Abstract
Cholangiocarcinoma (CCA), a malignancy of biliary epithelium, is related to liver stem cell deregulation. FoxAs are a group of transcription factors that play critical roles in liver stem cell differentiation. In this study, the expression levels of FoxAs (i.e., FoxA1, FoxA2 and FoxA3) were detected in intrahepatic CCA tissues and the functions of FoxAs were studied in CCA cell lines. FoxA1 and FoxA2 were mainly localized in the nuclei of normal bile duct (NBD) cells and some of the cancer cells. Low expression of FoxA1 in CCA tissues (72%) was significantly correlated with poor prognosis. FoxA3 expression of CCA cells was localized in the nucleus and cytoplasm, whereas it was slightly detected in NBDs. High expression of FoxA3 in cancer tissues (61%) was significantly related to high metastasis status. These findings suggest the opposing roles of FoxA1 and FoxA3 in CCA. Moreover, the FoxA1-over-expressing CCA cell line exhibited a significant reduction in proliferative and invasive activities compared to control cells. Knockdown of FoxA3 in CCA cells resulted in a significant decrease in proliferative and invasive activities compared with control cells. Taken together, in CCA, FoxA1 is down-regulated and has tumor suppressive roles, whereas FoxA3 is up-regulated and has oncogenic roles.
Highlights
The forkhead box (Fox) proteins are the transcription factors which share homology in their forkhead DNA binding domain
FoxA1 was highly detected in the nucleus and cytoplasm of normal bile duct (NBD) epithelial cells adjacent to tumor tissues and some CCA cells in the tumor tissues, as shown in Figure 1
Our results indicate that FoxA1 was down-regulated in CCA and had tumor suppressive roles in CCA progression; down-regulation of FoxA1 in CCA tissues was related with poor prognosis
Summary
The forkhead box (Fox) proteins are the transcription factors which share homology in their forkhead (winged helix) DNA binding domain. The forkhead box of FoxA1, FoxA2 and FoxA3 resembles the structure of the linker histone H1 and plays major roles in chromatin remodeling [3]. Their functions have been identified as “pioneer factors” that bind to promoters and enhancers enable chromatin access for other tissue-specific transcription factors. They play important roles in multiple stages of mammalian life, beginning with the early development, continuing during organogenesis, and in the metabolism and homeostasis of the adult stage [4]. Liver stem cells are defined to the liver stem/progenitor cells that have ability to differentiate into hepatocytes and cholangiocytes, which are called bi-potential liver stem cells or hepatic stem cells [7]
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