CYLD controls c-MYC expression through the JNK-dependent signaling pathway in hepatocellular carcinoma.
Author
Summary, in English
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.
Department/s
- Cell Pathology, Malmö
- Department of Translational Medicine
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2014
Language
English
Pages
461-468
Publication/Series
Carcinogenesis
Volume
35
Issue
2
Links
Document type
Journal article
Publisher
Oxford University Press
Topic
- Cancer and Oncology
Status
Published
Research group
- Cell Pathology, Malmö
ISBN/ISSN/Other
- ISSN: 0143-3334