Opposing mechanisms by which miRNAs mediate distinct Nrf1 and Nrf2 regulation of epithelial–mesenchymal transition in hepatocellular carcinoma

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 <i>Nrf1α</i>^{<i>–/–</i>}-leading EMT results from a significant decrease in the epithelial CDH1 expression, plus another increased expression of the mesenchymal CDH2. Such distinct phenotypes of <i>Nrf1α</i>^{–<i>/</i>–} from <i>Nrf2</i>^{–<i>/</i>–} cell lines were also attributable to differential regulation of two key microRNAs, i.e. <i>miR-3187-3p</i> and <i>miR-1247-5p</i>. Further experiments also unravelled that Nrf1 activates the <i>miR-3187-3p</i> expression, directly targeting for the inhibition of <i>SNAI1</i>, leading to CDH1 activation but with CDH2 inhibition insomuch as to prevent the process of EMT. By contrast, Nrf2 inhibits the <i>miR-1247-5p</i> 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 <i>via</i> the miR-3187-3p signalling to SNAI1-CDH1/2 axis, but conversely promoted by Nrf2 through the miR-1247-5p-MMP15/17 signalling axis.