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-α, 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, ~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-α 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-α and c-FOS transcription through miR-139-5p in the NF-κB signaling pathway. We conclude that the specific miRNA miR-139-5p might be involved in the pathogenesis of PBC, especially during clinical progression.
Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.
Tomohiro
T
Katsumi
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Masashi
M
Ninomiya
Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.
Taketo
T
Nishina
Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.|CREST, Yamagata University Faculty of Medicine, Yamagata, Japan.
Kei
K
Mizuno
Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.|CREST, Yamagata University Faculty of Medicine, Yamagata, Japan.
Kyoko
K
Tomita
Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.
Hiroaki
H
Haga
Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.
Kazuo
K
Okumoto
Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.
Takafumi
T
Saito
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Tooru
T
Shimosegawa
Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.|CREST, Yamagata University Faculty of Medicine, Yamagata, Japan.
Yoshiyuki
0000-0001-5623-4250
Y
Ueno
D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002460:Cell Line; D002761:Cholangitis / Q000097:blood* / Q000145:classification*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017403:In Situ Hybridization; D008099:Liver / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015415:Biomarkers; C555098:MIRN139 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D014409:Tumor Necrosis Factor-alpha
Lancet. 1996 Nov 23;348(9039):1399-402
8937278
J Autoimmun. 2012 Aug;39(1-2):34-42
22178199
N Engl J Med. 2009 Jun 11;360(24):2544-55
19458352
Hepatol Res. 2014 Oct;44(10):E189-97
23834361
Gastroenterology. 2005 Feb;128(2):297-303
15685541
Proc Natl Acad Sci U S A. 1988 Oct;85(19):7317-21
3174635
Nat Cell Biol. 2002 May;4(5):E131-6
11988758
Cell Res. 2008 Oct;18(10):997-1006
18766170
J Hepatol. 2012 May;56(5):1181-8
22245904
J Clin Gastroenterol. 2010 Mar;44(3):208-13
20087196
Science. 2001 Oct 26;294(5543):858-62
11679671
Science. 2001 Oct 26;294(5543):862-4
11679672
Oncogene. 2001 Apr 30;20(19):2438-52
11402339
Hepatology. 2008 Sep;48(3):871-7
18752324
Methods. 2013 Jan;59(1):101-7
22926236
Nature. 2005 Jun 9;435(7043):834-8
15944708
Clin Rev Allergy Immunol. 2015 Jun;48(2-3):142-53
25771770
J Gastroenterol Hepatol. 2002 Feb;17(2):196-202
11966951
Biochem Biophys Res Commun. 2010 Jan 1;391(1):73-7
19896465
Immunity. 2009 Mar 20;30(3):372-83
19285436
J Autoimmun. 2009 May-Jun;32(3-4):246-53
19345069
Gastroenterology. 2004 Aug;127(2):485-92
15300581
Hepatology. 2009 Jul;50(1):291-308
19554543
Nat Genet. 2010 Aug;42(8):658-60
20639880
Genome Biol. 2010;11(3):R25
20196867
Gastroenterology. 1989 Jun;96(6):1552-9
2785470
Am J Hum Genet. 2012 Oct 5;91(4):721-8
23000144
Hepatology. 2012 Aug;56(2):687-97
22383162
PLoS One. 2013 Jun 12;8(6):e66086
23776611
Gastroenterology. 1986 Feb;90(2):508-9
3510149
Nucleic Acids Res. 2011 Jan;39(Database issue):D52-7
21115458
Clin Chem. 2008 Mar;54(3):482-90
18218722
Cell. 2004 Jan 23;116(2):281-97
14744438
Hepatol Res. 2014 Feb;44(2):141-8
23905712
Gastroenterology. 2006 Mar;130(3):715-20
16530513
Science. 2001 Oct 26;294(5543):853-8
11679670
Hepatology. 2007 Oct;46(4):963-5
17894325
Gastroenterology. 2002 Oct;123(4):1044-51
12360466
Hepatology. 2011 Nov;54(5):1767-76
22045675
Gastroenterology. 1979 Jun;76(6):1326-32
437429
Int Immunol. 2006 May;18(5):671-7
16569682
Nat Genet. 2011 Mar 13;43(4):329-32
21399635
Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10513-8
18663219
Am J Gastroenterol. 1999 Jan;94(1):47-53
9934730
J Immunol. 1987 May 15;138(10):3525-31
3571977
Ter Arkh. 2004;76(2):8-11
15106405
Nucleic Acids Res. 2011 Jan;39(Database issue):D152-7
21037258