Uncovering Novel Roles of miR-122 in the Pathophysiology of the Liver: Potential Interaction with NRF1 and E2F4 Signaling

SIMPLE SUMMARY: The microRNA miR-122 plays a crucial role in liver function, but its full impact on gene regulation and disease mechanisms remains unclear. To better understand miR-122, two different methods were used: studying its effects on translation through ribosome occupancy analysis and at the protein level. We found that miR-122 could potentially antagonize the activity of disease-related transcription factors and influence the expression of malignancy-associated proteins. Many of these proteins have been validated as novel targets of miR-122 and linked to liver disease biogenesis. In summary, this study sheds new light on the role of miR-122 by proposing a novel molecular mechanism on how disruption of this miRNA may contribute to the development of liver disease. ABSTRACT: MicroRNA miR-122 plays a pivotal role in liver function. Despite numerous studies investigating this miRNA, the global network of genes regulated by miR-122 and its contribution to the underlying pathophysiological mechanisms remain largely unknown. To gain a deeper understanding of miR-122 activity, we employed two complementary approaches. Firstly, through transcriptome analysis of polyribosome-bound RNAs, we discovered that miR-122 exhibits potential antagonistic effects on specific transcription factors known to be dysregulated in liver disease, including nuclear respiratory factor-1 (NRF1) and the E2F transcription factor 4 (E2F4). Secondly, through proteome analysis of hepatoma cells transfected with either miR-122 mimic or antagomir, we discovered changes in several proteins associated with increased malignancy. Interestingly, many of these proteins were reported to be transcriptionally regulated by NRF1 and E2F4, six of which we validated as miR-122 targets. Among these, a negative correlation was observed between miR-122 and glucose-6-phosphate dehydrogenase levels in the livers of patients with hepatitis B virus-associated hepatocellular carcinoma. This study provides novel insights into potential alterations of molecular pathway occurring at the early stages of liver disease, driven by the dysregulation of miR-122 and its associated genes.