HBP1-mediated transcriptional repression of AFP inhibits hepatoma progression.
HBP1-mediated transcriptional repression of AFP inhibits hepatoma progression.
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HBP1 介导的 AFP 转录抑制可抑制肝癌进展。
DOI：
10.1186/s13046-021-01881-2
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发表时间：
2021-04-01
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Cao Z;Cheng Y;Wang J;Liu Y;Yang R;Jiang W;Li H;Zhang X
肝癌是一种常见的肝脏恶性肿瘤。甲胎蛋白（AFP）的异常高表达与肝癌的发生发展密切相关，但AFP基因在肝癌中的转录调控和特异性激活机制尚不清楚。进一步分析接受手术或TACE治疗的肝癌组织中转录因子HBP 1和AFP的表达及其临床意义，然后监测复发长达10年。采用Western blotting、荧光素酶、Realtime-PCR、ChIP和EMSA等方法分析HBP 1对AFP转录的调控作用。在验证HBP-AFP的轴后，通过MTT、Transwell和FACS检测其对肝癌细胞的影响以及HBP 1 −/−小鼠的成瘤作用。HBP 1和AFP的相对表达与肝癌患者的生存和预后有关。HBP 1通过与AFP基因启动子直接结合抑制AFP基因的表达。B型肝炎病毒（HBV）编码的蛋白HBx通过直接与HBP 1结合而促进肝癌细胞恶性化。淫羊藿苷是中药淫羊藿的有效成分，通过增强HBP 1对AFP的反式阻遏作用，抑制肝癌细胞的恶性。HBP 1对AFP的抑制作用减弱了AFP对PTEN、MMP 9和caspase-3的作用，从而抑制了肝癌细胞的增殖和迁移，并诱导了肝癌细胞的凋亡。HBP 1对AFP的失调促进了小鼠肝癌的进展。本研究阐明了HBP 1抑制AFP表达及其抑制肝癌细胞恶性化的机制，为肝癌的诊断和治疗提供了更全面的理论依据和潜在的解决方案。在线版本包含补充材料，可通过10.1186/s13046-021-01881-2获得。
Hepatoma is a common malignancy of the liver. The abnormal high expression of alpha-fetoprotein (AFP) is intimately associated with hepatoma progress, but the mechanism of transcriptional regulation and singularly activation of AFP gene in hepatoma is not clear. The expression of transcription factor HBP1 and AFP and clinical significance were further analyzed in hepatoma tissues from the patients who received surgery or TACE and then monitored for relapse for up 10 years. HBP1-mediated transcriptional regulation of AFP was analyzed by Western blotting, Luciferase assay, Realtime-PCR, ChIP and EMSA. After verified the axis of HBP-AFP, its impact on hepatoma was measured by MTT, Transwell and FACS in hepatoma cells and by tumorigenesis in HBP1−/− mice. The relative expressions of HBP1 and AFP correlated with survival and prognosis in hepatoma patients. HBP1 repressed the expression of AFP gene by directly binding to the AFP gene promoter. Hepatitis B Virus (HBV)-encoded protein HBx promoted malignancy in hepatoma cells through binding to HBP1 directly. Icaritin, an active ingredient of Chinese herb epimedium, inhibited malignancy in hepatoma cells through enhancing HBP1 transrepression of AFP. The repression of AFP by HBP1 attenuated AFP effect on PTEN, MMP9 and caspase-3, thus inhibited proliferation and migration, and induced apoptosis in hepatoma cells. The deregulation of AFP by HBP1 contributed to hepatoma progression in mice. Our data clarify the mechanism of HBP1 in inhibiting the expression of AFP and its suppression in malignancy of hepatoma cells, providing a more comprehensive theoretical basis and potential solutions for the diagnosis and treatment of hepatoma. The online version contains supplementary material available at 10.1186/s13046-021-01881-2.
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