Background Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases. The dysregulation of liver sinusoidal endothelial cell (LSEC) phenotype is a critical early event in the fibrotic process. However, the biological function of lncRNAs in LSEC still remains unclear. Methods The expression level of lncRNA Airn was evaluated in both human fibrotic livers and serums, as well as mouse fibrotic livers. Gain- and loss-of-function experiments were performed to detect the effect of Airn on LSEC differentiation and hepatic stellate cell (HSC) activation in liver fibrosis. Furthermore, RIP, RNA pull-down-immunoblotting, and ChIP experiments were performed to explore the underlying mechanisms of Airn. Results We have identified Airn was significantly upregulated in liver tissues and LSEC of carbon tetrachloride (CCl4)-induced liver fibrosis mouse model. Moreover, the expression of AIRN in fibrotic human liver tissues and serums was remarkably increased compared with healthy controls. In vivo studies showed that Airn deficiency aggravated CCl4- and bile duct ligation (BDL)-induced liver fibrosis, while Airn over-expression by AAV8 alleviated CCl4-induced liver fibrosis. Furthermore, we revealed that Airn maintained LSEC differentiation in vivo and in vitro. Additionally, Airn inhibited HSC activation indirectly by regulating LSEC differentiation and promoted hepatocyte (HC) proliferation by increasing paracrine secretion of Wnt2a and HGF from LSEC. Mechanistically, Airn interacted with EZH2 to maintain LSEC differentiation through KLF2-eNOS-sGC pathway, thereby maintaining HSC quiescence and promoting HC proliferation. Conclusions Our work identified that Airn is beneficial to liver fibrosis by maintaining LSEC differentiation and might be a serum biomarker for liver fibrogenesis.
GDP dissociation inhibitor (GDI) regulates the GDP/GTP exchange reaction of most Rab proteins by inhibiting GDP dissociation. This study evaluated the potential prognostic and predictive value of GDI1 in colorectal cancer (CRC). To address the prognostic power of GDI1, we performed individual and pooled survival analyses on six independent CRC microarray gene expression datasets. GDI1-enriched signatures were also analyzed. Kaplan-Meier and Cox proportional analyses were employed for survival analysis. An immunohistochemistry (IHC) analysis was performed to validate the clinical relevance and prognostic significance of the GDI1 protein level in CRC tissue samples. The results revealed that GDI1 mRNA level was significantly linked with the aggressiveness of CRC, which is compatible with gene set enrichment analysis. A meta-analysis and pooled analysis demonstrated that a higher mRNA GDI1 expression was dramatically correlated with a worse survival in a dose-dependent manner in CRC patients. Further IHC analysis validated that the protein expression of GDI1 in both cytoplasm and membrane also significantly impacted the outcome of CRC patients. In CRC patients with stage III, chemotherapy significantly reduced the relative risk of death in low-GDI1 subgroup (hazard ratio (HR) = 0.22; 95% confidence interval (95% CI) 0.09-0.56, p = 0.0003), but not in high-GDI1 subgroup (HR = 0.63; 95% CI 0.35-1.14, p = 0.1137). Therefore, both high mRNA and protein levels of GDI1 were significantly related to poor outcomes in CRC patients. GD11 may serve as a prognostic biomarker for CRC.
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