Dynamic changes in the expression of MicroRNA-31 during inflammatory bowel disease-associated neoplastic transformation.
BACKGROUND
Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer. Aberrant microRNA (miR) expression has been linked to carcinogenesis; however, no reports document a relationship between IBD-related neoplasia (IBDN) and altered miR expression. In the current study we sought to identify specific miR dysregulation along the normal-inflammation-cancer axis.


METHODS
miR microarrays and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) were used to detect dysregulated miRs. Receiver operating characteristic curve analysis was employed to test for potential usefulness of miR-31 as a disease marker of IBDNs. In silico prediction analysis, Western blot, and luciferase activity measurement were employed for target identification.


RESULTS
Several dysregulated miRs were identified between chronically inflamed mucosae and dysplasia arising in IBD. MiR-31 expression increases in a stepwise fashion during progression from normal to IBD to IBDN and accurately discriminated IBDNs from normal or chronically inflamed tissues in IBD patients. Finally, we identified factor inhibiting hypoxia inducible factor 1 as a direct target of miR-31.


CONCLUSIONS
Our study reveals specific miR dysregulation as chronic inflammation progresses to dysplasia. MiR-31 expression levels increase with disease progression and accurately discriminates between distinct pathological entities that coexist in IBD patients. The novel effect of miR-31 on regulating factor inhibiting hypoxia inducible factor 1 expression provides a new insight on the pathogenesis of IBDN.
Olaru
Alexandru V
AV
Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland 21231, USA. aolarul@jhmi.edu
Selaru
Florin M
FM
Mori
Yuriko
Y
Vazquez
Christine
C
David
Stefan
S
Paun
Bogdan
B
Cheng
Yulan
Y
Jin
Zhe
Z
Yang
Jian
J
Agarwal
Rachana
R
Abraham
John M
JM
Dassopoulos
Themistocles
T
Harris
Mary
M
Bayless
Theodore M
TM
Kwon
John
J
Harpaz
Noam
N
Livak
Ferenc
F
Meltzer
Stephen J
SJ
D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D014408:Biomarkers, Tumor; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D008156:Luciferases