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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-09-26

AUTHORS

Tomohiro Katsumi, Masashi Ninomiya, Taketo Nishina, Kei Mizuno, Kyoko Tomita, Hiroaki Haga, Kazuo Okumoto, Takafumi Saito, Tooru Shimosegawa, Yoshiyuki Ueno

ABSTRACT

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. More... »

PAGES

1165-1177

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/labinvest.2016.95

DOI

http://dx.doi.org/10.1038/labinvest.2016.95

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1007576467

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27668889


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32 schema:description 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.
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39 NF-κB
40 PBC patients
41 PCR
42 RNA
43 TNF
44 adequate number
45 advanced primary biliary cholangitis
46 bile duct
47 biliary cholangitis
48 capture microdissection
49 cells
50 cholangitis
51 cholestatic liver disease
52 chronic cholestatic liver disease
53 clinical course
54 clinical progression
55 control
56 course
57 cytokines TNF
58 deep sequencing
59 destruction
60 disease
61 duct
62 etiology
63 examination
64 expression
65 expression levels
66 expression patterns
67 failure
68 fibrosis
69 gene transcription
70 group
71 heat mapping
72 hepatic failure
73 hepatocytes
74 histologic examination
75 hypertension
76 hypertension type
77 inflammatory regulation
78 intrahepatic bile ducts
79 laser capture microdissection
80 levels
81 levels of TNF
82 liver disease
83 liver tissue
84 mapping
85 mechanism
86 method
87 miR-139-5p
88 miRNA
89 miRNA expression patterns
90 miRNA profiles
91 miRNAs
92 microRNAs
93 microdissection
94 number
95 pathogenesis
96 pathogenesis of PBC
97 pathway
98 patients
99 patterns
100 portal hypertension
101 present study
102 previous studies
103 primary biliary cholangitis
104 pro-inflammatory cytokines TNF
105 profile
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108 quantitative reverse transcription PCR
109 reads
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112 samples
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117 short RNAs
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119 specific expression patterns
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123 supernatant
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125 suppression
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