Chen Juan, Feng Jing, Zhu Yuping, Hu Shaofan, Zhang Yiguo
The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering & Faculty of Medical Sciences, Chongqing University, Chongqing, China.
Department of Pathology, Bishan Hospital of Chongqing Medical University, Chongqing, China.
RNA Biol. 2025 Dec;22(1):1-21. doi: 10.1080/15476286.2025.2548628. Epub 2025 Aug 21.
Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical bottleneck leading to its treatment failure. Amongst them, the microRNAs arising from the lack of the antioxidant transcription factor Nrf2 lead to cancer metastasis. However, much less is known about the regulation of microRNAs by Nrf1, even though it acts as an essential determinon of cell homoeostasis by governing the transcriptional expression of those driver genes contributing to the EMT involved in its metastasis. In this study, distinct EMT phenotypes resulted from specific knockouts of Nrf1 and Nrf2 in HepG2 cells, as accompanied by their differential migratory and invasive capabilities. The -leading EMT results from a significant decrease in the epithelial CDH1 expression, plus another increased expression of the mesenchymal CDH2. Such distinct phenotypes of from cell lines were also attributable to differential regulation of two key microRNAs, i.e. and . Further experiments also unravelled that Nrf1 activates the expression, directly targeting for the inhibition of , leading to CDH1 activation but with CDH2 inhibition insomuch as to prevent the process of EMT. By contrast, Nrf2 inhibits the expression, relieving its inhibitory effect on MMP15 and MMP17 to promote the EMT. Collectively, these results demonstrate that the EMT of HCC is likely prevented by Nrf1 the miR-3187-3p signalling to SNAI1-CDH1/2 axis, but conversely promoted by Nrf2 through the miR-1247-5p-MMP15/17 signalling axis.
各种基因和表观遗传改变的积累被认为会导致肝细胞癌（HCC）的发生和发展，其高转移性被视为导致治疗失败的关键瓶颈。其中，缺乏抗氧化转录因子Nrf2会产生微小RNA，从而导致癌症转移。然而，关于Nrf1对微小RNA的调控作用，我们所知甚少，尽管它通过控制那些参与其转移过程中上皮-间质转化（EMT）的驱动基因的转录表达，而成为细胞稳态的重要决定因素。在本研究中，HepG2细胞中Nrf1和Nrf2的特异性敲除导致了不同的EMT表型，并伴随着它们不同的迁移和侵袭能力。主要的EMT是由于上皮细胞CDH1表达显著降低，以及间充质细胞CDH2表达增加所致。来自细胞系的这种不同表型也归因于两种关键微小RNA（即 和 ）的差异调控。进一步的实验还表明，Nrf1激活 表达，直接靶向抑制 ，导致CDH1激活但抑制CDH2，从而阻止EMT过程。相比之下，Nrf2抑制 表达，减轻其对MMP15和MMP17的抑制作用，以促进EMT。总体而言，这些结果表明，HCC的EMT可能通过Nrf1 miR-3187-3p信号传导至SNAI1-CDH1/2轴来预防，但相反，Nrf2通过miR-1247-5p-MMP15/17信号轴促进EMT。
