Abstract
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 (γH2AX) 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.
Highlights
Liver cancer is the fifth most common cancer and the third most frequent cancer-related of deaths worldwide
Hepatocyte-specific Ddx3x ablation leads to the development of hepatocellular tumors in aged mice
We showed that Alb-Cre/þ;Ddx3xflox/flox mice recapitulated these key features of human hepatocellular carcinoma (HCC) pathogenesis
Summary
Liver cancer is the fifth most common cancer and the third most frequent cancer-related of deaths worldwide. The majority of liver malignancies are hepatocellular carcinoma (HCC) and cholangiocarcinoma that have high morbidity and mortality in developing countries, but their incidences are increased in developed countries. Etiological studies of liver cancer have identified four major risk factors, including chronic infection with hepatitis B or C viruses, alcohol use, and the intake of aflatoxin-contaminated food [1,2,3]. Obesity-associated nonalcoholic fatty liver disease has continuously increased [4]. It is generally accepted that hepatocarcinogenesis is a multistep process with an accumulation of the genetic and epigenetic alterations of critical genes involving hepatocyte growth and proliferation, cell death, cell adhesion, and metabolism [5].
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