Role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinoma
Abstract Background Hepatocyte 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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-03-01
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| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12935-019-0767-4 |
| _version_ | 1819145993197715456 |
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| author | Qiqing Sun Wenyan Xu Shunrong Ji Yi Qin Wensheng Liu Qiangsheng Hu Zheng Zhang Mengqi Liu Xianjun Yu Xiaowu Xu |
| author_facet | Qiqing Sun Wenyan Xu Shunrong Ji Yi Qin Wensheng Liu Qiangsheng Hu Zheng Zhang Mengqi Liu Xianjun Yu Xiaowu Xu |
| author_sort | Qiqing Sun |
| collection | DOAJ |
| description | Abstract Background Hepatocyte 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. Methods By 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. Results Increased 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. Conclusion HNF4α 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. |
| first_indexed | 2024-12-22T13:06:51Z |
| format | Article |
| id | doaj.art-80689bd0efbb467a885b123592473b4d |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-12-22T13:06:51Z |
| publishDate | 2019-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-80689bd0efbb467a885b123592473b4d2022-12-21T18:24:51ZengBMCCancer Cell International1475-28672019-03-0119111310.1186/s12935-019-0767-4Role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinomaQiqing Sun0Wenyan Xu1Shunrong Ji2Yi Qin3Wensheng Liu4Qiangsheng Hu5Zheng Zhang6Mengqi Liu7Xianjun Yu8Xiaowu Xu9Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterAbstract Background Hepatocyte 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. Methods By 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. Results Increased 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. Conclusion HNF4α 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.http://link.springer.com/article/10.1186/s12935-019-0767-4Pancreatic adenocarcinomaHepatocyte nuclear factor 4αHuman equilibrative nucleoside transporter 1ProliferationGemcitabine resistance |
| spellingShingle | Qiqing Sun Wenyan Xu Shunrong Ji Yi Qin Wensheng Liu Qiangsheng Hu Zheng Zhang Mengqi Liu Xianjun Yu Xiaowu Xu Role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinoma Cancer Cell International Pancreatic adenocarcinoma Hepatocyte nuclear factor 4α Human equilibrative nucleoside transporter 1 Proliferation Gemcitabine resistance |
| title | Role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinoma |
| title_full | Role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinoma |
| title_fullStr | Role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinoma |
| title_full_unstemmed | Role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinoma |
| title_short | Role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinoma |
| title_sort | role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinoma |
| topic | Pancreatic adenocarcinoma Hepatocyte nuclear factor 4α Human equilibrative nucleoside transporter 1 Proliferation Gemcitabine resistance |
| url | http://link.springer.com/article/10.1186/s12935-019-0767-4 |
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