Abstract
BackgroundHepatocyte nuclear factor 4α (HNF4α) is a tissue-specific transcription factor that regulates the expression of numerous genes in hepatocytes and pancreatic β cells. HNF4α has been reported to affect cell proliferation and chemoresistance in several cancers. However, the role of HNF4α in pancreatic adenocarcinoma (PDAC) has not been studied extensively and remains unclear.MethodsBy utilizing immunohistochemical (IHC) staining, we measured the expression of HNF4α in PDAC tissues. By silencing HNF4α in PDAC cell lines, we assessed the impact of HNF4α on pancreatic cancer cell proliferation and gemcitabine sensitivity. We used CCK8 and colony formation assays to examine the effect of HNF4α on cell proliferation. A flow cytometry assay was used to assess cell apoptosis. The expression of gemcitabine-related genes was detected by quantitative real‑time PCR (qRT-PCR) and Western blotting. IHC was utilized to assess the correlation between HNF4α and human equilibrative nucleoside transporter 1 (hENT1) expression in PDAC patients. Chromatin immunoprecipitation (ChIP) and dual‑luciferase reporter assays were used to confirm that hENT1 is a target gene of HNF4α.ResultsIncreased HNF4α expression was detected in PDAC tissues; patients with higher HNF4α expression displayed worse prognosis. To elucidate the function of HNF4α, we examined its role in pancreatic cancer cell proliferation, apoptosis and gemcitabine resistance. In HNF4α-silenced Capan-1 and MiaPaCa-2 cells, we observed decreased cell proliferation and increased sensitivity to gemcitabine compared to those of controls. The mechanism of HNF4α in gemcitabine-related chemosensitivity was then explored. In response to HNF4α silencing, the expression levels of gemcitabine-related proteins, hENT1 and deoxycytidine kinase (dCK) were significantly increased. Additionally, hENT1 was negatively correlated with HNF4α in PDAC tissue samples. Moreover, we identified hENT1 as a downstream target of HNF4α.ConclusionHNF4α is a prognostic marker for overall survival, is required for pancreatic cancer cell proliferation and promotes resistance to gemcitabine by downregulating hENT1. Therefore, targeting HNF4α might reverse gemcitabine resistance and provide novel treatment strategies for PDAC.
Highlights
Hepatocyte nuclear factor 4α (HNF4α) is a tissue-specific transcription factor that regulates the expression of numerous genes in hepatocytes and pancreatic β cells
Our study provided novel findings, including that HNF4α silencing resulted in decreased cell proliferation and increased gemcitabine sensitivity, which was partly due to transcriptional repression of human equilibrative nucleoside transporter 1 (hENT1)
HNF4α expression is positively correlated with pancreatic adenocarcinoma (PDAC) prognosis We first used IHC to examine the HNF4α levels in 30 paired-patient samples of PDAC and adjacent normal tissues (Fig. 1a, b)
Summary
Hepatocyte nuclear factor 4α (HNF4α) is a tissue-specific transcription factor that regulates the expression of numerous genes in hepatocytes and pancreatic β cells. The role of HNF4α in pancreatic adenocarcinoma (PDAC) has not been studied extensively and remains unclear. Darsigny et al reported that HNF4α was highly expressed in colorectal cancer tissue samples and promoted murine tumor development by targeting redox-related genes [9]. A recent study has suggested a role for HNF4α in chemoresistance in gastric cancer, in which they reported that HNF4α may enhance multidrug resistance by regulating cell apoptosis and expression of B-cell lymphoma 2 (Bcl2) [11]. The role of HNF4α in PDAC development has not been reported widely and needs further investigation
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