LncRNA MEG9 Promotes Inflammation and Liver Fibrosis Through S100A9 in Biliary Atresia

Background

The pathogenesis of biliary atresia (BA) remains elusive. We aimed to investigate the role of long noncoding RNA (lncRNA) MEG9 in BA.

Methods

LncRNA microarray was conducted to identify differentially expressed lncRNAs in three BA and three para-hepatoblastoma liver tissues. RT-qPCR validated the results. Human intrahepatic bile duct epithelial cells (HIBECs) were stably transfected with lncRNA MEG9 knockdown/overexpression to investigate its cellular localization and function. RNA sequencing (RNA-seq), differentially expressed genes (DEGs) analysis and gene set enrichment analysis were applied to MEG9-overexpresed HIBECs. RNA pull-down and mass spectrometry explored the interacting protein of MEG9, while clinical information was reviewed.

Results

436 differentially expressed lncRNAs were identified, with MEG9 highly upregulated in BA. RT-qPCR further confirmed MEG9's overexpression in BA and diagnostic potential (AUC = 0.9691). MEG9 was predominantly located in the nucleus and significantly promoted cell proliferation and migration. RNA-seq revealed inflammation- and extracellular matrix-related pathways enriched in MEG9-overexpressing HIBECs, with upregulated cytokine genes like CXCL6 and IL6. MMP-7 and collagen I were also overexpressed. Furthermore, 38 proteins were identified to specifically interact with MEG9, and S100A9 was highly expressed in cell models. S100A9 was also significantly upregulated in BA liver tissue and correlated with MEG9 expression (r = 0.313, p < 0.05), albumin level (r = −0.349, p < 0.05), and platelet level (r = −0.324, p < 0.05).

Conclusion

MEG9 influences cholangiocyte proliferation, migration, and cytokine production, potentially regulating BA inflammation and fibrosis via S100A9 interaction.