Back to Search
Start Over
JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity.
- Source :
-
Cancer research [Cancer Res] 2017 Oct 01; Vol. 77 (19), pp. 5287-5300. Date of Electronic Publication: 2017 Aug 03. - Publication Year :
- 2017
-
Abstract
- Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents are rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared with pericarcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation, whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting. Cancer Res; 77(19); 5287-300. ©2017 AACR .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Animals
Apoptosis
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular metabolism
Cell Adhesion Molecules genetics
Cell Proliferation
Disease Progression
Humans
Liver Neoplasms genetics
Liver Neoplasms metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Nude
Non-alcoholic Fatty Liver Disease genetics
Non-alcoholic Fatty Liver Disease metabolism
Phosphorylation
Precancerous Conditions genetics
Precancerous Conditions metabolism
Prognosis
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
RNA, Small Interfering genetics
Signal Transduction
Tumor Cells, Cultured
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins metabolism
Xenograft Model Antitumor Assays
Carcinoma, Hepatocellular pathology
Cell Adhesion Molecules metabolism
Gene Expression Regulation, Neoplastic
Liver Neoplasms pathology
Non-alcoholic Fatty Liver Disease pathology
Precancerous Conditions pathology
Protein Serine-Threonine Kinases antagonists & inhibitors
Tumor Suppressor Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 77
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 28775168
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-17-0229