Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma
Abstract Background Icaritin, an active ingredient of the Chinese herb Epimedium, plays an anti-tumor role in liver cancer by inhibiting the proliferation of hepatocellular cells and promoting their apoptosis. In China, phase II and a large phase III clinical trial of icaritin reagent for the treatm...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-03-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-021-08043-9 |
| _version_ | 1818615634218450944 |
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| author | Hui Li Yujuan Liu Wei Jiang Junhui Xue Yuning Cheng Jiyin Wang Ruixiang Yang Xiaowei Zhang |
| author_facet | Hui Li Yujuan Liu Wei Jiang Junhui Xue Yuning Cheng Jiyin Wang Ruixiang Yang Xiaowei Zhang |
| author_sort | Hui Li |
| collection | DOAJ |
| description | Abstract Background Icaritin, an active ingredient of the Chinese herb Epimedium, plays an anti-tumor role in liver cancer by inhibiting the proliferation of hepatocellular cells and promoting their apoptosis. In China, phase II and a large phase III clinical trial of icaritin reagent for the treatment of hepatocellular cancer is under-going, but the specific mechanism of icaritin action was unclear. Alpha-fetoprotein (AFP), an oncofetal protein, produced in the healthy fetal liver and yolk sac. Intracellular AFP promoted cellular proliferation and inhibited cellular apoptosis in hepatocellular carcinoma (HCC). The study was aimed to investigate the effect of icaritin on HCC through p53/AFP pathway. Methods Real-time RT PCR and western blot were used to detect p53 and AFP expression levels in HCC cells treated with icaritin. The mechanism of icaritin affecting p53 expression was verified by ubiquitination experiment, and the binding activity of icaritin on p53 in AFP promoter region was verified by luciferase experiment. EdU, MTT and flow cytometry were used to determine whether icaritin affected HCC cellular proliferation and apoptosis through p53/ AFP pathway. Expression levels of p53 and AFP in xenograft mouse model were determined by western blotting. Results Our results showed icaritin inhibited AFP expression at mRNA and protein level. AFP was also identified as the target gene of the p53 transcription factor. Icaritin abrogated murine double minute (Mdm) 2-mediated p53 ubiquitination degradation to improve the stability of p53. Up-regulated p53 protein levels then transcriptionally inhibited the AFP promoter. Icaritin-mediated decrease of AFP through Mdm2/p53 pathways inhibited HCC cellular proliferation and promoted HCC cellular apoptosis. Conclusion Our findings revealed the mechanism of icaritin in promoting apoptosis and inhibiting proliferation in liver cancer cells. The regulatory mechanism of icaritin in AFP protein down-regulation provides a theoretical and experimental basis for further research into new drugs for the treatment of liver cancer. |
| first_indexed | 2024-12-16T16:37:01Z |
| format | Article |
| id | doaj.art-0fc2d694ab7445038c58f2b5d628d926 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-16T16:37:01Z |
| publishDate | 2021-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-0fc2d694ab7445038c58f2b5d628d9262022-12-21T22:24:26ZengBMCBMC Cancer1471-24072021-03-0121111210.1186/s12885-021-08043-9Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinomaHui Li0Yujuan Liu1Wei Jiang2Junhui Xue3Yuning Cheng4Jiyin Wang5Ruixiang Yang6Xiaowei Zhang7Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterAbstract Background Icaritin, an active ingredient of the Chinese herb Epimedium, plays an anti-tumor role in liver cancer by inhibiting the proliferation of hepatocellular cells and promoting their apoptosis. In China, phase II and a large phase III clinical trial of icaritin reagent for the treatment of hepatocellular cancer is under-going, but the specific mechanism of icaritin action was unclear. Alpha-fetoprotein (AFP), an oncofetal protein, produced in the healthy fetal liver and yolk sac. Intracellular AFP promoted cellular proliferation and inhibited cellular apoptosis in hepatocellular carcinoma (HCC). The study was aimed to investigate the effect of icaritin on HCC through p53/AFP pathway. Methods Real-time RT PCR and western blot were used to detect p53 and AFP expression levels in HCC cells treated with icaritin. The mechanism of icaritin affecting p53 expression was verified by ubiquitination experiment, and the binding activity of icaritin on p53 in AFP promoter region was verified by luciferase experiment. EdU, MTT and flow cytometry were used to determine whether icaritin affected HCC cellular proliferation and apoptosis through p53/ AFP pathway. Expression levels of p53 and AFP in xenograft mouse model were determined by western blotting. Results Our results showed icaritin inhibited AFP expression at mRNA and protein level. AFP was also identified as the target gene of the p53 transcription factor. Icaritin abrogated murine double minute (Mdm) 2-mediated p53 ubiquitination degradation to improve the stability of p53. Up-regulated p53 protein levels then transcriptionally inhibited the AFP promoter. Icaritin-mediated decrease of AFP through Mdm2/p53 pathways inhibited HCC cellular proliferation and promoted HCC cellular apoptosis. Conclusion Our findings revealed the mechanism of icaritin in promoting apoptosis and inhibiting proliferation in liver cancer cells. The regulatory mechanism of icaritin in AFP protein down-regulation provides a theoretical and experimental basis for further research into new drugs for the treatment of liver cancer.https://doi.org/10.1186/s12885-021-08043-9IcaritinAFPHepatocellular carcinomaHepatocellular proliferationp53 ubiquitination |
| spellingShingle | Hui Li Yujuan Liu Wei Jiang Junhui Xue Yuning Cheng Jiyin Wang Ruixiang Yang Xiaowei Zhang Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma BMC Cancer Icaritin AFP Hepatocellular carcinoma Hepatocellular proliferation p53 ubiquitination |
| title | Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma |
| title_full | Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma |
| title_fullStr | Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma |
| title_full_unstemmed | Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma |
| title_short | Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma |
| title_sort | icaritin promotes apoptosis and inhibits proliferation by down regulating afp gene expression in hepatocellular carcinoma |
| topic | Icaritin AFP Hepatocellular carcinoma Hepatocellular proliferation p53 ubiquitination |
| url | https://doi.org/10.1186/s12885-021-08043-9 |
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