MiR-139-5p is associated with inflammatory regulation through c-FOS suppression, and contributes to the progression of primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized pathologically by destruction of intrahepatic bile ducts. PBC is largely classified into three subtypes based on clinical course: (i) gradually progressive, (ii) portal hypertension, and (iii) hepatic failure. Previous studies have indicated that serum levels of the pro-inflammatory cytokine TNF-alpha, is elevated in PBC patients with fibrosis. Although the severity of cholangitis might also be related to the PBC subtype, its etiology has been unclear. Several studies have shown that microRNAs (miRNAs) demonstrate specific expression patterns in various diseases. In the present study, we evaluated miRNA expression patterns among the PBC subtypes using comprehensive deep sequencing. We also carried out histologic examination by laser capture microdissection and investigated how the identified miRNAs were involved in PBC clinical progression using the miRNA transfection method. On average, similar to 11 million 32-mer short RNA reads per sample were obtained, and we found that the expression levels of 97 miRNAs differed significantly among the four groups. Heat mapping demonstrated that the miRNA profiles from hepatic failure and portal hypertension type were clustered differently from those of the gradually progressive type and controls. Furthermore, we focused on miR-139-5p, which has an adequate number of total short reads. Quantitative reverse transcription PCR showed that miR-139-5p was significantly downregulated in clinically advanced PBC. Also, examination of liver tissues demonstrated that the expression of lymphocyte-derived miR-139-5p was significantly higher in hepatocytes. In vitro, the level of TNF-alpha was significantly elevated in supernatant of cells with upregulation of miR-139-5p. Furthermore, c-FOS gene transcription was repressed. Thus, we have demonstrated a novel inflammation-regulatory mechanism involving TNF-alpha and c-FOS transcription through miR-139-5p in the NF-kappa B signaling pathway. We conclude that the specific miRNA miR-139-5p might be involved in the pathogenesis of PBC, especially during clinical progression.