標題: DNA Damage, Liver Injury, and Tumorigenesis: Consequences of DDX3X Loss
作者: Chan, Chieh-Hsiang
Chen, Chun-Ming
Lee, Yan-Hwa Wu
You, Li-Ru
交大名義發表
生物科技學系
National Chiao Tung University
Department of Biological Science and Technology
公開日期: 1-Feb-2019
摘要: The pleiotropic roles of DEAD-box helicase 3, X-linked (DDX3X), including its functions in transcriptional and translational regulation, chromosome segregation, DNA damage, and cell growth control, have highlighted the association between DDX3X and tumorigenesis. However, mRNA transcripts and protein levels of DDX3X in patient specimens have shown the controversial correlations of DDX3X with hepatocellular carcinoma (HCC) prevalence. In this study, generation of hepatocyte-specific Ddx3x-knockout mice revealed that loss of Ddx3x facilitates liver tumorigenesis. Loss of Ddx3x led to profound ductular reactions, cell apoptosis, and compensatory proliferation in female mutants at 6 weeks of age. The sustained phosphorylation of histone H2AX (gamma H2AX) and significant accumulation of DNA single-strand breaks and double-strand breaks in liver indicated that the replicative stress occurred in female mutants. Further chromatin immunoprecipitation analyses demonstrated that DDX3X bound to promoter regions and regulated the expression of DNA repair factors, DDB2 and XPA, to maintain genome stability. Loss of Ddx3x led to decreased levels of DNA repair factors, which contributed to an accumulation of unrepaired DNA damage, replication stress, and eventually, spontaneous liver tumors and DEN-induced HCCs in Alb-Cre/+Ddx3xflox/flox mice. Implications: These data identify an important role of DDX3X in the regulation of DNA damage repair to protect against replication stress in liver and HCC development and progression.
URI: http://dx.doi.org/10.1158/1541-7786.MCR-18-0551
http://hdl.handle.net/11536/148803
ISSN: 1541-7786
DOI: 10.1158/1541-7786.MCR-18-0551
期刊: MOLECULAR CANCER RESEARCH
Volume: 17
起始頁: 555
結束頁: 566
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