Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous, multigene-driven malignant tumor. ZNF384 is an overexpressed gene with a high frequency of alteration in HCC, but research on the function of ZNF384 in HCC is lacking. In this study, the expression level of ZNF384 in HCC was analyzed through immunohistochemical (IHC) staining, Western blot analysis and qRT-PCR. We also generated ZNF384 knockdown and knockout HCC cell lines using short hairpin RNA (shRNA) and CRISPR/Cas9 systems. MTS, colony formation, and 5-ethynyl-20-deoxyuridine (EdU) assays; flow cytometry; and a xenograft mouse model were used to evaluate the effects of ZNF384 on cell proliferation. Western blot analysis, a dual luciferase reporter assay and a ChIP assay were performed to explore the potential mechanism. We found that overexpression of ZNF384 in HCC and elevated expression of ZNF384 in HCC tissues was significantly correlated with tumor recurrence (P = 0.0097). Kaplan–Meier survival analysis revealed that high expression levels of ZNF384 were correlated with poor overall survival (P = 0.0386). Downregulation of ZNF384 expression suppressed HCC cell proliferation by inhibiting the expression of Cyclin D1. These findings suggest that ZNF384 tends to act as an oncogene in the development of HCC. ZNF384 promotes the proliferation of HCC cells by directly upregulating the expression of Cyclin D1 and might serve as a prognostic predictive factor for HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is a heterogeneous disease with a poor 5-year survival rate of less than 10%1
We found that the rate of genetic alteration of ZNF384 was as high as 9.4% and that mRNA upregulation accounted for 70.6% of these alterations (Fig. 1a)
We found that ZNF384 expression was significantly increased in HCC tissues compared to that in adjacent normal liver tissues in the The Cancer Genome Atlas (TCGA) RNA-seq database (Fig. 1b)
Summary
Hepatocellular carcinoma (HCC) is a heterogeneous disease with a poor 5-year survival rate of less than 10%1. Multiple risk factors involve in the initiation and progression of HCC including HBV and/or HCV infections, Official journal of the Cell Death Differentiation Association. He et al Cell Death and Disease (2019)10:444 genes that have changed in HCC sequencing research in the development of HCC. ZNF384 gene encodes a C2H2-type zinc finger protein which functions as a transcription factor regulates the transcription of the extracellular matrix genes[9]. Sakuma et al.[12] found that the over expression of ZNF384 would promote the migration of melanoma cells. Mori et al.[13] demonstrated that ZNF384 bound to APOBEC3B (A3B) promoter and functions as a modulator of A3B expression in cervical cancer. Various evidences indicated that ZNF384 might be a potential oncogene, which promotes the occurrence and development of cancers, the research about ZNF384 in HCC is vacant
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