Enhanced expression of miR-21 and miR-150 is a feature of anti-mitochondrial antibody-negative primary biliary cholangitis

Abstract

Background & Aims: Anti-mitochondrial-autoantibodies (AMA) remain a hallmark of Primary Biliary Cholangitis (PBC) however approximately 10% of patients test negative for these antibodies. They do not differ in terms of biochemistry or clinical presentation from AMA positive ones. Epigenetics play a key role in immune signalling. Two microRNAs (miRs), namely, miR-21 and miR-150 are known to be involved in liver inflammation and fibrosis. The expression of those two microRNAs and their downstream targets were analyze in the context of AMA-status and the stage of liver fibrosis. Methods: The relative levels of miR-21 and miR-150 and their target genes: cMyb, RAS-guanyl-releasing protein-1(RASGRP1), and DNA-methyltransferase-1(DNMT1) were determined by Real-Time PCR in serum, liver tissue and peripheral blood mononuclear cells (PBMCs) of patients with PBC. Results: Serum expressions of miR-21 and miR-150 were significantly enhanced in AMA-negative patients, and they inversely correlated with disease-specific AMA titers in PBS patients. In PBMCs, an increased expression of miR-21 correlated with decreased levels of RASGRP1 and DNMT1 mRNAs whereas, the level of miR-150 remained comparable to controls; and cMyb mRNA was downregulated. In cirrhotic livers, the level of miR-21 was unchanged while miR-150 expression was increased. Conclusion: This study convincingly report, that AMA-negative PBC is characterized by notable alternations of miR-21 and miR-150 and their downstream targets compared to AMA-positive patients underlining their possible importance in the induction of the disease and its progression to fibrosis.

Suppression of Hepatic PPARα in Primary Biliary Cholangitis Is Modulated by miR-155

“…miR-21 was previously implicated in the development of fibrosis; however, in this study, a small increase was observed in the early stages of PBC (F0-F2), followed by a substantial increase in cirrhotic PBC. There was no correlation between the levels of miR-21 and the stages of fibrosis, which is in agreement with previous reports [ 49 , 50 ]. Even though miR-21 ablation has been shown to protect from fibrosis and acute oxidative stress in the livers of mice with bile duct ligation, it was an acute model of cholestasis, which did not completely mimic the sustained cholestasis that occurs in PBC [ 51 ].…”

A Focused Review of Ras Guanine Nucleotide-Releasing Protein 1 in Immune Cells and Cancer

“…For the regulation of RasGRP1, it is known that signal termination can be mediated by DGKα and DGKζ via the conversion of DAG to PA. For the activation, RasGRP1 can be phosphorylated at T184 by PKCα. Other less-well characterized mechanisms include HSP90- [ 46 ] and miR-21-mediated degradation [ 47 , 48 ].…”

“…Additionally, the degradation of RasGRP1 can be mediated by HSP90 acetylation [ 46 ]. There is emerging evidence that microRNAs also play a role in the RasGRP1 expression; specifically, miR-21 was shown to suppress the expression of RasGRP1 [ 47 , 48 ]. Conversely, the downregulation of miR-21 increased the RasGRP1 expression in vitro [ 49 ].…”

Roles of Non-Coding RNAs in Primary Biliary Cholangitis

“…In the present review, some functional ncRNAs are listed in Table 1, mainly including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) (Katsushima et al, 2014;Nakagawa et al, 2017;Wang et al, 2017;Wasik et al, 2017;Afonso et al, 2018;Wasik et al, 2020). We aimed to elucidate the dysregulated ncRNAs in PBC that contribute to the understanding of the pathogenesis of PBC by reviewing all currently published studies.…”