GATA6 is a transcription factor that regulates endoderm differentiation and lineage specification. Dysregulation of GATA6 expression had been reported in cancers of endoderm-derived organs such as the lungs, stomach and pancreas. The aim of this study is to determine the clinical significance of GATA6 in hepatocellular carcinoma (HCC) and characterize its potential functional roles.
GATA6 mRNA expression was assessed in 74 clinical HCC samples by quantitative polymerase chain reaction (qPCR). Correlation between GATA6 expression and clinicopathological parameters was analyzed. Stable GATA6 knockdown clones were established by a lentiviral-based approach in HCC cell line Huh7, which showed relatively high endogenous GATA6 expression. Functional effects upon GATA6 manipulation were investigated by cell proliferation, migration, invasion and tumorsphere formation assays in vitro.
GATA6 expression was significantly downregulated in HCC tumor tissues when compared with the corresponding non-tumoral liver tissues (p = 0.007). A lower GATA6 expression was correlated with poorer cellular differentiation (p = 0.004). Silencing of GATA6 stimulated HCC cell proliferation, and promoted cell invasive and migratory abilities in vitro. This increase in metastatic capacity was mediated through the activation of epithelial-mesenchymal transition (EMT), as demonstrated by the loss of E-cadherin and gain of vimentin protein expression levels. Suppression of GATA6 augmented the self-renewal ability of HCC cells as demonstrated by the enhanced number and size of tumorspheres formed in both primary and secondary generations. In addition, the expression of various stemness markers such as Nanog, Oct4 and Sox2 were upregulated upon GATA6 silencing.
Our findings suggest that GATA6 is downregulated in HCC which may help to convert HCC cells to a more poorly differentiated state and enhance proliferation, self-renewal ability and metastatic potential.
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Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
All authors have declared no conflicts of interest.