4536-b871-5fa1962934d5,
  abstract     = {{Post-translational modification of different proteins via direct ubiquitin attachment is vital for mediating various cellular processes. CYLD, a deubiquitination enzyme, is able to cleave the polyubiquitin chains from the substrate, and to regulate different signaling pathways. Loss, or reduced expression, of CYLD is observed in different types of human cancer, such as hepatocellular carcinoma (HCC). However, the molecular mechanism by which CYLD affects cancerogenesis has to date not been unveiled. The aim of the present study was to examine how CYLD regulates cellular functions and signaling pathways during hepatocancerogenesis. We found that mice lacking CYLD were highly susceptible to chemically induced liver cancer. The mechanism behind proved to be an elevated proliferation rate of hepatocytes, owing to sustained JNK1-mediated signaling via ubiquitination of TRAF2 and expression of c-MYC. Overexpression of wild type CYLD in an HCC cell lines prevented cell proliferation, without affecting apoptosis, adhesion, and migration. A combined immunohistochemical and tissue microarray analysis of 81 human HCC tissues revealed that CYLD expression is negatively correlated with expression of proliferation marker Ki-67 and c-MYC. To conclude, we found that downregulation of CYLD induces tumor cell proliferation, consequently contributing to the aggressive growth of HCC. Our findings suggest that CYLD holds potential to serve as a marker for HCC progression, and its link to c-MYC via JNK1 may provide the foundation for new therapeutic strategies for HCC-patients.}},
  author       = {{Rajeswara, Pannem Rao and Dorn, Christoph and Ahlqvist, Kristofer and Bosserhoff, Anja K and Hellerbrand, Claus and Massoumi, Ramin}},
  issn         = {{0143-3334}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{461--468}},
  publisher    = {{Oxford University Press}},
  series       = {{Carcinogenesis}},
  title        = {{CYLD controls c-MYC expression through the JNK-dependent signaling pathway in hepatocellular carcinoma.}},
  url          = {{http://dx.doi.org/10.1093/carcin/bgt335}},
  doi          = {{10.1093/carcin/bgt335}},
  volume       = {{35}},
  year         = {{2014}},
}