期刊
CANCER LETTERS
卷 429, 期 -, 页码 1-10出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.04.041
关键词
Alpha-ketoglutarate; Cancer metabolism; IDH1 mutations; 2-Hydroxyglutarate; Bile duct tumors
类别
资金
- National Institutes of Health [R01CA-123544, P20GM103430-12]
- American Association for the Study of Liver Diseases
- (Pinnacle Research Award in Liver Disease)
- Rhode Island Foundation [134279]
Cholangiocarcinoma (CCA) is a highly lethal and aggressive disease. Recently, IDH1/2 mutations have been identified in approximately 20% of CCAs which suggests an involvement of 2-oxoglutarate (2-OG) -dependent dioxygenases in oncogenesis. We investigated if the 2-OG dependent dioxygenase, aspartate beta-hydroxylase (ASPH) was important in tumor development and growth. Immunoassays were used to clarify how ASPH modulates CCA progression by promoting phosphorylation of the retinoblastoma protein (RB1). A xenograft model was employed to determine the role of ASPH on CCA growth. Knockdown of ASPH expression inhibited CCA development and growth by reducing RB1 phosphorylation. Expression of ASPH promoted direct protein interaction between RBI, cyclin-dependent kinases, and cyclins. Treatment with 2-OG-dependent dioxygenase and ASPH inhibitors suppressed the interaction between RB1 and CDK4 as well as RBI phosphorylation. Knockdown of ASPH expression inhibited CCA progression and RB1 phosphorylation in vivo and they were found to be highly expressed in human CCAs. Knockdown of ASPH expression altered CCA development by modulating RB1 phosphorylation, as one of the major factors regulating the growth of these tumors.
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