MicroRNAs link inflammation and primary biliary cholangitis
Editorial

MicroRNAs link inflammation and primary biliary cholangitis

Marta Panella1,2, Pietro Carotenuto1, Chiara Braconi1,2,3

1The Institute of Cancer Research, London, UK; 2Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy; 3The Royal Marsden NHS Trust, Surrey and London, UK

Correspondence to: Chiara Braconi, MD, PhD. Division of Cancer Therapeutics, The Institute of Cancer Research, Gastrointestinal Unit, The Royal Marsden Hospital, 7N1 Haddow Bldg, 15 Cotswold Rd, Sutton SM2 5NG, UK. Email: Chiara.Braconi@icr.ac.uk.

Provenance: This is an invited Editorial commissioned by the Section Editor Dr. Meiyi Song (Division of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, Shanghai, China).

Comment on: Erice O, Munoz-Garrido P, Vaquero J, et al. MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation. Hepatology 2018;67:1420-40.


Received: 30 April 2018; Accepted: 11 May 2018; Published: 28 May 2018.

doi: 10.21037/ncri.2018.05.02


Primary biliary cholangitis (PBC) is an autoimmune slowly progressive liver disease characterized by the destruction of intrahepatic bile ducts, which gradually evolves into cirrhosis and liver failure (1). Ursodeoxycholic acid (UDCA) is the first choice for the treatment of PBC patients and has shown to significantly reduce the need for liver transplantation (2). The precise aetiology of PBC is not known, but is considered to be related to a combination of genetic, epigenetic and environmental factors. Selected HLA single nucleotide polymorphisms have been associated to PBC (1); however, they are not sufficient to explain the pathogenesis of the disease. Genome-wide association studies showed the existence of additional risk loci that are linked to inflammatory mediators such as interleukins (IL) and members of the tumour necrosis factor (TNF) family (3-5). Genetic alterations account for no more than 20% of PBC, and growing evidence supports the role of epigenetic modifications in the pathogenesis of PBC. Derangement of non coding RNAs (ncRNA) has been associated to PBC. MicroRNAs (miRNA, miR) are small ncRNAs that act at the post transcriptional level and regulate gene expression (6). MiRNAs are involved in a large variety of physiological processes playing crucial roles in maintaining cell homeostasis and finely regulating cellular phenotypes. miRNA profiling of untreated or refractory human PBC tissues showed deregulation of a number of miRNAs that control expression of transcripts involved in cell proliferation, apoptosis, oxidative stress, inflammation, and metabolism (7). More recently, miRNAs were shown to induce a pro-inflammatory cytokine storm that contributes to the development of liver autoimmune cholangitis in a murine model of PBC (8). miR-506 was previously found to be over-expressed in human liver tissues of PBC patients in comparison to healthy donors (7,9). Furthermore, miR-506 is located on the X chromosome in line with the predominant prevalence of PBC in women (10). Banales et al. have previously shown that miR-506 can directly target the Cl/HCO3 anion exchanger 2 (AE2), which controls the intracellular pH homeostasis by stimulating the hepatobiliary secretion of bicarbonate (9). AE2 also mediates the restoration of the secretin response observed following treatment with UDCA (11,12), confirming a central role for AE2 in the pathogenesis of PBC. Despite the beneficial effects of UCDA, novel treatments are urgently needed as around 40% of PBC patients are refractory to UCDA treatment (13). Thus, a better understanding of the mechanisms involved in the pathogenesis of PBC could provide additional opportunities for therapeutics development. In this work, Erice et al. investigated the mechanisms responsible for miR-506 upregulation and explored the effect of this miRNA in the inflammatory reaction associated to PBC. Using recombinant luciferase reported vectors the authors identified the region of miR-506 promoter that regulates its expression. miRNAs were shown to be regulated by a variety of mechanisms that include genetic alterations (14), promoter methylation (15), and transduction signalling (16). Recent evidence points to a regulation of miR-506 by long non coding RNAs that act as competing endogenous RNAs (17). Here, authors show that miR-506 expression is regulated by a number of proinflammatory cytokines, which are known to be involved in PBC such as IL-12, IL18, and TNF. Overexpression of miR-506 in human cholangiocytes determined changes of the proteomic profile, in particular the downregulation of OPA1 and ATP5H and the up-regulation of CAPN1, involved in mitochondrial metabolic processes. Interestingly, miR-506 was able to induce cellular proliferation, and changes in the cholangiocyte phenotype with loss of epithelial markers and increase of mesenchymal, profibrotic and inflammatory markers. Enforced expression of miR-506 could increase DNA damage and primed cholangiocytes to the toxic effect of bile acids. An increase in mitochondrial metabolism and oxidative stress was also observed after stable expression of miR-506 in cholangiocytes.

Recent evidence suggests that the peripheral blood mononuclear cells (PBMC) of PBC patients hold a deranged profile of miRNAs that can induce an aberrant immune and inflammatory response (18). In this work, Erice et al. showed that PBMC proliferation and function is educated by cholangiocytes with over-expression of miR-506 towards an inflammatory status. These data add significant insights into the pathogenesis of PBC and provide the bases for the exploration of miR-506 as a target of therapy given the inhibition of its expression could not only control the aberrant phenotype of cholangiocytes, but could also reduce the host aberrant immune response that contributes to the poor prognosis of the disease.

Of note, miR-506 was found to be downregulated in a variety of solid tumours (19). However, miR-506 was never described as a driving miRNA in primary liver cancers (20-22). Indeed, hepatic tumours are a rare evolution of PBC and only sporadic cases have been described (23). Interestingly, Erice et al. noticed that neither IL-6 nor TGF-b, which are known to be pro-tumorigenic in cholangiocytes (24), can induce expression of miR-506, and miR-506 can in turn stimulates a cytokine storm that does not include pro-tumorigenic cytokines. It could be speculated that the over-expression of miR-506 in PBC acts as a limiting factor for the malignant transformation of cholangiocytes, even though more data are warranted to support this hypothesis.

In conclusion this study provides useful insights into the mechanisms of regulation and the biological effect of miR-506 in human cholangiocytes. It defines a central role for miR-506 in the pathogenesis and inflammatory response of PBC and paves the way for the development of novel therapies for this disease.


Acknowledgements

None.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.


References

  1. Joshita S, Umemura T, Tanaka E, et al. Genetics and epigenetics in the pathogenesis of primary biliary cholangitis. Clin J Gastroenterol 2018;11:11-8. [Crossref] [PubMed]
  2. Shi J, Wu C, Lin Y, et al. Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials. Am J Gastroenterol 2006;101:1529-38. [Crossref] [PubMed]
  3. Liu X, Invernizzi P, Lu Y, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet 2010;42:658-60. [Crossref] [PubMed]
  4. Mells GF, Floyd JA, Morley KI, et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet 2011;43:329-32. [Crossref] [PubMed]
  5. Cordell HJ, Han Y, Mells GF, et al. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat Commun 2015;6:8019. [Crossref] [PubMed]
  6. Previdi MC, Carotenuto P, Zito D, et al. Noncoding RNAs as novel biomarkers in pancreatic cancer: what do we know? Future Oncol 2017;13:443-53. [Crossref] [PubMed]
  7. Padgett KA, Lan RY, Leung PC, et al. Primary biliary cirrhosis is associated with altered hepatic microRNA expression. J Autoimmun 2009;32:246-53. [Crossref] [PubMed]
  8. Ando Y, Yang GX, Kenny TP, et al. Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse. J Autoimmun 2013;41:111-9. [Crossref] [PubMed]
  9. Banales JM, Sáez E, Uriz M, et al. Up-regulation of microRNA 506 leads to decreased Cl-/HCO3- anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis. Hepatology 2012;56:687-97. [Crossref] [PubMed]
  10. Bentwich I, Avniel A, Karov Y, et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 2005;37:766-70. [Crossref] [PubMed]
  11. Prieto J, García N, Martí-Climent JM, et al. Assessment of biliary bicarbonate secretion in humans by positron emission tomography. Gastroenterology 1999;117:167-72. [Crossref] [PubMed]
  12. Medina JF. Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology 1997;25:12-7. [Crossref] [PubMed]
  13. Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology 2009;136:1281-7. [Crossref] [PubMed]
  14. Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 2004;101:2999-3004. [Crossref] [PubMed]
  15. Lujambio A, Ropero S, Ballestar E, et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res 2007;67:1424-9. [Crossref] [PubMed]
  16. Valeri N, Braconi C, Gasparini P, et al. MicroRNA-135b promotes cancer progression by acting as a downstream effector of oncogenic pathways in colon cancer. Cancer Cell 2014;25:469-83. [Crossref] [PubMed]
  17. Tan HY, Wang C, Liu G, et al. Long noncoding RNA NEAT1-modualted miR-506 regulates gastric cancer development through targeting STAT3. J Cell Biochem 2018. [Epub ahead of print]. [Crossref] [PubMed]
  18. Nakagawa R, Muroyama R, Saeki C, et al. miR-425 regulates inflammatory cytokine production in CD4+ T cells via N-Ras upregulation in primary biliary cholangitis. J Hepatol 2017;66:1223-30. [Crossref] [PubMed]
  19. Li J, Ju J, Ni B, et al. The emerging role of miR-506 in cancer. Oncotarget 2016;7:62778-88. [PubMed]
  20. Meng F, Henson R, Lang M, et al. Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 2006;130:2113-29. [Crossref] [PubMed]
  21. Selaru FM, Olaru AV, Kan T, et al. MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3. Hepatology 2009;49:1595-601. [Crossref] [PubMed]
  22. Braconi C, Patel T. MicroRNA expression profiling: a molecular tool for defining the phenotype of hepatocellular tumors. Hepatology 2008;47:1807-9. [Crossref] [PubMed]
  23. Ide R, Oshita A, Nishisaka T, et al. Primary biliary cholangitis metachronously complicated with combined hepatocellular carcinoma-cholangiocellular carcinoma and hepatocellular carcinoma. World J Hepatol 2017;9:1378-84. [Crossref] [PubMed]
  24. Park J, Tadlock L, Gores GJ, et al. Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology 1999;30:1128-33. [Crossref] [PubMed]
doi: 10.21037/ncri.2018.05.02
Cite this article as: Panella M, Carotenuto P, Braconi C. MicroRNAs link inflammation and primary biliary cholangitis. Non-coding RNA Investig 2018;2:29.