Background/Aim: Forkhead box O4 (FOXO4) has been demonstrated to be a tumor suppressor and proposed as target for treatment of a variety of cancer types. However, the role of FOXO4 in cholangiocarcinoma (CCA), a dangerous cancer of bile-duct epithelium, has rarely been explored. Materials and Methods: The proliferative rate of CCA cell lines KKU-213B, KKU-055 and KKK-D068 was investigated using the sulforhodamine B (SRB) assay. Levels of FOXO4, cyclin E1 (CCNE1), CCNE2, cyclin-dependent kinase 2 (CDK2) and cell division cycle 25A (CDC25A) expression were measured using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). The cell-cycle profile was explored using flow cytometry. Results: The SRB assay demonstrated that KKU-213B expressed low levels of FOXO4 but its proliferative rate was highest of all cell lines tested. Interestingly, ectopic expression of FOXO4 significantly suppressed proliferation of KKU-213B cells. Cell-cycle analysis revealed that the cell population in the G 0 /G 1 phase was significantly higher in FOXO4-transfected KKU-213B cells than in controls. RT-qPCR analysis demonstrated that the levels of expression of genes that play a role in the G 1 /S transition, namely CCNE1, CCNE2, CDK2 and CDC25A, were significantly lower in FOXO4-transfected KKU-213B cells compared to controls. Conclusion: FOXO4 suppressed CCA cell proliferation partly via down-regulating the expression of genes involved in the G 1 /S transition, leading to G 0 /G 1 arrest.Our findings suggest that induction of FOXO4 expression might be an alternative approach for the treatment of CCA.Cholangiocarcinoma (CCA), a cancer originating from bileduct epithelial cells, used to be a largely neglected disease but its incidence has been increasing in many parts of the world in recent years (1). Although the cause of CCA is obscure, primary sclerosing cholangitis is an important risk factor for CCA development in Western countries, whereas infection with small human liver flukes (Opisthorchis viverrini and Clonorchis sinensis) is an important risk factor for CCA in Southeast Asia and East Asia, respectively (2). Liver flukeassociated CCA in Asia differs from CCA elsewhere in the world in terms of genetic and epigenetic abnormalities (3-5). However, most patients with CCA have similar clinical characteristics, including poor survival and limited response to standard chemotherapy. Thus, apart from seeking early diagnostic biomarkers, research on novel targets for effective treatment of CCA is also urgently needed.It has been widely accepted that altered expression of transcription factors is involved in all aspects of cancer biology such as proliferation, apoptosis, progression and metastasis, as well as response to treatment. Forkhead box class O proteins (FOXOs) are a family of transcription factors consisting of FOXO1, FOXO3, FOXO4 and FOXO6. FOXOs are regarded as tumor-suppressor transcription factors (6). Thus it is not a surprise that FOXOs have been suggested as potential targets for cancer therapy (6)...
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